Principles and Practice of Brachytherapy: Using Afterloading Systems

Principles and Practice of Brachytherapy using afterloading systems Edited by C.A. Joslin Emeritus Professor of Radiot...

Author: C. A. Joslin | A. Flynn | E. J. Hall

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Principles and Practice of Brachytherapy using afterloading systems Edited by

C.A. Joslin Emeritus Professor of Radiotherapy, Leeds University, Tunbridge Building, Regional Cancer Treatment Centre, Cookridge Hospital, Leeds, UK

A. Flynn Head of Brachytherapy Physics, Department of Medical Physics and Engineering, Cookridge Hospital, Leeds, UK

and

E.J. Hall Professor of Biophysics, Radiology and Radiation Oncology, Director-Center for Radiological Research, Department of Radiation Oncology, Columbia University, New York, USA

A member of the Hodder Headline Group LONDON Co-published in the United States of America by Oxford University Press Inc., New York

First published in Great Britain in 2001 by Arnold, a member of the Hodder Headline Group 338 Euston Road, London NW1 3BH http://www.arnoldpublishers.com Co-published in the United States of America by Oxford University Press Inc., 198 Madison Avenue, New York, NY10016 Oxford is a registered trademark of Oxford University Press © 2001 Arnold All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronically or mechanically, including photocopying, recording or any information storage or retrieval system, without either prior permission in writing from the publisher or a licence permitting restricted copying. In the United Kingdom such licences are issued by the Copyright Licensing Agency: 90 Tottenham Court Road, London W1P OLP. Whilst the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors, editors nor the publisher can accept any legal responsibility or liability for any errors or omissions that may be made. In particular (but without limiting the generality of the preceding disclaimer) every effort has been made to check treatment schedules, instructions or ideas contained in the material herein. However it is still possible that errors have been missed. For these reasons, and because of rapid advances in the medical sciences, the reader is strongly urged to consult the latest references before utilising any of the treatment schedules, instructions or ideas contained in this book. British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress ISBN 0 340 74209 7 1 2 3 4 5 6 7 8 9 10 Publisher: Joanna Koster Development Editor: Sarah de Souza Project Manager: Marian Haimes Production Editor: Lauren McAllister Production Controller: Martin Kerans Typeset in 10/12 Minion by Phoenix Photosetting, Chatham, Kent Printed and bound in Great Britain by the Bath Press

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Contents

Contributors

v

Preface

PART I

viii

THE PHYSICS OF BRACHYTHERAPY

1

1

Sources in brachytherapy

3

2

Source specification and dosimetry

3

Calibration of sources

4

Systems of dosimetry

5

Computers in brachytherapy dosimetry

6

Dose specification and reporting: the ICRU recommendations

7

Afterloading systems

8

Quality assurance in low dose-rate afterloading

9

Quality assurance in high dose-rate afterloading

Edwin Aird J.M.Wilkinson

11

Colin H.Jones

19

Anne Welsh and Karen D'Amico

35

Robert van der Laarse and Robert W. Luthmann Andre Wambersie and Jan J. Battermann

A. Flynn

49 81 103

Eric D. Slessinger Colin H. Jones

112 133

10

Radiation protection in brachytherapy

A.M. Bidmead

147

PART II

THE RADIOBIOLOGY OF BRACHYTHERAPY

11

The radiobiology of low dose-rate and fractionated irradiation

12

Dose-rate effects with human cells

13

Radiobiology of high dose-rate, low dose-rate, and pulsed dose-rate brachytherapy

159 Joel S. Bedford

G. Gordon Steel and John H. Peacock

161 180

David J. Brenner, Roger Dale, Colin Orton, and Jack Fowler

189

14

Predictive assays for radiation oncology

205

15

Principles of the dose-rate effect derived from clinical data

John A. Cook and James B. Mitchell Eric J. Hall and David J. Brenner

PART III CLINICAL PRACTICE

215

223

16

Endobronchial brachytherapy in the treatment of lung cancer

17

Brachytherapy in cancer of the esophagus

18

High dose-rate afterloading brachytherapy for prostate cancer

19

Low dose-rate brachytherapy for breast cancer

20

Brachytherapy in the treatment of head and neck cancer

Burton L Speiser

A.D. Flores

225 243

P.J. Hoskin

Julia R. White and J. Frank Wilson A. Gerbaulet and M. Maher

257 266 284

iv Contents 21

22

High dose-rate interstitial and endocavitary brachytherapy in cancer of the head and neck Peter Levendag, Connie de Pan, Dick Sipkema, Andries Visser, Inger-Karine Kolkman, and Peter Jansen

296

Brachytherapy in the treatment of pancreas and bile duct cancer Srinath Sundararaman, and Margot Heffernan

317

Dattatreyudu Nori, Suhrid Parikh,

23

Brachytherapy for treating endometrial cancer

24

Low dose-rate brachytherapy for treating cervix cancer: changing dose rate

25

High dose-rate brachytherapy for treating cervix cancer

26

Brachytherapy for brain tumors

27

H.A. Ladner, A. Pfleiderer, S. Ladner, and U. Karck R.D. Hunter and S.E. Davidson

C.A Joslin

373

A.M. Nisar Syed and

Ajmel A. Puthawala 28

343 354

Maarten C.C.M. Hulshof and Jan J. Battermann

Interstitial brachytherapy in the treatment of carcinoma of the cervix

333

379

Interstitial brachytherapy in the treatment of carcinoma of the anorectum

Ajmel A. Puthawala and

A.M. Nisar Syed

387

29

High dose-rate brachytherapy in the treatment of skin tumors

C.A. Joslin and A. Flynn

30

Hyperthermia and brachytherapy Peter M. Corry, Elwood P. Armour, David B. Gersten, Michael J. Borrelli, and Alvaro Martinez

400

31

The costs of brachytherapy

410

32

Quality management: clinical aspects

33

Safe practice and prevention of accidents in afterloading brachytherapy

Graham Read C.A. Joslin

423

C.A. Joslin 34

Pulsed low dose-rate brachytherapy in clinical practice Index

393

A. Flynn, S.E. Griffiths, and 433

Patrick S. Swift

443 451

Contributors

Edwin Aird Medical Physics Department, Mount Vernon Hospital, Middlesex, UK

S.E. Davidson The Christie Hospital NHS Trust, Manchester, UK

Elwood P. Armour

Connie de Pan Department of Radiation Oncology, Dr Daniel den Hoed

Department of Radiation Oncology, William Beaumont

Cancer Centre, Rotterdam, The Netherlands

Hospital, Michigan, USA Jan J. Battermann

A.D. Flores 7955 E, Chaparral Unit 125, Scottsdale, Arizona 85250, USA

Department of Radiation Oncology, Academisch Ziekenuis Utrecht, The Netherlands

A. Flynn Medical Physics Department, Cookridge Hospital, Leeds, UK

Joel S. Bedford Department of Radiological Health Sciences, Colorado State University, Colorado, USA

Jack Fowler Department of Human Oncology K4/336, University of Wisconsin Cancer Center, Wisconsin, USA

A.M. Bidmead Physics Department, Royal Marsden NHS Trust Hospital, London, UK

A. Gerbaulet Brachytherapy Department, Institut Gustave-Roussy, Villejuif, France

Michael J. Borrelli Department of Radiation Oncology, William Beaumont Hospital, Michigan, USA

David B. Gersten Department of Radiation Oncology, William Beaumont Hospital, Michigan, USA

David J. Brenner Center for Radiological Research, Columbia University, New York, USA

S.E. Griffiths Department of Radiotherapy, Regional Cancer Treatment Centre, Cookridge Hospital, Leeds, UK

John A. Cook Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Maryland, USA

Eric J. Hall College of Physicians and Surgeons Center for Radiological Research, Columbia University, New York, USA

Peter M. Corry Department of Radiation Oncology, William Beaumont Hospital, Michigan, USA

Margot Heffernan Tumor Registry, New York Hospital Medical Center of Queens, New York, USA

Roger Dale District Department of Medical Physics, Charing Cross Hospital, London, UK

P.J. Hoskin Marie Curie Research Wing, Mount Vernon Hospital, Middlesex, UK

Karen D'Amico Medical Physics Department, Cheltenham General Hospital, Cheltenham, UK

Maarten C.C.M. Hulshof Academisch Medisch Centrum, Amsterdam, The Netherlands

vi Contributors R.D. Hunter

Suhrid Parikh

The Christie Hospital NHS Trust, Manchester, UK

Radiation Oncology, New York Hospital Medical Center -

Peter Jansen

Cornell, New York, USA and New York Hospital Medical Center of Queens, New York, USA

Department of Radiation Oncology, Dr Daniel den Hoed Cancer Centre, Rotterdam, The Netherlands

John H. Peacock

Colin H. Jones

Surrey, UK

Radiotherapy Research Unit, Institute of Cancer Research,

Physics Department, Royal Marsden NHS Trust, London, UK A. Pfleiderer C.A. Joslin Leeds University, Department of Radiotherapy, Regional Cancer Treatment Centre, Cookridge Hospital, Leeds, UK

University Hospital for Women, Freiburg, Germany Ajmel A. Puthawala Department of Radiation Oncology, Long Beach Memorial Medical Center, California, USA

U. Karck University Hospital for Women, Freiburg, Germany

Graham Read Oncology Services, Royal Preston Hospital, Preston, UK

Inger-Karine Kolkman Department of Radiation Oncology, Dr Daniel den Hoed Cancer Centre, Rotterdam, The Netherlands

Dick Sipkema Department of Radiation Oncology, Dr Daniel den Hoed Cancer Centre, Rotterdam, The Netherlands

H.A.Ladner University Hospital for Women, Freiburg, Germany

Eric D. Slessinger Regional Cancer Center, Community Hospital Indianapolis,

S. Ladner

Indiana, USA

University Hospital for Women, Freiburg, Germany Burton L Speiser Peter Levendag

St Joseph's Hospital and Medical Center, Department of

Department of Radiation Oncology, Dr Daniel den Hoed

Radiation Oncology, Arizona, USA

Cancer Centre, Rotterdam, The Netherlands Robert W. Luthmann St Vincent's Medical Center, Department of Radiation Oncology, Florida, USA M. Maher Radiotherapy Department, Mater Private Hospital, Dublin, Ireland Alvaro Martinez Department of Radiation Oncology, William Beaumont Hospital, Michigan, USA

G. Gordon Steel Radiotherapy Research Unit, Institute of Cancer Research, Surrey, UK Srinath Sundararaman Radiation Oncology, New York Hospital Medical Center of Queens, New York, USA Patrick S. Swift Radiation Oncology, Alta Bates Comprehensive Cancer Center, California, USA A.M. Nisar Syed Department of Radiation Oncology, Long Beach Memorial

James B. Mitchell

Medical Center, California, USA

Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Maryland, USA

Robert van der Laarse Nucletron BV, Veenendaal, The Netherlands

Dattatreyudu Nori Radiation Oncology, New York Hospital Medical Center Cornell, New York, USA and New York Hospital Medical Center of Queens, New York, USA

Andries Visser Department of Radiation Oncology, Dr Daniel den Hoed Cancer Centre, Rotterdam, The Netherlands

Colin Orton

Andre Wambersie

Gershenson Radiation Oncology Center, Harper Hospital and Wayne State University, Michigan, USA

Unite de Radiobiologie et de Radioprotection, Faculte de Medecine, Universite Catholiquede Louvain, Bruxelles, Belgium

Contributors vii Anne Welsh Medical Physics Department, Cheltenham General Hospital, Cheltenham, UK

J.M. Wilkinson North Western Medical Physics, Christie Hospital, Manchester, UK

Julia R. White Medical College of Wisconsin, Wisconsin, USA

J. Frank Wilson Medical College of Wisconsin, Wisconsin, USA

Preface

Brachytherapy was for many years in a state of decline, principally because of the radiation hazards to users and those associated with the management of patients. The introduction of afterloading machines in the 1960s provided the means to control the movement and position of individual radioactive sources and greatly reduced the radiation exposure to staff. As a result, brachytherapy underwent a renaissance and provided the necessary stimulus to promote the development of afterloading brachytherapy techniques. These developments have been further supported by the availability of nuclides, particularly cobalt-60, cesium-137, and iridium-192 and, more recently, radioactive seeds of iodine-125 and palladium 105. In parallel with the technological advances in afterloading machines, there have been major developments in imaging techniques and computerized planning. Cancer management generally has undergone major advances since the 1960s and brachytherapy has played an increasingly important role. The optimal management of cancer patients requires expert teams who specialize in certain cancer sites within which brachytherapy may have a specific place. Much of this work is now being provided on an outpatient or day-care basis and prolonged hospital stay is proving to be unnecessary. Clinical training is largely obtained by observation of and training from one's peers and also from supervised hands-on experience. In parallel with the development

of clinical experience, an understanding of the principles of radiobiology and physics is of great importance. It is also prudent that clinical radiation oncologists continue to update their state of knowledge with respect to current practice. The purpose of this book is not only to present to the trainee clinical oncologist the scientific background and principles of brachytherapy afterloading techniques, but also to update those who specialize in brachytherapy. The book is presented in three sections: physics, radiobiology, and clinical treatment. The sections attempt to cover the scientific principles, technical procedures, and clinical applications of'afterloaded' brachytherapy. The editors have aimed at a consistent presentation for the various chapters without attempting to interfere with the different styles of the individual authors. Some chapters will be found to be more extensive than others, which is mainly a reflection of the widespread application of brachytherapy techniques within the subject of those chapters. We hope that readers of this textbook will find the contents helpful in their work. The editors would like to express their appreciation to all authors for their well-prepared manuscripts and for their tolerance during the book's production. C.A. Joslin, A. Flynn, and Eric J. Hall

PART

The physics of brachytherapy

1 2 3 4 5 6 7 8 9 10

Sources in brachytherapy Source specification and dosimetry Calibration of sources Systems of dosimetry Computers in brachytherapy dosimetry Dose specification and reporting: the ICRU recommendations Afterloading systems Quality assurance in low dose-rate afterloading Quality assurance in high dose-rate afterloading Radiation protection in brachytherapy

3 11 19 35 49 81 103 112 133 147

I

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1 Sources in brachytherapy EDWIN AIRD

1.1 1.1.1

INTRODUCTION Radium

Radium was discovered by Marie Curie in 1898. Within 3 years of this discovery the first patients were treated with radium implanted into their tumors. In the UK, St Bartholomew's Hospital received its first radium for clinical use in 1906. Early clinical experience with these sources led to radiation necrosis and it became clear that this was due, in part, to the intense beta-ray dose from the radium. It was not until 1920 that successful filtration of the beta-rays was achieved. Radium was then used extensively throughout the world. Physicists in the major clinical centers developed dosimetry systems for interstitial and intracavity brachytherapy. The Manchester and Paris systems are probably still the most widely used for interstitial therapy. However, in general radium has been replaced by other radionuclides because, although it has a long halflife, it has several disadvantages: • Radium and several of its daughter products, including radon, are alpha emitters. Radon is a noble gas which is soluble in tissue. This gas could escape through a hairline crack - not easily detected by a visual check - in the radium capsule. If an implanted radium source were to be ruptured within the patient's body, radium and its daughter products may become deposited more or less permanently in the bone. • There is also the possibility of damage - by incineration or mechanical means - when the sources are lost or while they are being processed, with the subsequent release of toxic radioactivity to the environment.

• The gamma radiation from a radium source is of higher energy than is necessary for brachytherapy. Radiation protection for these sources requires large thicknesses of lead, which can cause problems when it comes to: transporting sources in heavy containers using very heavy protective screens around the patient the need for a heavy rectal shield in applicators used for gynecological treatment. • The practical maximum activity concentration (the specific activity) of radium salt is low (approximately 50 MBq mm~3 of active volume). Sources of higher activity are therefore bulky and not suitable for afterloading systems. 1.1.2

Radium substitutes

This was the phrase used to describe the first set of new (artificial) radionuclides which were found useful for brachytherapy from about 1950 onwards, though it is only very recently that most radiotherapy centers have stopped using radium. It was found that there were very few radionuclides with the appropriate properties of the ideal brachytherapy source. These properties are as follows: (A full discussion of these points may be found in the British Journal of Radiology Supplement 21 (1987); an abbreviated set is stated here.) • Photon energy should be low to medium (0.03-0.5 MeV) to minimize radiation protection problems (with the proviso that low-energy radionuclides should not be used near bone because of the enhanced dose to bone at these energies). • For permanent stock, a long half-life is desirable such that the radioactive decay within the practical lifetime

4 Sources in brachytherapy

•

• • •

of the source and its container (typically 10 years) is small. For permanent implantation, a fairly short half-life is essential in order to minimize the time over which special precautions, towards relatives of a radioactive patient and members of the public, need to be in place. The nuclide should be available at high specific activity. There should be no gaseous disintegration product. The nuclide should be available in a form which does not powder or otherwise disperse if the source is damaged or incinerated.

The first sources to be used as alternatives to radium were cobalt-60, gold-198, cesium-137 and iridium-192. These are all described briefly below. The most commonly used sources at this time are cesium-137 and iridium-192, both of which are used in after-loading systems. Iridium-192 has the possibility of high specific activity, which allows it to be used as a high dose-rate (HDR) source.

1.1.3

New sources

The newer sources are not known as radium substitutes, mainly because they have very different properties from radium, namely very much higher specific activity (for example the HDR iridium-192 source) and very different energy. The only new source that has been accepted into routine clinical use in certain centers throughout the world is iodine-125. Palladium-103 is also now available as a standard commercial source. The other sources that are still at the research stage of development, to find out whether they can be of use clinically, are samarium-145, americium-241, and ytterbium-169.

1.2

PRODUCTION OF RADIONUCLIDES

The most common method of producing the radionuclides used in brachytherapy, apart from cesium-137 (which is a fission product), is by neutron bombardment in a nuclear reactor. The reaction is that of neutron capture, normally in the stable isotope of the element required (except for iodine-125, see below). Thus, for iridum the reaction is:

For cobalt-60 the reaction is:

This method of production has the disadvantage that the radioactive isotope cannot be separated from the

stable isotope and limits the specific activity possible. However, for iodine-125, the reaction proceeds in two stages, with xenon as the initial target element:

The radioactive xenon decays by beta emission, with a half-life of 8 days, to the required125/53I,which can then be chemically extracted as a pure radioisotope. To estimate the yield of a given radionuclude, it is possible to use the simple form (for short irradiation time and low fluxes) of the yield equation given in The Radiochemical Manual [ 1 ]:

where s is the reaction cross-section; (j is the neutron flux; n0 is number of atoms in target (=N 0 wq/A, where w is target mass, q is the isotopic abundance of the nuclide of interest in the target element, and A is the atomic mass of the target element, N0 = Avogadro's number); t = bombardment time; l = decay constant of the product element. The specific activity, S, of the target nuclide may be approximated to:

For long irradiation times:

and S ® Ssat, the maximum activity possible for a given neutron flux. Example. For indium-191, the neutron capture crosssection is 910 barns. (This is very high, compared with cobalt-60, for example, which has a cross-section of 43 barns.) If the neutron flux is high (typically 1013 rt.cm-2S-1), using the above equations, it is possible to show that the maximum theoretical specific activity for iridium-192 is about 29 TBq g-1, which equates to about 2.5 TBq for an HDR source of 0.086 g. In practice, although the neutron flux is probably higher:

The irradiation times are shorter, so that only a fraction of Ssat is reached. The typical specific activity produced for HDR sources is 4.3 TBq g-1 (for a 370 GBq source). It is interesting to compare the specific activities (in terms of activity per unit length) available for the different radionuclides used now in brachytherapy with those in the older sources. Iridium wire Iridium HDR source

37 MBq mm-1 74 GBq mm-1 actual source length

Brachytherapy sources used in afterloading systems 5

Cesium miniature cylindrical

Cobalt-60 beads

Compared with radium

333 MBq mm -1 actual source length (for manual afterloading source trains) 592 MBq mm-1 actual source length (in a set of active beads) 50 mg in 13.5 mm active length, 20 mm actual length, equates to 92.5 MBq mnT-1 actual length

Table 1.2

Examples of source trains suitable for Manchester

System

Medium vaginal ovoid Medium intrauterine Medium tandem a

3 5 11

1.7 2.1 5.4

127 158 412

The nominal output is expressed in terms of air kerma rate (AKR) at 1 m from the center of the source.

13 BRACHYTHERAPY SOURCES USED IN AFTERLOADING SYSTEMS Except where otherwise stated, reference data concerning sources come from the Amersham Catalogue of Radiation Source for Oncology.

13.1

Image Not Available

Cesium-137 (Table 1.1)

FORMS FOR MANUAL AFTERLOADING Miniature cylindrical sources (Figure 1.1) contain cesium-137 glass beads encapsulated in stainless steel. They are used in source trains in machine and manual afterloading systems for gynecological brachytherapy.

Figure 1.1 Cylindrical cesium-137 sources as used in the Amersham afterloading source train. (Reproduced by kind permission of Nycomed Amersham plc.)

AMERSHAM MANUAL AFTERLOADING SYSTEM In the Amersham Manual Afterloading System (Figure 1.2) a source train consists of a flexible stainless-steel holder containing miniature cylindrical sources separated by spherical steel spacers 1.8 mm in diameter. The

Table 1,1

Properties of cesium-137

Production

Half-life

A fission product Small quantities (less than 1% cesium-134 present [2], which decays with a half-life of about 2 years)

Image Not Available

30.17 years

Decay scheme Beta energies 0.512 MeV 1.173MeV

Emission probability-betas* 94.6% 5.4%

Photon energies 0.662 MeV

Emission probability - photons 90.1%

Barium X-rays 0.032-0.038 MeV

-7%

Beta filtration

0.5 mm of platinum or stainless steel

Half value layer in lead

6.5mm

* Data from The Radiochemical Manual [1].

Figure 1.2 Source train used in the Amersham afterloading system. (Reproduced by kind permission of Nycomed Amersham

Pic.)


sources and spacers are retained in the holder by a steel spring, secured by a screwed-in end plug. They are designed to locate in the Amersham manual afterloading plastic applicators. The standard set of 11 source trains is suitable for the Manchester System of Gynecological tube dosage. Some examples are given in Table 1.2.

CESIUM-137 SOURCES FOR BUCKLER* AFTERLOADING

These are cylindrical sources used in the fixed ovoids of the Buchler Gynaecological System. The sources vary from 10.1 GBq with active dimensions 2 mm x 3.5 mm to fit applicators 6 mm diameter for low dose rates (LDRs), to 148 GBq with active dimensions 4.1 mm x 11.5 mm to fit applicators 8 mm diameter for HDRs.

WALSTAM-TYPE SOURCES [3] CESIUM-137 SOURCES FOR CURIETRON

These are short, cylindrical sources with hemispherical ends. They consist of cesium-137 in a ceramic matrix contained in a welded stainless-steel capsule. They are used in dome or cylindrical gynecological applicators. The sources approximate a point source of activity higher than that used in the Amersham (Manchester) System (Table 1.3).

These are cylindrical sources that are very similar to those of the Amersham Manual Afterloading System, but for use in a remote afterloading system in which the source trains are attached to a cable drive.

1.3,2 Table 1.3

Cobalt-60 (Table 1.4)

Waktnm-tvnr snurrtx;

FORM OF SOURCE

0.37-74 GBq

28.5-570.0 mGy h-1

REMOTE AFTERLOADING CESIUM-137 SOURCES

Although used in various forms in the past, the most common form in recent years is in 'bead' form, with a design very similar to that used for cesium-137 beads in the Selectron unit. However, the activity of cobalt-60 beads is higher and they are used for HDR brachytherapy.

Spherical Sources

Spherical sources are used in the Selectron (Nucletron BV) afterloading system (Figure 1.3). The cesium-137 is incorporated into a glass bead and encapsulated in stainless-steel ball bearings (referred to as 'beads' or 'pellets') which, together with inactive spacer beads, can be pneumatically loaded from the intermediate safe into a patient applicator along a plastic tube (nominal activity 1.48 GBq per bead, air kerma rate 112mGyh-1m2).

Table 1.4

Properties of cobalt-60

Production

By neutron activation of the stable isotope cobalt-59

Half-life

5.27 years

Decay scheme Beta energies 0.318 MeV

Emission probability - beta 99.9%

Photon energies 1.17 MeV 1.33 MeV

Emission probability - photon 99.9% 100.0%*

Beta filtration

Typical source wall thickness

Half value layer in lead 10mm * Data from The Radiochemical Manual [1].

Image Not Available

133

lridium-192 (Table 1.5)

FORMS OF IRIDIUM-192 Wire In Europe, platinum-covered iridium-192 wire is supplied in 500 mm length coils. The wire consists of an active iridio-platinum core, 0.1 mm thick, encased in a sheath of platinum, 0.1 mm thick. Figure 1.3 Spherical cesium-137 source as used in the Selectron afterloading system. (Reproduced by kind permission of Nucletron BV.)

* Buchler GmbH, Braunschweig, Germany.


Table 1.5

Properties of iridium-192

Production

By neutron activation of the stable isotope iridium-191; the process also produces quantities of iridium-194 (from the activation of iridium-193); because this has a half-life of only 17 h, it does not contribute a significant dose by the time the source is used in the patient

Half-life

73.83 days

Decay scheme Beta energies 0.079-0.672 MeV

Emission probability-betas 0.1-48.1%

Photon energies Range 0.2-1.06 MeV

Emission probability-photons

Effective photon energy 0.37 MeV (unencapsulated) 0.4 MeV (encapsulated)

Significant photon energies (>10%) for those greater than 10% 0.296 MeV 28.7% 0.308 MeV 29.8% 0.316 MeV 83.0% 0.468 MeV 47.7% Beta filtration

0.1 mm platinum

Half value layer in lead

4.5mm

Data from The Radiochemical Manual [1].

Iridium-192 wire is not classified as a 'sealed radiation source.' Because it is activated by neutron irradiation, its cladding remains slightly active. This is not significant in its clinical use. For radiation protection purposes, iridium wire is know as a 'closed radiation source.' Available source strength is shown in Table 1.6. Table 1.6

Available source strength of indium wire

1.11-37.00 MBqmnr

126 nGy h-1 mm-1-4.19 mGy h-1 mm-1

Wire is cut to the required lengths and loaded into plastic tubes or hypodermic needles.

Hairpins (Figure 1.4)

Platinum-covered iridium wire is supplied in the form of 'hairpin' or 'single-pin' shapes. The wire has a diameter of 0.6 mm to give it added strength; the beta filtration remains at 0.1 mm platinum. Hairpins are 131 mm overall length, with leg length 60 mm nominally (the legs can be cut to the required length) and with a range of source strength (Table 1.7).

Image Not Available

Figure 1.4 Platinum-covered iridium-192 wire hairpin (a) and slotted hairpin guide needles (b) as supplied by Nycomed Amersham pic. (Reproduced by kind permission of Nycomed Amersham plc.)


Table 1.7

Available source strength of iridium hairpins

13.4

lodine-125(Table1.8[5])

FORMS OF SEED (Figure 1.6a, b) 1.48-11.10 MBq mm-1

168-1257 m G y - 1 mm-1

Single pins are 73 mm overall length with a nominal leg length of 60 mm and with a range of source strength the same as the hairpins. Slotted stainless-steel guides are used for implanting hairpins and single pins. lridium-192 'seeds'

In the USA these are used instead of wire. Two seed styles are commercially available: 1. 0.1 mm diameter core of active wire (30% iridium, 70% platinum) surrounded by 0.2 mm cladding of stainless steel (Best Industries, Springfield, VA). 2. 0.3 mm diameter core (10% iridium, 90% platinum) surrounded by 0.1 mm cladding of platinum (Alpha-Omega, Bellflower, CA). Both seeds are 3 mm active length and are supplied inside strands of nylon of 0.8 mm outside diameter. Normal spacing is 1 cm, but other spacings are available. Maximum overall length is about 18 cm. Air kerma strengths range from 120 to 650 MBq per seed. Miniature iridium-192 sources for high dose rate

There is a variety of types of these sources, ranging from 0.2 to 1.3 mm diameter and 1 to 20 mm active length, with typically up to 370 GBq activity (air kerma rate 42 mGy h-1). Figure 1.5 shows the HDR sources in use throughout the world at the present time. They are always permanently attached to a cable drive. The active wire is encased in stainless steel. There is now a 'new design source' for the Nucletron BV microSelectron-HDR machine [4] with slightly smaller dimensions (4.95 mm length, 0.90 mm diameter) and similar dose distribution, except for some improvement near the source tip and in the shadow of the cable assembly.

Type 6711 seeds (Nycomed Amersham plc, Amersham, UK) are used for permanent implant. Each seed consists of a welded titanium capsule containing iodine-125 adsorbed onto a silver rod (which also acts as X-ray marker). The active length is 3.0mm and diameter 0.5mm. The overall length is 4.5mm and diameter 0.8 mm. Sources are available with air kerma rates at 1 m of 0.13-7.58 [mGyh-1. The seeds are used with special applicators to introduce them into the patient a fixed distance apart. A new type of absorbable suture called Rapid Strand™ (Figure 1.7), from Nycomed Amersham plc, has become available that encases ten seeds at a fixed distance apart (1cm) in tissue until the suture dissolves (5mm or 15 mm is also available in this form). The suture material is braided Vicryl which is stiffened thermally and sterilized by ethylene oxide gas. It eventually dissolves in tissue. These seeds also emit silver characteristic X-rays Table 1.8

Properties of iodine-125

Production

Neutron activation of xenon-124 to xenon-125, which then decays to iodine-125

Half-life

59.4 days

Decay scheme

Iodine-125 decays by electron capture to the first excited state of tellurium-125, which undergoes internal conversion 93% of the time; the other 7% is occupied by the production of a gamma ray photon of 35.5 keV.

The electron capture and internal conversion processes give rise to characteristic X-rays as follows: (X-ray) Photon energy 27.4 keV 31.4keV

Decay photons emitted 15% 25%

Tenth value layer in lead

0.01 mm

Image Not Available

Figure 1.5 MicroSelection iridium-192 HDR sources. (Reproduced by kind permission of Nucletron BV)


Image Not Available

Image Not Available

Figure 1.6 (a) Type 6777 iodine-125 seed, (b) Type 6702 iodine125 seed. (Reproduced by kind permission of Nycomed

Figure 1.7 Rapid Strand. (Courtesy Nycomed Amersham plc.)

Amersham plc.)

of 22.1 and 25.5 keV. The average photon energy is taken to be 27.4 keV. Type 6702 seeds are used for temporary interstitial implants. These consist of a welded titanium capsule containing three resin spheres onto which the iodine125 is adsorbed by an ion exchange. Sources are available with air kerma rates at 1 m of 6.4-51.9 (mGyh-1. The effective energy of the photons from this seed is taken to be 28.5 keV. A further type of iodine-125 seed is available in North America from Best Industries. The Model 2300 contains radioactive iodine adsorbed on a tungsten wire that is encapsulated by two walls of titanium. This source offers the following advantages: Because it contains radioactive iodine on the ends as well as on the surface of the tungsten, it produces a more isostropic dose distribution than the other sources [6]. It is available in a wide range of source strengths and therefore suitable for both temporary and permanent implantation. The tungsten wire acts as a radiographic marker. The double-walled encapsulation reduces the risk of radioactive leakage. There is another new source of iodine-125 seeds on the US market, designated as MED 3631-A/S and manufactured by North America Scientific Incorporated, North Hollywood, California [7], This source has now been reconfigured (MED 3631-A/M) with the intent of providing greater facility for radiographic source identification while achieving reduced isotropy [8].

13.5

Palladium-103 sources (Table 1.9)

FORMS OF SEEDS

The active material is coated onto two graphite pellets 0.9 mm long and 0.6 mm in diameter. Between these is a 1 mm long lead marker for radiography. These seeds are encapsulated in a 0.05 mm thick titanium tube, laser welded, that is 4.5 mm long and 0.8 mm diameter (the same dimension as the iodine-125 seed).

Table 1.9 Properties of palladium-103 sources

,

Production

Palladium-103 is formed when stable palladium-102 absorbs a neutron

Half-life

16.97 days

Decay scheme

By electron capture, mostly to the first and second excited states of ruthenium-103

An excitation is almost totally by internal conversion, leading to the production of characteristic X-rays: Photon energy 20.1 keV 23.0 keV

Photons em itted 65.6% 12.5%

Effective energy

21 keV


0.03mm


13.6

Other proposed sources [9,11]

The properties of other proposed sources are shown in Tables 1.10, 1.11, and 1.12. Table 1.10

Properties of samarium-145

Photon energy range

38.2-61.4 keV

Mean photon energy

41keV

Half-life

340 days

Maximum specific activity

73 GBq mm-3 (compared with 370 GBqmm-1for iodine-125)


0.2mm

Purpose

To improve dose distribution and shelf-life compared with iodine-125; in addition, it is noted that the photon energy emitted allowssensitization of biological cells to radiation damage by the addition of iodinated deoxyuridine; there are no commercially available sources at the present time

Table 1.11

Properties of ameridum-241

Mean photon energy

13.9-125 keV (but dominated by 59.5 keV) GOkeV

Half-life

432 years


0.34 GBq mm-3


0.42 mm

Purpose

Could be used as an alternative to cesium-137 for cancers of the cervix and endometrium

Disadvantages

An a emitter Only low specific activity available

Photon energy range

Table 1.12

Properties of ytterbium-169 [10]

Photon energy range

50-308 keV

Mean photon energy

93keV

Half-life

32.0 days


340 GBq mm-3

Tenth value layer in lead Seed dimensions

1.6mm

Purpose

Similarto iodine-125 Possible benefit-less attenuation in tissue than iodine-125 or palladium-153 and higher specific activity

REFERENCES 1. Longworth, G. (ed.) (1998) The Radiochemical Manual. Harwell, UK, AEA Technology plc. 2. Godden, T.J. (1988) Physical Aspects of Brachytherapy, Medical Physics Handbooks 19. Bristol, Adam Hilger. 3. Walstram, R. (1965) Studies in therapeutic short distance and intracavitary gamma beam techniques. Physical considerations with special reference to radiation protection. Acta Radial., Supplement 236,1-129. 4. Daskalov, G.M., Loffler, E. and Williamson, J.F. (1998) Monte Carlo-aided dosimetry of a new high dose-rate brachytherapy source. Med. Phys., 25, 2200-8. 5. Nath, R., Anderson, L.L, Luxton, G., Weaverk, A., Williamson, J.F. and Meigooni, A.S. (1995) Dosimetry of interstitial brachytherapy sources: recommendations of the AAPM Radiation Therapy Committee Task Group No.43. Med. Phys., 22, 209-34. 6. Nath, R. and Melillo, A. (1993) Dosimetric characteristics of a double wall 1-125 source for interstitial brachytherapy. Med. Phys., 20,1475-83. 7. Wallace, R.E. and Fan, J.J. (1998) Evaluation of a new brachytherapy iodine-125 source by AAPM TG43 formalism. Med. Phys., 25, 2190-6. 8. Wallace, R.E. (1999) Report on the dosimetry of a new design iodine-125 brachytherapy source. Med. Phys., 26, 1925-31. 9. Battista, J.J. and Mason, D.L.D. (1994) New radionuclides for brachytherapy. In Brachytherapy from Radium to Optimization, ed. R.F. Mould, J.J. Battermann, A.A. Martinez and B.L Speiser. Veenendaal, The Netherlands, Nucletron International, 373-84. 10. Mason, D.L.D., Battista, J.J., Barnett, R.B. and Porter, A.T. (1992) Ytterbium-159: calculated physical properties of a new radiation source for brachytherapy. Med. Phys., 19, 695-703. 11. Williamson, J.F. (1995) Recent developments in basic brachytherapy physics. In Radiation Therapy Physics, ed. A.R. Smith. New York, Springer-Verlag, 247-302.

2 Source specification and dosimetry J.M.WILKINSON

2.1 2.1.1

SOURCE SPECIFICATION BY CONTENT Radium and radium mass

Early brachytherapy was practiced with two radionuclides from the uranium/radium series, namely radium-226 and its immediate daughter, radon-222. Both exist in equilibrium with later radionuclides in the series, and indeed their usefulness as brachytherapy sources arises from the gamma emissions that occur in the transitions from lead-214 (referred to at one time as radium B) to bismum-214 (radium C), and from bismuth-214 to polonium-214 (radium C'). Both radium and radon require heavy metal screenage (at least 0.5 mm of platinum or gold) to remove the particulate emissions, leaving practical brachytherapy sources with almost identical gamma spectra. Radium-226 sources were specified in terms of the mass of radium element, in milligrams, that each contained, and, given the very long half-life for the decay of radium, 5.85 x 105 days, it was usually regarded as unnecessary to correct the mass specification during a period of less than about 20 years, that is to say, during the normal working life of the source.

2.1.2

quially as the 'k' factor, and an assumed knowledge of the attenuating properties of the materials used in the source construction. The specific gamma ray constant for radium was defined as the product of the exposure rate, in roentgen per hour, and the square of the distance, in cm2, from a 1 mg point source, encapsulated in a platinum sheath of 0.5 mm thickness. Early workers adopted a value of 8.4 Rh-1cm-2mg-1 for this constant, but subsequently this was revised to what is now the generally accepted value of 8.25 Rh-1cm-2mg-1. To determine the exposure rate at a point near to a line source required an evaluation of the Sievert Integral [1]. This was originally expressed as an angular integration, as illustrated in Figure 2.1, and the integral itself is that given in equation 2.1:

The Sievert Integral

It was anticipated that the degree of radiation damage in tissue would be closely related to the magnitude of the exposure. The exposure rate at a point outside a radium source was determined by using a calculated value of the specific gamma ray constant, sometimes referred to collo-

Figure 2.1 The exposure rate at point P is obtained by the angular integration of the Sievert Integral from f1 to f2.

12 Source specification and dosimetry

where dX/dt is the exposure rate at the point P, M is the radium mass, k0 is the specific gamma ray constant corrected back to zero filtration, m, is an appropriate filtration coefficient, and the other symbols are as indicated in Figure 2.1. There is no analytic solution to the integral, but tabulated values have been published (see, for example, reference 2). This approach is not too unreasonable at relatively high gamma energies, but in fact represents a considerable simplification of the true physical problem, which becomes apparent when doses in the vicinity of a source are calculated by Monte Carlo techniques [3]. The classical Sievert Integral assumes that increased scattering at short distances will compensate for attenuation in the irradiated medium to within the precision tolerances required for practical brachytherapy work. Furthermore, there is no allowance for internal absorption in the source material itself and there is no obvious way to determine an appropriate value for the filtration coefficient for the sheathing material. Early workers used a single value of 0.2 mm-1 for filtration of radium gammas in platinum [4], but Whyte [5] suggested that a better approximation could be achieved by using decreasing values with increasing thicknesses to counter the hardening of the energy spectrum.

2*13

The milligram-hour concept

Systems of brachytherapy dosimetry for radium applications were devised which dictated the relative distribution of active material for different treatment geometries. Of these, the best known were the Manchester System [4, 6-9] and the Quimby System [10-12]. Such 'systems' recognized that, for a predetermined geometry and predetermined relative distribution of active material, the exposure rate at any point was proportional to the total amount of radium used, and that, for a complete treatment, the total exposure was proportional to the product of the amount (specified as radium mass in milligrams) and the duration (specified as time in hours). Hence the milligram-hour (which was the name given to both the quantity and its unit) became a key parameter in early brachytherapy dosimetry. It was assumed that this product would have to remain constant, for any particular source geometry, in order to achieve consistency in the observed clinical result. It is interesting to note that this assumption was, in effect, challenged at a very early stage by the use of time factor corrections [13, 14], but the application of such corrections, now generally called dose rate corrections, remains the subject of much debate. Brachytherapy systems are discussed in more detail in Chapter 4. They are introduced here to demonstrate how the radium mass specification was a fundamental component of these early clinical dosimetry procedures.

2.1.4

Radon and radium mass equivalent

A radon source was specified, at any particular instant in time, by its radium mass equivalent, defined as that mass of radium, encapsulated by a 0.5 mm thickness of platinum, which would give the same exposure rate at 1 cm from the axis of the source. Radon-222 has a half-life of 3.83 days and so both the radium mass equivalent and the exposure rate at any defined reference point decrease during an application. Radon seeds were used both for superficial mould treatments and for permanent implantation. The total exposure for an application was calculated by multiplying the initial exposure rate by an 'effective' treatment time, determined by integrating the area under the exponential decay curve. The generalized expression for 'effective' treatment time, teff, is that in equation 2.2, where l, is the decay constant and t is the duration of the application:

For a permanent implant of radon seeds, this reduced to teff = half-life/loge2, or 132.5 h. The use of radium and radon has now generally been discontinued due to radiation safety considerations. Radionuclides that have subsequently been substituted for radium and radon, for example cesium-137 or gold198, have also been specified in terms of the radium mass equivalent as this facilitates their use with the established radium systems that use the milligram-hour concept. However, such nuclides have different gamma emission spectra and may be encapsulated in different materials. Hence the dose distribution around a substitute source may be different from that around a radium or radon source of similar physical dimensions. In practice, the radium mass equivalent was frequently determined by comparing the source in question with a similar-sized radium source, of known mass content, in a well-type ionization chamber. This appears to have been satisfactory and there is no evidence to suggest that clinical results have been adversely affected by such practice. 2.1.5

Specification by activity content

An alternative quantity for specification by content is the activity of the radionuclide that is encapsulated in the source. The activity, A, of an amount of radioactive nuclide, in a particular energy state and at a given time, is defined by equation:

where dN is the expectation value of the number of spontaneous nuclear transitions from that energy state in the time interval dt [15]. The early unit of activity, the curie (Ci), was originally defined as the activity of 1 g of radium, or approximately

Specification by emission 13

3.7 x 1010 transitions per second. A subsequent redefinition of the curie made it exactly this figure. The curie is now obsolete as the unit of activity and has been replaced by the SI unit the becquerel (Bq). One becquerel is one transition per second. In order to calculate exposure rate at a point external to a source specified by its activity content, it was again necessary to assume a knowledge of the attenuating properties of the source and source encapsulation material, and also, now, to know the value of the exposure rate constant, Gd. This latter quantity replaces the specific gamma ray constant. The two constants are very similar in concept and for many nuclides are assigned the same value. However, the specific gamma ray constant does not allow for possible contributions from internal conversion X-rays, and these may be significant for low energy emitters. The definition of the exposure rate constant, as given in reference 16, is the quotient:

where(dX/dt)Gdis the exposure rate due to photons of energy greater than 5, at a distance / from a point source of a nuclide containing activity A. The exposure rate constant is characteristic of the particular radionuclide. For radium and radon, d is determined for a point source with a filter thickness of 0.5 mm platinum and hence is numerically equal to the specific gamma ray constant. For all other radionuclides, the constant is determined for unfiltered emissions and hence a correction is required to allow for source encapsulation.

2.1.6

Equivalent activity

In practice, it was difficult to determine the activity content of an existing source and so the equivalent activity, A eq , was often used in its place [17]. This was calculated by determining the exposure rate external to the source, and then using the exposure rate constant to obtain the activity of a hypothetical, unfiltered, point source that would give the same result. There is scope here for much confusion and possible error, particularly if those commercial computer systems that offer a brachytherapy dosimetry package fail to specify clearly whether it is the true activity content, or the equivalent activity, that is required when entering source data.

2.2

2.2.1

SPECIFICATION BY EMISSION

Air kerma strength

As an alternative to using a content quantity, such as radium mass, radium mass equivalent, or activity, a brachytherapy source may be specified directly in terms

of an emission property, so avoiding errors due to uncertainties in the exposure rate constant or any other similar parameter. At the same time dosimetry errors that may be made when allowing for the encapsulation material will be reduced. The benefits of this approach are summarized by Jayaraman et al. [18]. Specification in terms of a reference exposure rate was proposed by Wambersie et al. [19], and in the following year this was the subject of a formal recommendation by the National Council on Radiation Protection and Measurements [20]. However, as exposure rate has now been replaced by air kerma rate in many aspects of fundamental radiation dosimetry, specification quantities that are based on air kerma rate are now being recommended instead. The French Committee on Measurements of Ionising Radiations (CFMRI) [21] and the American Association of Physicists in Medicine (AAPM) [22,23] have each independently recommended a quantity that is defined as the product of the air kerma rate at a distance /, measured along the transverse bisector of the source, and the square of the distance /. The distance / must be large enough that both the source and the detector may be treated mathematically as points. The CFMRI called the quantity le debit de kerma normal, and the AAPM use the term air kerma strength. The latter term will be used in this chapter, but an international readership must be wary not to translate strength as force, which is the dictionary translation for some European languages. The AAPM have assigned the symbol U to the unit of air kerma strength, where, for a point source:

2.2.2

Reference air kerma rate

Various other national and international organizations [24-27] have defined an air kerma specification quantity as the air kerma rate at a reference distance of 1 m from the center of the source. The precise wording of the definition differs slightly in the different publications, but the quantity is, in practice, the same, and several of the reports and recommendations assign the name reference air kerma rate. The definition given in the BIR/IPSM recommendations [27] is that the reference air kerma rate is the kerma rate to air, in vacuo, at a reference point which is 1 m from the center of the source, and that for needles, tubes, and other similar rigid sources, the direction from source center to the reference point is that at right-angles to the long axis of the source. It was recognized by the authors of the report that measurements at 1 m, in vacua, and in scatter-free conditions, would not be possible, and that the magnitude of the reference air kerma rate for any given source would have to be derived from measurements made in other conditions, the most likely being ionization measurements made in air, and conceivably at distances of less than 1 m. In deriving the


reference air kerma rate from such measurements, it will be necessary to convert the measured charge released to a statement of energy released by using a calculated value of the average energy required to produce one unit of ionization in air. It will also, in principle, be necessary to correct for attenuation and scattering in air, for the response of any detector that cannot be regarded as a point detector, and for any deviation from the inverse square law when extrapolating from the actual measurement distance to 1 m. Other techniques of measurement, and other methods of deriving the magnitude of the specification quantity from such measurements, although very unlikely, are not excluded by the BIR/IPSM definition. The recommended units for the reference air kerma rate are mGy h-1 for low dose-rate sources, i.e., those used in applications where treatment durations are quoted in hours, progressing to mGy min-1 and mGy s-1 where the treatment durations would be expressed in minutes or seconds respectively. The air kerma strength of a source, expressed in U, and the reference air kerma rate, expressed in (mGy h-1, although dimensionally different, will be numerically the same for all practical brachytherapy purposes. The discussions that follow on the relationship between the older content specifications and reference air kerma rate will therefore be equally applicable to air kerma strength.

2.2.3 Radium mass equivalent and reference air kerma rate All advocates of source specification by emission recommend that the practice of source specification by content should be discontinued. However, there is a practical problem here in that many commercial software packages, and some source suppliers, continue to use content quantities. It is therefore necessary, at least during a transition period, to convert from reference air kerma rate to milligram radium equivalent or to equivalent activity. Using a specific gamma ray constant of 8.25 Rh-1cm2 mg~' for radium with 0.5 mm platinum filtration, the average energy per unit charge released by ionization in air of 33.97 J C-1 [28], and taking the charge released per unit mass of air by one roentgen of exposure to be 2.58X 104 C kg-1 [15], then a point source containing 1 mg radium equivalent will give an air kerma rate of 7.23 mGy h-1 at 1 m.

2.2.4 Equivalent activity and reference air kerma rate To convert between reference air kerma rate and equivalent activity requires knowledge of the appropriate air kerma rate constant. With the demise of the quantities exposure and exposure rate, the air kerma rate constant has replaced the exposure rate constant in modern radi-

ation dosimetry. Unfortunately, the ICRU has assigned the same symbol Gd to both constants. The air kerma rate constant is defined by the quotient:

where (dK/dt)d is the air kerma rate due to photons of energy greater than 8, at a distance / from a point source of the nuclide containing activity A [15]. The weakness of this approach is that different parties may adopt different values for the air kerma rate constant. For iridium-192 several values have been proposed; for example, Godden [29] recommends 0.111 LlGyrr'm'MBq-1, whereas Dutreix et al. [30] suggest 0.1157 mGyh-1m2MBq-1. Clearly, great care is required to avoid significant systematic error.

2*3 DOSE-RATE CALCULATION FROM A REFERENCE AIR KERMA RATE SPECIFICATION

2*3*1 Reference air kerma rate and spherical sources with isotropic emission For small spherical sources with isotropic emission, the most commonly used expression for calculating the dose rate to water in water, dD(r)water/dt, at radial distance, r, is:

where (dfCair/dt)ref is the reference air kerma rate specification for the source, f(r) is a radial function describing the net effect of attenuation and scattering in water, the term in square brackets is the ratio of the mass energy absorption coefficient for water to the mass energy transfer coefficient for air, and (djr)2 gives inverse square scaling from the reference distance dr, (df equals 100 when r is in cm). The value of absorption coefficient to transfer coefficient ratio may be calculated from the data published by Hubbell [31], and for photon energies between 150 keV and 1.5 MeV is in the range 1.107-1.112. Hence a single value of 1.11 may be adopted without incurring serious error for most of the commonly used brachytherapy radionuclides. Strictly speaking, however, this ratio is a function of photon energy and care must be exercised when using this approach with nuclides of low energy emissions and where the energy spectrum will be further significantly degraded by scatter. Inverse square scaling will also break down when very close to a finite-sized source, but this has no practical dosimetric consequences.

2*3*2 Attenuation and scattering in the irradiated medium The net effect of attenuation and scattering in water has been investigated both experimentally and by Monte

The AAPM recommendations 15

Carlo techniques. Meisberger et al. [32] summarize the earlier work and recommend values for coefficients of third-order polynomials for the function f(r). The Meisberger polynomials became the most common correction method, but early Monte Carlo calculations [33] suggested that these polynomials were suspect. However, more recent Monte Carlo work, for example Sakelliou et al. [34], is in much closer agreement. The BIR/IPSM report [27] recommends polynomials based on Sakelliou's work. Klevenhagen [35] demonstrated that the polynomial approximation must break down both at very small and at very large distances, but, as the correction is usually very small when using the common radionuclides at short distances, this may be ignored in practice.

233

Seed sources

Small seeds containing, originally, radon, but more recently gold-198 or iridium-192, should strictly be considered as cylindrical sources. However, where a large number of such seeds are randomly orientated in a permanent implant, a more practical approach is to treat them as point sources but to include an anisotropy correction giving the average emissions over all angles. Anisotropy corrections may not be applicable, however, when the seeds are arranged in more controlled geometries, such as on a plaque for a superficial treatment. 2.3.4

Reference air kerma rate and

cylindrical line sources For a line source the BIR/IPSM recommendations [27] advocate an adaptation of the Sievert Integral evaluated by a summation of the contributions to the total dose rate from N contiguous line source elements, each no more than 1 mm in length. Each line element is subjected to a different inverse square scaling, to a different water absorption and scattering correction, and to oblique filtration corrections for both the source encapsulation material and also for the source material itself. With reference to Figure 2.2, the expression for the dose rate at radial distance r and angle 0 is:

Figure 2.2 Intregral evaluated as the sum of the dose contributions from many small contiguous line source elements.

expression (equation 2.7). The angle convention in the above equation has been changed from the original BIR/IPSM publication so as to be consistent with the AAPM formalism, which will be described later in this chapter. The BIR/IPSM approach represents an improvement over the original Sievert Integral in as far as there is now an allowance for self-absorption in the source material, and in that water attenuation and scattering are included, but there remains the problem of choosing appropriate values for the filtration coefficients. The BIR/IPSM report recommends the use of the linear absorption coefficients, as opposed to the linear attenuation coefficients, for the mean photon energy of the radionuclide concerned. For the higher energy emitters with stainless-steel encapsulation, this will be a good approximation, but will be less good when there is a low energy component and when significant thicknesses of high-density, high atomic number materials are involved. For iridium-192 sources, for example, there will be moderately large errors in local dose calculations at points close to the axis where the oblique filtration thicknesses in the source material itself are relatively large [36]. However, this is of academic interest only and will not significantly affect the calculation of treatment times for clinical applications.

2.4

THE AAPM RECOMMENDATIONS

2.4.1 Low energy emitters and the general AAPM formalism

where ts(qi) is the thickness of the encapsulation material at angle qi, and ta(qi) is the thickness of source material at the same angle measured from the source axis; ms and ma are the corresponding filtration correction coefficients. The ratio of water absorption coefficient to air transfer coefficient has been given the value 1.11, assuming that the source will be one of the higher energy emitters. The other symbols are as for the spherical source

As indicated in the previous section, the BIR/IPSM approach is not satisfactory with low energy emitters, and indeed is starting to be suspect with iridium-192. In North America, most interstitial brachytherapy is done using seeds of either iridium-192 or the very low energy emitter iodine-125. Two other low energy emitters, palladium-103 and ytterbium-169, have also been


metry, at 1 cm from the center of a unit air kerma rate source of that type. Thus:

Figure 2.3 The geometry pertaining to the formalism recommended by the MPM Radiation Therapy Task Group.

investigated for brachytherapy applications (see, for example, Meigooni et al. [37], or Chiu-Tsao and Anderson [38] for palladium, and Perera et al. [39] or MacPherson and Battista [40] for ytterbium). The formalism recommended by the AAPM [23] attempts to solve the problem by incorporating 'a direct use of measured or measurable dose distributions produced by a source in a water equivalent medium.' However, the difficulties associated with measuring low dose rates, in very high dose gradients, and with finite-sized detectors which may or may not be energy dependent, should not be underestimated, and anyone attempting to implement this protocol should only use data that have been validated and approved by the appropriate AAPM task group. In practice, it would appear that much reliance is being placed on Monte Carlo calculations. A critical review of published work on Monte Carlo calculations and dose distribution measurements for those brachytherapy sources commonly used in interstitial treatments in North America has been included with the published AAPM recommendations [23]. The geometry for the AAPM formalism is shown in Figure 2.3. In addition to the source specification quantity, air kerma strength, symbol Sk, the general formalism introduces several other new quantities. These are the dose rate constant, A; the geometry factor, G(r,q); the radial dose function, g(r); and the anisotropy function, -F(r,q). For cylindrically symmetric sources, the expression for calculating the dose rate by this formalism, is:

The symbol dD(r,q)water/dt, for dose rate to water in water at radial distance r and angle q, has been retained so as to maintain consistency with the previous notation in this chapter.

2.4.2

The dose-rate constant, A

The dose-rate constant for a particular source type is the dose rate to water in water, in the radial plane of sym-

It is an absolute quantity which includes consideration of the source geometry, the spatial distribution of the active material within the source, self-absorption of the radiation and scattering within the source material, attenuation and scattering within the encapsulation material, and attenuation and scattering within the water medium. As the quantity is inversely proportional to the air kerma strength, any future systematic change in the air kerma strength specification for a particular source type, such as may arise from a change in calibration technique, must be accompanied by an equal and opposite change in the value of the dose rate constant. The other terms in the formalism are all relative quantities and normalize to unity at r=l cm and 0=71/2.

2.4.3

The geometry factor, G(r,q)

The geometry factor is included in the formalism to enhance the accuracy of interpolation between tabulated discrete values of both the radial dose function and the anisotropy function in regions of very high dose gradient. Its purpose is to remove the effects of the inverse square law on the dose distribution, and its use is perhaps most easily understood when considering the case of a small, spherical source with isotropic emission (i.e., when F(r,q) is unity for all values of r and 9). In such a case, the geometry factor takes the value of 1/r2 for all angles, leaving the radial dose function, g(r), as a very slowly varying function of radial distance describing only the net effect on the dose rate of attenuation and scattering in water. For a line source it takes the value of the Sievert Integral for zero filter thickness, thus:

2.4.4

The radial dose function, g(r)

The radial dose function describes the relative variations in the dose to water in water along the transverse axis of the source (i.e., in the radial plane of symmetry only). It excludes the effect of inverse square fall off, but includes the net effect of absorption and scattering in the medium and, for points close to the line source, any effects of oblique filtration in both the source and the source encapsulation materials. It may be defined mathematically as: g(r) = [dD(r,p/2) water /dfG(r = l,p/2)]/[dD(r =l,p/2)water/dtG(r,p/2)]

(2.12)

References 17

2.4.5

The anisotropy function, F(r,®jq)

The two-dimensional anisotropy function describes the relative variations in dose at points away from the transverse axis of the source. It may be defined mathematically as:

It allows for the effects of oblique filtration in both the source material and the sheathing material, the effects of internal scattering within the source, and the effects of attenuation and scattering in the surrounding water medium.

2.4.6 Anisotropy factor, q an (r) t and anisotropy constant, f)an The complete formalism using the anisotropy function describes the dose distribution around individual line sources. In practical cases where there are a large number of randomly orientated small seed sources, and where the distances involved are generally greater than the source dimensions, it may be more convenient to use a point source approximation. The formalism may then be simplified as follows:

where f an (r) is the so-called anisotropy factor. It gives the averaged dose rate over all angles at radial distance r, relative to the dose rate at the same radial distance, r, on the transverse axis. For the more common seed sources it is possible to replace the anisotropy factor with a distanceindependent anisotropy constant without any significant loss in accuracy. Typical values of the anisotropy constant range between 0.9 and 0.98, depending on the radionuclide concerned and details of the source construction. It should be noted, therefore, that when using this simplified formalism the calculated dose rates will be typically 2-10% less than those on the transverse axis, and this could result in significant error in techniques where the source orientation is controlled.

2.5

SUMMARY

It is unfortunate that two authoritative, but apparently contradictory, formalisms for brachytherapy dosimetry are currently being recommended. It is particularly unfortunate that there are two air kerma specification quantities, which have different names and different unit dimensions, but which, for practical purposes, are interchangeable. A recent European publication [41] uses the American formalism in conjunction with a reference air kerma rate specification, and perhaps this hybrid

approach will become more generally accepted in the future. The BIR/IPSM formalism may be used with confidence for steel-encapsulated cesium-137 sources, and will give very acceptable results for clinical dosimetry when using high dose-rate iridium-192 stepping sources, and for iridium wires and iridium seeds in ribbons. However, the Sievert Integral approach is certainly not satisfactory with the lower energy emitters and a formalism based on measured parameters has its attractions, but the difficulties encountered in making precise and accurate dose rate measurements in the immediate vicinity of low activity sources are considerable. Confidence in Monte Carlo calculations in brachytherapy suffered a setback when early attempts were subjected to criticism and revision, but the more recent code should be better and, when used in conjunction with measurements, offers a reasonable method of determining the parameters for use in the AAPM formalism.

REFERENCES 1. Sievert, R. (1921) Die Intensitatsverteilung der primaren Gammastrahlung in der Nahe medizinischer Radiumpraparate. Acta Radial., 1,89-128. 2. Shalek, R.J. and Stovall, M. (1990) Brachytherapy dosimetry. In The Dosimetry of Ionizing Radiations, Vol. Ill, ed. K.R. Kase, B.E. Bjarngard and F.H. Attix. San Diego, Academic Press. 3. Williamson, J.F., Morin, R.L and Khan, F.M. (1983) Monte Carlo evaluation of Sievert Integral for brachytherapy dosimetry. Phys. Med. Biol., 28,1021-32. 4. Paterson, R. and Parker, H.M. (1938) A dosage system for interstitial radium therapy. Br.J. Radiol., 1,252-340. 5. Whyte, G.N. (1955) Attenuation of radium gamma radiation in cylindrical geometry. Br.J. Radiol., 28,635-6. 6. Paterson, R. and Parker, H.M. (1934) A dosage system for gamma ray therapy. Br.J. Radiol., 7, 592-632. 7. Tod, M.C. and Meredith, W.J. (1938) A dosage system for use in the treatment of cancer of the uterine cervix. Br. J. Radiol.,11,809-24. 8. Tod, M.C. and Meredith, W.J. (1953) Treatment of cancer of the cervix uteri - a revised Manchester method. Br. J. Radiol., 26,252-7. 9. Meredith, W.J. (ed.) (1967) Radium Dosage: the Manchester System, 2nd edn. Edinburgh, Livingstone. 10. Quimby, E.H. (1932) The grouping of radium tubes and packs to produce the desired distribution of radiation. Am.J. Roentgenol. Radium Ther., 27,18-38. 11. Quimby, E.H. (1935) Physical factors in interstitial radium therapy. Am.J. Roentgenol. Radium Ther., 33, 306-16. 12. Quimby, E.H. (1947) Radium dosage in radium therapy. Am.J. Roentgenol. Radium Ther., 57,622-7. 13. Cowell, MAC. (1937) Research into time factors in radiotherapy. 14th Annual Report of the British Empire Cancer Campaign. London, British Empire Cancer Campaign, 97-103.

18 Source specification and dosimetry 14. Paterson, R. (1948) The Treatment of Malignant Disease by Radium and X-rays. London, Edward Arnold. 15. ICRU (1980) ICRU Report 33. Radiation Quantities and Units. Washington, DC, International Commission on Radiation Units and Measurements.

Sciences in Medicine. London, British Institute of Radiology. 28. Moretti, C.J. (1992) Changes in the National Physical Laboratory standard for X-ray exposure and air kerma. Phys. Med. Biol., 37,1181-3.

16. ICRU (1971) ICRU Report 19. Radiation Quantities and

29. Godden, T.J. (1986) Physical Aspects of Brachytherapy.

Units. Washington, DC, International Commission on Radiation Units and Measurements. 17. ICRU (1962) ICRU Report 10c. Radioactivity. Washington, DC, International Commission on Radiation Units and

Bristol, Adam-Hilger. Philadelphia. 30. Dutreix, A., Marinello, G. and Wambersie, A. (1982) Dosimetrieen Curietherapie. Paris, Masson. 31. HubbellJ.H. (1982) Photon mass energy absorption

Measurements. 18. Jayaraman, S., Lanzl, LH. and Agarawal, S.K. (1983) An overview of errors in line source dosimetry for gamma-ray brachytherapy. Med. Phys., 10,871-975. 19. Wambersie, A., Prignot, A. and Gueulette, J. (1973) A propos du remplacement du radium par le caesium-137 en Curietherapie. y. Radiol. d'Electrol. Med. Nud., 54, 261-70. 20. NCRP (1974) Report No. 41. Specification of Gamma Ray Brachytherapy Sources. Washington, DC, National Council on Radiation Protection and Measurements. 21. CFM Rl (1983) Recommendations pour la Determination des Doses Absorbees en Curietherapie. Rapport du Comite Francais'Mesuredes Rayonnements lonisants' No. 1. Paris, Bureau National de Metrologie. 22. AAPM (1987) Specification of Brachytherapy Source Strength. Report 21. Task Group 32 of the American Association of Physicists in Medicine. New York, American Institute of Physics. 23. Nath, R., Anderson, LL, Luxton, G. et al. (1995) Dosimetry of interstitial brachytherapy sources: recommendations of the AAPM Radiation Therapy Committee Task Group No. 43. Med. Phys., 22,209-34. 24. BCRU (1984) Specification of brachytherapy source. Memorandum from the British Committee on Radiation Units and Measurements. Br.J. Radiol., 57,941-2. 25. ICRU (1985) ICRU Report 38. Dose and Volume Specification for Reporting Intracavitary Therapy in Gynecology. Bethesda, Maryland, USA. International Commission on Radiation Units and Measurements. 26. NCORD (1991) Recommendations for Dosimetry and Quality Control of Radioactive Sources used in Brachytherapy. Amsterdam, Netherlands Commission on Radiation Dosimetry. 27. Bl R/l PSM (1993) Recommendations for Brachytherapy Dosimetry. Report of a Joint Working Party of the British Institute of Radiology and the Institute of Physical

coefficients from 1 keV to 20 MeV. Int.J. Appl. Radial Isot., 33,1269-90. 32. Meisberger, LL, Keller, K.J. and Shalek, R.J. (1968) The effective attenuation in water of the gamma rays of gold198, iridium-192, caesium-137, radium-226 and cobalt60. Radiology, 90, 953-7. 33. Webb, S. and Fox, R.A. (1979) The dose in water surrounding point isotropicgamma emitters. Br.J. Radiol., 52,482-4. 34. Sakelliou, L, Sakellariou, K., Sarigiannis, K. et al. (1992) Dose rate distributions around Co-60, Cs-137, Au-198, Ir-192, Am-241,1-125 (models 6702 and 6711) brachytherapy sources and the nuclide Tc-99m. Phys. Med. Biol., 37,1859-72. 35. Klevenhagen, S.C. (1993) Oral presentation at the British Institute of Radiology, London. 36. Williamson, J.F. (1996) The Sievert Integral revisited: evaluation and extension to 1251,169Yb, and 192lr brachytherapy sources. Int.J. Radial Oncol. Biol. Phys., 36,1239-50. 37. Meigooni, A.S., Sabnis, S. and Nath, R. (1990) Dosimetry of 103

Pd brachytherapy sources for permanent implant. Endocuriether. Hypertherm. Oncol., 6,107-17.

38. Chiu-Tsao, S.T. and Anderson, LL (1991) Thermoluminescent dosimetry for 103Pd (model 200) in a solid water phantom. Med. Phys., 18,449-52. 39. Perera, H., Williamson, J.F., Li, Z., Mishra, V. and Meigooni, A.S. (1994) Dosimetric characteristics, air kerma strength calibration and verification of Monte Carlo simulation for a newytterbium-169 brachytherapy source. Int.J. Radial Oncol. Biol. Phys., 28,953-70. 40. MacPherson, M.S. and Battista, J.J. (1995) Dose distribution and dose rate constant for new ytterbium-169 brachytherapy seeds. Med. Phys., 22,89-96. 41. Permattei, A., Azario, L, Rossi, G. etal. (1995) Dosimetry of 169 Yb seed model X1267. Phys. Med. Biol., 40, 1317-30.

3 Calibration of sources COLIN H.JONES

3.1

INTRODUCTION

Although commercial suppliers of brachytherapy sources provide a measure of source strength, it is unwise to rely solely on this value for patient dose calculations. Manufacturers usually specify source strengths within a broad range of activity. Most departments planning to provide brachytherapy should have the ability to verify source strengths independently and to improve the overall precision of the measurement. The radiation characteristics of an encapsulated source are strongly dependent upon the chemical composition of the radionuclide, the inert filler material, their distribution within the source, and the details of the source encapsulation. Also in relation to source calibration, the presence of radioactive impurities may require a storage period after initial production to allow for the decay of short half-life isotopes. Details of the construction of sources are given in Chapter 1. Such information is important, because attenuation in the source capsule may significantly alter the dose distribution around the source and affect the dose calibration in a variety of ways, especially when measurements are made with re-entrant ionization chambers. It is possible for two sources of different construction to have the same source strengths but significantly different radiation distributions close to the sources. The possibility that such differences might influence calibration measurements must be taken into account. Source specification is considered in Chapter 2. In summary, the source strength is specified as the air kerma rate, in air, at a reference distance of 1 m, corrected for attenuation and scatter in air. The unit to use for low dose-rate brachytherapy sources is (mGy tr1 and

mGys-1for high dose-rate (HDR) applications. The specification quantity is called the reference air kerma rate (RAKR), which is the name used by the ICRU [1].

3.2 REFERENCE STANDARDS AND TRACEABILITY The calibration of sources is traceable to national or international standards at various levels [2]. Direct traceability is established when a source or calibrator has been calibrated at a national standards laboratory or an accredited dosimetry calibration laboratory. Secondary traceability is established when the source is calibrated in comparison with a source of the same design and comparable strength which has direct traceability or when the source is calibrated using an instrument with direct traceability. Secondary traceability by statistical inference is a term that is used for multiple sources of the same activity from which a suitable random sample has been calibrated with secondary traceability. Remote traceability occurs if the user relies upon the manufacturer's calibration as the only standard, which may, or may not, be traceable to a national or international standard. Ideally, brachytherapy sources used clinically should have calibrations with direct or secondary traceability to national standards. In the UK, the traceability routes for the calibration of brachytherapy sources supplied by Nycomed Amersham plc have been summarized by Rossiter [3]. The first line of traceability for this supplier's cobalt-60 sources is in terms of the quantity 'activity.' Reference sources were

20 Calibration of sources

compared with a base standard of cobalt-60 whose activity was measured by absolute counting at the National Physical Laboratory (NPL). The air kerma rate of the base standard was calculated from the measured activity and associated energy fluence, making allowances for gamma ray absorption in the capsule, in the material itself, and in air. Radium-226 sources have been treated similarly, the activity being determined by comparison with the British National Radium Standard. Two additional methods have been used to confirm traceability to national standards of source air kerma rates. The first, used for both cobalt-60 and cesium-137, involved ionometric comparisons with a standard radium-226 source, and the second the measurement of the exposure rate of sources in a scatter-free area at NPL by a large volume chamber (200 mm diameter) directly calibrated against the national primary standard [4]. This work was repeated by Rossiter et al. [5] for cobalt-60, cesium-137, and radium-226, and extended to include iridium-192 wire sources. The results, shown in Tables 3.1 and 3.2, indicate good agreement between NPL and Amersham

source output measurements and provide assurance on source air kerma rate figures provided by this major source supplier and which are based on a traceability route to standards of activity. In the USA, the National Institute of Standards and Technology (NIST) maintains air kerma strength standards for sealed sources of iodine-125, iridium-192, and cesium-137. It should be noted, however, that the strength specification of sealed sources is in terms of air kerma strength (Sk), which is defined as the product of air kerma rate in free space, K(d), measured along the transverse bisector of the source, and the square of the measurement distance d:

The distance d must be large enough that both source and detector may be treated as mathematical points. Such standardization measurements are performed in air using air-attenuation corrections if needed. Sk has units of mGy m2 h-1 and these units are denoted by the

Table 3.1 Comparison of air kerma rate values in vacuo at1 m distance. (Rossiter, Williams, and Bass, 1991 [5].j

137 60

Cs(1802MC)

Co(HR117)

18.7.89

78.70

18.7.89

88.71

226Ra (S5)

18.7.89

36.56

192

13.3.90 13.3.90

29.44

lr(A49945) 192 lr(A49946)

29.39

77.79 87.77a

88.1 7b 36.52 29.25 29.22

1.012 1.011 1.006 1.001 1.006 1.006

' Comparison with60Coreference source. b Comparison with 226Ra reference source. NPL= National Physical Laboratory.

Table 3.2 Air kerma rate measurement uncertainties. (Rossiter, Williams and Bass, 1991 [5].)

60

Co, 137Cs, 226Ra Random Non-random

Determination of secondary standard calibration factor Source measurements Determination of secondary standard calibration factor (all energies) Measurement of pressure Measurement of temperature Measurement of distance Air attenuation correction Correction for finite chamber size

±0.4 ±0.4 ±1.2 ±0.1 ±0.2 ±0.1 ±0.2 ±0.2 ±2.5(60Co)

±1.4

Overalla

±1.8(137Cs) ±0.9 (226Ra)

192|

r

Non-random Overalla aQuadrature sum. NPL= National Physical Laboratory.

Uncertainties as above Weighting procedure for secondary standard factor

±1.4 ±0.4 ±1.5

Calibration methods 21

symbol U. A set of equations has been developed for unambiguously converting source strength estimates and renormalizing published dose-rate tables, which assume traditional quantities and units, into forms consistent with air kerma strength [6]. These authors list the factors to convert source strength of a selection of nuclides from apparent millicuries (mCi) to air kerma strength. The factors are independent of source geometry, but depend on the nominal exposure rate constant value selected by the vendor. Conversion factors applicable to mass of radium or true activity depend upon both source geometry and radionuclide identity. It should be noted that because many of these conversion factors depend upon vendor choices of physical constants and exposure rate constants, users should review source strength specification practices employed by the vendor. This is a requirement even when an independent calibration is made, because a comparison of the measured source strength with that provided by the vendor is a useful and necessary quality assurance procedure. Although an institution might accept the manufacturer's calibration, it is the responsibility of the institution to verify that the manufacturer's stated value is correct. If the measured source strength disagrees with the manufacturer's data by more than 5%, the source of disagreement should be investigated and any unresolved disparity should be reported to the manufacturer. In the case of a batch of sources, a 3% tolerance is probably more applicable, because individual sources may differ from the mean by a greater amount. Discrepancies greater than the accuracy limits specified by the manufacturer should always be explored further. For further reading on this subject, the reader is referred to reference 7.

33

CALIBRATION METHODS

There are three principal methods of calibrating brachytherapy sources. The most frequently used method employs a calibrated re-entrant ionization chamber. The second method makes use of an ionization chamber to measure the air kerma rate at a known distance from the source. In the former method, calibration of the reentrant chamber is actually achieved by use of a radiation source, the air kerma strength of which has been previously measured in air. The third method uses a solid phantom into which source(s) and ion chamber can be introduced in a convenient and reproducible way. In addition, experiments have been conducted on novel dosimetry methods [8], but are not suitable for routine calibrations at the present time. Re-entrant chambers are preferred for the calibration of conventional low-strength brachytherapy sources [9,10], and ionization chambers measuring the air kerma rate at a distance are preferred for HDR sources

[11,12]. However, ionization chambers have been used successfully for conventional dose-rate sources [13], and re-entrant chambers can be used for HDR sources [14]. Baltas et al. [15] report on a comparison of different calibration methods for HDR sources, and conclude that satisfactory results can be obtained by both re-entrant chambers and phantom methods.

3.3.1

Re-entrant ionization chambers

These instruments are characterized by a cylindrical well and an ion collection volume, which surrounds the source approximating at 4p measurement geometry. The re-entrant (well-type) ionization chamber should respond linearly throughout its measuring range; its energy response must be known and care must be taken to ensure that when measuring high activities there is no drop in sensitivity. The response of the chamber will be dependent upon the geometric configuration of the source, its filtration, and encapsulation. The use of such an instrument for intercomparison of sources requires great care and it is advisable for potential users to ascertain the characteristics of the chamber before embarking on measurements. The report of AAPM Radiation Therapy Committee Task Group 40 [2] describes the physical characteristics of a suitable calibrator. It is recommended that the reproducibility of the calibrator should be better than 2% and the signal-to-noise ratio greater than 100:1. The response of the chamber is dependent on the orientation of the source and its position in the well [16], so it is essential to devise a source holder that will reproduce the source positioning. It is also recommended that the scale factor and linearity of each scale used on the electrometer be determined and monitored. The collection efficiency should be better than 99% for commercial well chambers using conventional brachytherapy sources. The sensitivity of reentrant ionization chambers depends on the energy of the photons, thus a calibrated source of one radionuclide cannot be used to determine the source strength of another radionuclide. Similarly, because of dose anisotropy about the source, the relative orientation of the source axis is important for any calibrator. The source should be moved through the active volume of the chamber to verify and quantitate the extent of the change in sensitivity with source position. Figure 3.1 illustrates a typical re-entrant chamber and Figure 3.2 shows the variation of sensitivity with source location in the chamber well. The source-length dependence of the chamber should also be investigated: this is best achieved by determining the chamber response for wire sources of different lengths. The source-length dependence may also be a function of the radionuclide. Williamson et al. [16] showed that a calibrated source of one encapsulation may not be reliable for determining the strength of a source of the same radionuclide but different encapsu-


Figure 3.1 Selectron Source Dosimetry System (SDS): PTW-Freiburg re-entrant (well-type) chamber with Perspex holders for LDR/MDR Selectron sources and HDR microSelectron sources.

Figure 3.2 Relative response of SDS (PTW-Freiburg) chamber with iridium-192 source inserted at various depths.

lation. For example, two cesium-137 sources of equal strength and of similar size but encapsulated in platinum and stainless steel, respectively, might cause different chamber responses. In practice, it is usual to use a positioning device to assure reproducible positioning of the source close to the longitudinal chamber axis and where the chamber sensitivity is high but least dependent upon geometrical positioning of the source. AAPM Report 13 [17] describes the use of re-entrant (well-type) ionization chambers for measuring different types of brachytherapy sources. • Long-lived sources (cesium-137, cobalt-60 etc.)

1. For each radionuclide (and encapsulation) to be measured, one source should be identified as the standard source. The source should be marked or otherwise identified so that it can be recognized at a later date. It is appropriate to ensure that the source selected is typical of other sources in the batch. 2. The standard source should be sent to an appropriate calibration laboratory for calibration. 3. The standard may be used to calibrate all other similar sources by sequential placement of the standard source and the sources to be calibrated in the same geometry within the chamber and

Calibration methods 23

comparing readings. By correcting for decay of the source, it is also possible to use the standard source to check for long-term chamber stability and chamber malfunction. • Short-lived sources (iridium-192, gold-198 etc.) 1. Identify a long-lived source as the reference source. This source may be a standard source for another radionuclide. 2. Obtain a standard source of the appropriate short-lived isotope and compare this with the reference source. This intercomparison will be used to establish a baseline comparison of the relative sensitivity of the system to the two sources. 3. Submit the standard source to a suitable calibration laboratory for calibration. 4. There are two methods that can be used to transfer the calibration: (a) The chamber is calibrated with the shortlived standard source, and the reference source is used to check that the chamber is functioning properly. This requires temperature and pressure corrections to be made if unpressurized ambient air chambers are used. (b) A correction factor defined as the ratio of two measurements of chamber response using the standard source is calculated. The correction factor relates the response of the chamber to the short-lived standard source in terms of the response to the reference source. 5. Whichever method is used, the reference source is measured every time the chamber is used to calibrate the short-lived sources. 6. After decay of the standard source, the reference source is used for subsequent calibrations. Ideally, every radioactive source that is to be used in a patient should be calibrated. In practice, this is not always possible. For short half-life sources such as iodine-125 and iridium-192 seeds, traceability by statistical inference may be appropriate, depending upon the number of ribbons or seeds in the designated strength groupings under consideration. Kutcher et al. [2] recommend that if the grouping contains only a few seeds or ribbons, all seeds should be calibrated. For groupings with a large number of loose seeds, it is recommended that a random sample containing at least 10% of the seeds be calibrated. For a large number of seeds in ribbons, a minimum of 10% or two ribbons (whichever is larger) should be calibrated. For sources purchased in a sterile configuration, the report recommends purchasing and calibrating a single (non-sterile) seed for each designated strength grouping. The calibration of iodine-125 seeds is traceable to a calibration at the NIST. The dosimetry is more complex

than other brachytherapy sources as the nuclide decays principally by electron capture emitting characteristic X-rays at energies from 27.2 to 31.8 keV and 35.5 keV gamma rays. The construction of the source affects the mean energy of the emitted radiation and any calibration must be made with a calibrated source of the same design as the sources being investigated. All long half-life sources should be calibrated. The use of re-entrant chambers is illustrated further in the following sections, where specific calibration procedures are described.

3.3.2 In-air' method using ionization chambers The 'in-air' measurement technique is the primary method of determining the strength of a brachytherapy source. Unfortunately, the method has several inherent problems and, consequently, with the exception of the calibration of strong sources (used for HDR afterloading), its use is confined largely to specially equipped laboratories. For a low strength source, the air kerma rate at a large distance from the source will be low and difficult to measure; scattering from surroundings is also a problem, for which allowance must be made. Measurements can be made closer to the source, but as the measurement distance is decreased, the significance of the physical dimensions of both the source and the ion chamber increase. Positioning uncertainty also becomes a problem for shorter distances. In the absence of a calibrated re-entrant chamber, the 'in-air' ion chamber method is a convenient means of checking the relative strengths of individual sources by comparing the signal strength for the unknown source against that for a reference source of known air kerma strength [13]. The method is less dependent upon the effects of differences in encapsulation than for re-entrant chamber measurements. To measure low air kerma rates requires large volume chambers to achieve a signal-to-noise ratio better than 100:1 and a wide range of chamber types have been employed. One of the corrections that has to be applied to the electrometer reading is to allow for the dose gradient across the chamber response, which causes the chamber response to differ from that of a point detector. This effect depends upon the relative position of the chamber with respect to the source and the physical dimensions of the chamber. It has been analyzed by Tolli [18], who provides a means of calculating a factor to correct for the gradient effect. This factor is referred to in more detail when the calibration of HDR sources is described. The ideal jig for reproducible 'in-air' calibrations should provide mechanical rigidity without contributing scatter to the chamber. Mechanical devices are suitable for shorter distances of 100-200 mm, but for measure-


ments made at much longer distances, some form of optical alignment might be more appropriate. It is sometimes possible to make use of radiotherapy machine laser alignment devices for this purpose. Corrections for room-scattered radiation can be made by making measurements at various distances. Room scatter, which can be assumed to be constant over the distances measured, can be determined from examination of the data, assuming that the dose data set after correction for room scatter should comply with the inverse-square-law. The ion chamber and electrometer used for calibration purposes should have a traceable calibration for radiation of the same energy that is being investigated and preferably be relatively insensitive to changes in photon energy over a wide range.

source strengths (such as those used in the HDR Nucletron Selectron). • Single HDR sources (similar to those used in the HDR Nucletron microSelectron, the Gammamed HDR system, the CIS Curietron 192 HDR, and the Varian Varisource HDR remote afterloader). • Pulse dose-rate (PDR) sources.

The following source types are considered:

It is good working practice when calibrating sources used in remote after-loading brachytherapy equipment for a written procedure to be drawn up and followed. Measurements and observations must be fully documented. Whenever possible, the definitive calibration should be derived from two independent sets of measurements made by two physicists experienced in radiotherapy, using different dose instruments. The calibration measurement should be compared with the supplier's certificate of calibration. When necessary, data from the certificate of calibration should be re-calculated using the same units and conversion factors as those employed in the definitive calibration. Any difference between the corrected data and the definitive calibration must be reconciled. Using the clinical data calculated from these measurements, the response of a suitable dosimeter must be calculated for a different treatment time from that used in the calibration. In the case of equipment into which a value of source strength can be programmed, it is recommended that the calculated treatment time should be based on the displayed source strength. The definitive calibration is confirmed if the predicted reading is obtained within the limits of experimental uncertainty. In some situations an allowance will have to be made for any dose that is delivered during transit of the source. In practice, to comply with the above recommendations it is useful to have sufficient instrumentation to facilitate measurements with a calibrated re-entrant ionization chamber and also either an 'in-air' or phantomtype calibration measurement. It is appropriate to note that, despite international agreement that source strength should be specified in terms of the reference air kerma rate, it is recognized that some commercially supplied computer software requires source information in terms of activity. The use of such software requires great care in converting an RAKR specification to an effective content specification. An equivalent activity may be determined from the RAKR by using the following expression:

• Low dose-rate (LDR) sources in the form of wires or ribbons (such as those used in the Nucletron microSelectron). • Low dose-rate preloaded cesium-137 source trains (similar to those used in the CIS Curietron machine). • Multiple low dose-rate cesium-137 sources of similar strengths (such as those used in the LDR/MDR Nucletron Selectron). • Multiple high dose-rate cobalt-60 sources of similar

where Aeq is the equivalent activity, and 10-6 is the mGy to Gy conversion factor. Ft is a constant and equal to 1/3600,1/60 or 1 depending on whether the RAKR is in mGy h-1, mGy min-1 or mGy s-1, respectively; dr is the distance at which the RAKR is defined and is unity; and Gg is an appropriate air kerma rate constant in m2 GyBq-1s-l.

333

Source calibrations in solid phantoms

The third method of calibrating sources employs a solid acrylic phantom, which contains a centrally placed ion chamber with two or more cavities for source catheters positioned radially around the chamber. Source measurements in a solid phantom are more reproducible and straightforward than 'in-air' measurements. In practice, however, for reference air kerma rate measurements, allowance has to be made for phantom attenuation and scatter. Furthermore, at the point of measurement, it is necessary to take into account the replacement of the phantom material by the ionization chamber. These factors, which are characteristic of the measurement set-up, are difficult to determine with precision, so the overall accuracy of the measurement is reduced. Even so, once a solid phantom has been calibrated satisfactorily, the high reproducibility of the technique and its convenience make it very useful for routine quality assurance-type source measurements. Some phantoms are designed to be filled with water: this simplifies attenuation corrections, but the need for scatter and chamber displacement factors still applies.

3.4 CALIBRATION OF SOURCES USED IN REMOTE AFTERLOADING SYSTEMS

Calibration of sources used in remote afterloading systems 25

3.4.1 Low dose-rate sources in the form of wires or ribbons Remote afterloaders that are designed to treat interstitially with wire sources or catheters loaded with radioactive ribbons are equipped with up to 20 or so channels. These may be connected to flexible or rigid implants using iridium-192 wires, or ribbons of cesium-137 microseeds. A re-entrant-type chamber can be used to determine the activity of the individual seeds. In the case of the wire sources, it might be necessary to measure the source strength per unit length along the wire. Special scanning devices have been developed for this purpose; generally, these devices are collimated detectors that can be used to scan the length of the wire, which may be up to 135 mm. Usually, for calibration, a re-entrant ionization chamber is the instrument of choice. This is best achieved by using wire that has been measured at a national standards laboratory. The measurement of this wire provides a baseline value, which can be compared against a source with a longer half-life; this reference source can be used to monitor chamber response over the long time periods in-between the definitive source calibrations. With long wire sources, it is particularly important to use an appropriate source holder in order to maintain the source centrally in the chamber well: offaxis displacement can increase the chamber signal by up to 20%. As part of the calibration procedure, a reference curve should be constructed that shows the dependence of the chamber output upon the length of the source. This may be achieved by using a 10 mm piece of wire to measure the response for different positions of wire inside a thin, straight tube which is positioned precisely along the axis of the well. The characteristics of well-type chambers vary according to commercial design, but a typical response with a 10 mm wire source should be within about 2% over a 100 mm length [19]. Calibration measurements should be made on all sources after wires have been cut to length and sealed in catheters. Steggerda and Mijnheer [20] make reference to the use of a solid phantom in which a 0.6 cm3 Farmer-type ionization chamber is used for dose rate measurements. The Perspex phantom (see section 3.4.3) is 20 cm in diameter and 15 cm high. Three stainless-steel afterloading catheters are positioned in the phantom at a distance of 5.0 cm from the axis of the cylindrical phantom and at 120° angles. Although the phantom was designed originally for measuring Selectron sources, it can also be used for calibrating iridium-192 line sources and cesium-137 microseed trains. 3.4.2 Low dose-rate preloaded cesium-137 source trains A preloaded source train consists of one or more cesium-137 sources in the form of small source capsules

separated by inactive spacers (usually small ball bearings), all of which are contained in a flexible, stainlesssteel spring catheter. Before being used clinically, the location of individual capsules in the source train should be ascertained. One method of achieving this is by autoradiography and by densitometric scanning of the autoradiograph to locate the center of each source. The calibration of individual source capsules is not easily accomplished, especially when sources are very close to each other. It is important for potential users of preloaded source trains to liaise fully with manufacturers before source trains are made up. The manufacturer should be able to guarantee that the strength of each source loaded into the source train does not differ by more than 5% from that stated. It is useful to purchase one or more source capsules for reference purposes, which can be used to study the effect of the steel spring and also to examine the response of the re-entrant calibration chamber when the source is moved along its longitudinal axis. Individual sources encapsulated within a flexible spring can be measured satisfactorily against a reference source either in air using an ion chamber or in a re-entrant chamber. Source trains with multiple sources are more difficult to measure with high precision. The manufacturer is better placed to obtain information about the strength of individual sources prior to fabrication of the source trains. The user can check the relative distribution of activity by film dosimetry, thermoluminescent dosimetry (TLD), and by judicious use of a re-entrant chamber, but overall it is better to obtain as much information as possible about the strength of individual sources prior to loading of the source trains. The location and relative strength of individual sources in a source train can also be recorded by means of a device employing a highly collimated detector.

3.43 Multiple low dose-rate sources of similar strengths To calibrate cesium-137 sources such as those used in the Nucletron LDR/MDR Selectron machine, it is necessary to measure the strength of each source. This is best achieved with a suitably calibrated re-entrant ionization chamber. The sources are cesium-137 glass beads encapsulated in a 2.5 mm diameter stainless-steel pellet; a machine can take up to 48 pellets. The pellets are not readily identifiable and are used effectively in a random manner. Ideally, all pellets would have the same strength, but in practice this is not the case. Figure 3.3 shows two typical sets of source strength measurements. A reentrant chamber is usually calibrated in terms of the source strength (mGy h-1 at 1 m), which produces a current of a n A. When a chamber has not been suitably calibrated, an alternative method of determining source strength must be used.


3. From the ratio of the measured and calculated air kerma rates in water, the mean actual reference air kerma rate of the set of sources can be determined. Meertens [22] gives the following details about the air kerma measurements and calculations.

KERMA RATE MEASUREMENTS IN WATER

The air kerma rate in water, km, was determined from readings obtained with the ionization chamber and an electrometer using the following formula [23]: Figure 3.3 Source-strength frequency distribution for two batches of cesium-137 LDR/MDR Selectron sources.

Where M is the corrected instrument reading: Aukett [21] has described a method in which a Farmer ionization chamber is used for the direct measurement of the air kerma rate in air for small, spherical cesium137 sources at distances of 35-70 mm. A 2 mm Perspex build-up cap was used on the chamber, which was supported centrally, in air, equidistant from three stainlesssteel applicator tubes, each carrying six sources. Geometry correction factors were calculated for each group of sources. The resultant measurement was found to differ from expected values by 4.4%. An alternative method has been described by Meertens [22]. The method is based on the use of a phantom consisting of three parallel Perspex catheters with a wall thickness of 0.11 cm, fixed together in a cylindrical geometry at 120° angles. A Perspex support for a 0.6 cm3 graphite-walled Farmer-type NE 2505/3A ionization chamber was mounted between the three catheters parallel to their axes; the distance between each of the catheters and the chamber centre was 5 cm. The catheters and the ionization chamber were placed in a 36 x 32 x 20 cm (full scatter) water phantom. The technique was designed to position sources in all three catheters simultaneously in such a configuration that the dose gradients through the chamber volume were minimized. By using multiple sources (ten sources in each catheter), the dose rate was high enough to measure satisfactorily and, by eliminating dose gradients, the need to apply a correction factor for the finite size of the chamber is overcome. To obtain a uniform dose rate at the point of measurement, the ten sources in each catheter were distributed in two batches (2 x 5), separated by 50 mm above and below the level of the chamber center. The procedure designed to measure the mean source strength of a set of sources is as follows. 1. The air kerma rate in water at a point about 5.5 cm distance from a number of sources is measured. 2. The air kerma rate in water at the same point for the same set of sources is calculated for a reference air kerma rate of 100 (mGy h-1 at 1 m in free air for each source.

M=

MuncorPtPpPhum

Muncor is the uncorrected instrument reading; Pt> Pp, Phum are the air temperature, pressure, and humidity correction factors respectively; Pion is the ion recombination correction factor; and Ppol is the correction factor for polarity effects. The last three correction factors were assumed to be unity. Nk (Jkg-1) is the air kerma factor. The product of the correction factors pki (0.989) is given by:

where katt (0.990) is a correction for attenuation in the wall and build-up cap of the ionization chamber; km (0.999) is a correction for the difference in composition between the wall plus build-up cap and air; kst (1.000) is a correction for the stem effect for the employed field size; and kce (1.000) is a correction for the effect of the central electrode on the response of the chamber during calibration. The product of the correction factors ppi (0.972) to be applied to the measurement in water for cesium-137 photons is given by:

where pwall (1.002) corrects for the difference in composition between the ionization chamber wall and water; pd (0.970) is the displacement direction factor that corrects for the displacement of the effective center of the ionization chamber and is a function of the photon energy, the source to chamber distance, and the size of the ionization chamber. This value 0.970 for the 0.6 cm3 (0.3 cm radius) Farmer chamber was estimated from preliminary results of experiments with ionization chambers with radii ranging from 0.1 to 0.8 cm, Pce (1.000) corrects for the effect of the central electrode on the response of the chamber during the measurements in the water phantom. The integration time, t, applied for the ionization current measurements was 0.033 h (120 s).


KERMA RATE CALCULATIONS IN WATER

The contribution of one point source with a given reference air kerma rate, Ktefy in mGyh-1 at 1 m free air to the calculated air kerma rate Kc, in cGylr1 in water at a distance, d, in cm from the point source was calculated according to the following formula:

where S(d) is the absorption and scatter correction factor according to Meisberger et al. [24].

and A0 = 1.0091, B0 = -9.015 x 10-3 cnr-1, C0 = -3.459 x 10-4 cm-2, and D0 = -2.817 x 10-5 cm-3. Kc in the calibration point of the water phantom for sources in the three catheters, each with a KKf value of 100 mGyhr1. Meertens [22] also reports on the use of a Perspex calibration phantom smaller than the water phantom but of a similar design. From experiments, it was determined that the cylindrical Perspex phantom 20 cm diameter and 15 cm high gave results 4% lower than those obtained with the water phantom. The measurements in water had a reproducibility of 0.3% (1 SD), with an uncertainty that could not be evaluated by statistical methods of about 1.2%. Perspex phantoms similar to the one described ensure good reproducibility of set-up and, once an appropriate factor relating measurements made in Perspex to those in water has been determined, the smaller solid phantom can be used for routine calibration purposes. The method has also been used by Jones [25] with a different source configuration. Figures 3.4 and 3.5 show the water phantom and the resultant distribution using eight sets of five sources with a 40 mm separation between each set of sources.

straight applicator and measure the air kerma rate with the Farmer-type chamber at a distance of 500 mm. This method has been described and used by Chenery et al [26] and Messina et al. [27]. The chamber used should have a calibration traceable to a national calibration laboratory; it should be used with a build-up cap for cobalt60. For reproducible measurements, some form of fixation device should be used to ensure that the applicator and the ion chamber are parallel and held so that the applicator is not displaced by transfer of the sources. The applicator can be metal or plastic as long as it is rigid. If both types are available, measurements can be made to determine the attenuation effect of the metal applicator. Both applicator and ionization chamber should be at least 1 m from the floor, the walls, or any other large scattering medium. Room scatter will be characteristic of the local environment and an estimate should be made of its magnitude. In most situations it is likely to be between 3% and 4% for the source-chamber geometry described. The principal error is likely to be associated with the position of the sources inside the applicator: they are not constrained to lie perfectly on the axis of the applicator, but tend to zigzag, with displacements of over 0.5 mm occurring 16% of the time [26]. The positional errors, including those associated with the measurement of the applicator-chamber separation, produce an uncertainty in the measured dose rate

3.4.4 Multiple high dose-rate cobalt-60 sources of similar source strengths The cobalt-60 sources used in the Nucletron remote afterloading machine consist of 1.5 x 1.5 mm cylinders encapsulated in titanium spheres 2.5 mm diameter; there are 20 sources in each machine. The relative strength of each source may be determined with a reentrant ionization chamber. If the chamber has not been calibrated for these sources, a Farmer-type 0.6 cm3 ion chamber can be used. A measurement device and source configuration similar to that described in the preceding section might be used, replacing the set of four sources by a single source so that the chamber would be exposed to eight sources simultaneously. An alternative method is to use all 20 sources in a

Figure 3.4 Perspex/water calibration phantom with central cavity for Farmer chamber and four stainless-steel catheters distributed radially at 50 mm.


Figure 3.5 IGE (Target) computer calculation of dose distribution of four straight Selectron catheters each loaded with

2x5

LDR/MDR Selectron pellets with 40 mm separation between each set of pellets (1.4 GBq per pellet). The calibration chamber is positioned centrally in the region of low dose gradient. Units of distribution are cGyh-1; magnification factor (%) = WO.

of less than 1%. It should be noted that chamber leakage should be measured, for which an appropriate correction might be made. This leakage should not be greater that 0.1-0.2%.

3.4.5

Single high dose-rate sources

High dose-rate remote afterloading devices, such as those listed above (section 3.4), make use of an iridium192 source with an activity of up to 370 GBq. The source is typically in the form of a small pellet (0.5 mm diameter, 4 mm active length, with a 0.3 mm stainless-steel wall), connected to a wire that pushes and pulls it through a plastic catheter to guide it to the desired location. The half-life of iridium-192 is 73.83 days so source replacement is relatively frequent. The principal supplier of these sources is Mallinckrodt Diagnostica in the Netherlands, which provides a calibration certificate with each new source that states the overall uncertainty in activity to be ± 5%. An independent recalibration is required after installation of a source before the machine is used to treat patients. There are three methods of calibrating a single HDR source: 'in-air' measurements with a calibrated ion

chamber positioned at a distance of 10-20 cm from the source; measurements with a re-entrant ionization chamber that has a calibration traceable to a national standards laboratory; and measurements with an ion chamber and a solid phantom (or water phantom). IN-AIR'CALIBRATIONS A Joint Working Party of the BIR and IPSM recommended that iridium-192 HDR sources should be calibrated in air with a Farmer-type 0.6 cm3 ion chamber held at a distance of 100 mm from the source [28], and that the traceability route for such measurements should be through the external-beam standard. The recommended method has the advantage of being widely applicable and experience suggests that the method produces very reproducible results. It also has the advantage that the purchase of additional calibration instrumentation is not required. However, although the procedure is straightforward, a number of interrelated factors have to be taken into consideration. These include the effects of ion chamber geometry, source-chamber distance, positioning reproducibility, dose gradient, signal strength, and room scatter. Furthermore, because national calibration laboratories do not offer calibration of ionization


chambers with the gamma ray spectrum of iridium-192, some form of procedure must be employed to determine an appropriate factor for the ion chamber used in the measurement procedure. These matters have been considered comprehensively by Ezzell [29], Goetsch et al. [12], Piermattei [30], Grimbergen and van Dijk [31], and Biiermann et al. [32]. At a source-chamber distance of 100 mm, the correction required to allow for the fluence gradient across the Farmer (0.6 cm3) ion chamber is 0.9% [18]. For shorter distances, the positioning becomes more critical and a larger factor will be required to correct for the finite chamber size (Table 3.3). With a suitable measurement jig, it is possible to restrict dose errors due to positional uncertainties to less than 0.5%. Both source and detector need to be mounted well above floor level and well away from walls or other large structures so as to reduce the effects of room scatter to negligible levels. Several devices have been described in the literature, two of which are shown in Figure 3.6. The ideal jig for reproducible 'inair' calibrations would provide mechanical rigidity without contributing scatter to the chamber. In practice, a small correction will be required to allow for room scatter, including any scatter that might arise from the jig itself. If it is assumed that the air kerma rate at the point of measurement caused by room scatter does not depend on the distance from the source, then:

where d = distance from the source to the point of measurement; d0 = distance from the source to a reference point; X = total exposure at the point of measurement; X0 = primary exposure at the reference distance; and Xs = room scatter exposure (assumed constant for all d). The value for the room scatter correction factor at the distance d is then given by:

Table 3.3 Dose gradient correction factors for NE 2571 Farmer 0.6 cm3 ion chamber as a function of distance from a point source to chamber center.

1.0 2.0 5.0 10.0 15.0 20.0

(T6lli,1997,[18].)

1.342 1.116 1.026 1.009 1.005 1.004

Figure 3.6 Two 'in-air' calibration jigs: (a) Nucletron device, and (b) 'Royal Marsden Hospital device. Both jigs are shown with Farmer chamber without build-up cap.

Since X and d are measurable quantities and d0 is an arbitrarily chosen distance, the values for X0 and Xs may be determined by fitting a line to data relating X to d. Ezzell [29] used this method and obtained data at 200, 300, 400, and 500 mm from the source. The average reading at each point was corrected for leakage and timer error and the reference distance was chosen to be 200 mm. The four data points fell on a straight line with a correlation coefficient of unity. The author concluded that, for the calibration jig used and at a reference distance of 200 mm, room scatter was 0.6% of the measured dose. A similar series of measurements was made by Goetsch et al [12] using an Exradin A3 spherical chamber of 3.6 cm3 with air-equivalent plastic walls (including cap) at nominal distances from 100 mm to


396.4 mm from an iridium-192 source. The room scatter at a source-chamber distance of 200 mm was found to be 0.63%. Table 3.4 summarizes both sets of measurements. For relatively large distances, and in the typical hospital laboratory, room scatter may introduce errors that are not negligible. As an extended time period will be required to collect sufficient charge for acceptable precision, it is important that leakage for the electrometer system is measured and, if necessary, an appropriate correction made. Iridium-192 has a very complex emission spectrum which includes approximately 24 lines occurring in the energy range 9-885 keV. The lowest energy emissions are attenuated by the source capsule and do not influence measurements. The exposure-weighted average of the remaining lines is 397 keV, which falls approximately halfway between the cesium-137 gamma ray energy of 662 keV and the average energy (146 keV) of a 250 kVP medium-filtration X-ray beam (half value thickness = 3.2 mm Cu). For a beam of this radiation quality, the choice of calibration factor and choice of build-up cap are not straightforward. There are three factors to consider. First of all, Goetsch et al. [12] have demonstrated that for in-air measurements at short distances, it is necessary to exclude high-energy photoelectrons emitted from the source capsule. This can be achieved either by placing a build-up cap over the ion chamber or by introducing the source itself into a narrow-bore Perspex tube where a wall thickness of 1 mm will be sufficient to remove the electron contamination. Secondly, Goetsch et al [12] have also suggested that iridium-192 measurements require that the ionization chamber's wall thickness must be sufficient to provide charged particle equilibrium for the highest energy secondary electrons present. These authors conclude, from measurements made with ion chambers that have graphite caps of various thicknesses, that the total thickness of wall and cap should be at least 0.3 g cm-2 to assure charged particle equilibrium: a Farmer-type chamber has a wall of 0.065 g cm-2. The third consideration concerns the instrument calibration factor. There are two components: an intercom-

5.0 10.0 15.0 20.0 30.0 40.0 50.0

1.00 0.999 0.997 0.994 0.988

—

-

0.999 0.997 0.994 0.986 0.975

0.966

-

' For local conditions as described by Ezzell (1989) [29], and Goetsch et a I. (1991) [12].

parison ratio between the field instrument and a secondary standard, and a calibration factor for the secondary standard appropriate to this energy. The former component may be determined using an iridium source at sufficiently large distance to ensure that the correction for finite chamber size will be the same for the two detectors. The second component is more difficult to establish. The reason for this is that there is an absence of primary standards for radiation from iridium-192 sources and the calibration factor of the chamber has to be obtained by other means. In the UK, no factor for calibration against the primary standard is normally available between that for heavily filtered 280 kVP X-rays (for use with measurements made without a build-up cap) and that for 2 MV X-rays (for use with measurements made with a build-up cap). In the USA and in some European laboratories, a factor for calibration against cesium-137 (gamma ray energy of 662 keV) is also available. The subject has been discussed comprehensively by Grimbergen and van Dijk [31] and Goetsch et al. [12]. The method described by Goetsch is a linear interpolation between a medium filtered 250 kV X-ray quality and cesium-13 7, with correction for differences in wall attenuation between X-rays, cesium-137, and iridium192 radiation. The correction factor was derived from wall attenuation measurements with one type of ionization chamber. This method is used extensively in the USA and forms the basis of calibrating iridium-192 sources that are subsequently used in the calibration of re-entrant ionization chambers. Grimbergen and van Dijk describe the air kerma calibration procedure that can be provided by the Netherlands Measurements Institute (NMI), which is based on weighting the chamber response according to the air kerma spectrum of the iridium-192 source [5]. This 'energy response curve' method is probably the most accurate, but is time consuming and expensive to realize. The authors calculated the photon spectrum of iridium-192 source-type used in the microSelectron HDR afterloading equipment using the EGS4 Monte Carlo System. The energy response was calculated for two widely used ion chambers: the NE 2561, which is used in the UK as a secondary standard, and the NE 2571, which is used as a field instrument. The calibration of the chambers was performed against the primary standards in beams of X-rays, cesium-137, and cobalt-60 gamma radiation; during the measurements the chambers were fitted with build-up caps. To determine the chamber response at the energy of each iridium-192 spectrum line, a polynomial was fitted through the chamber calibration data (see Figures 3.7 and 3.8). A comparison was then made for each chamber: a calibration factor was derived using the 'energy response curve' method and also one was derived using the average of the medium filtered 250 kV X-ray and cesium-137 calibration factors. It was found that for both chambers the two-point method results in a 0.3% lower value than that derived by matching the energy response curves. The


Image Not Available

Figure 3.7 Energy response (E) of the NE2561 (S/N 051) with build-up cap. The error bars indicate two standard deviations. The line is the polynomial fit used to determine the response at the iridium-192 spectrum energies. (Reproduced with permission from Grimbergen and van Dijk, 1995 [31].)

Image Not Available

and build-up caps. These data are also presented in IAEATECDOC1079 [7] together with a description of an in-air calibration using the method based on the technique by Goetsch et al, [12]. The principle of the method for calibrating an 192Ir HDR source, is to calibrate it at an appropriate X-ray quality and at 137Cs, or in 60Co if a 137Cs beam is not available. With the knowledge of the air kerma calibration factors at these two energies, the air kerma calibration factor for 192Ir is obtained by interpolation making use of the wall correction factors. This method requires the total wall thickness to be the same at each quality that the chamber is calibrated. In the UK, a Joint BIR and IPSM Working Party [28] set up to report on brachymerapy dosimetry recommended that the calibration for use with iridium should be that for the highest available kilovoltage quality, that is, the factor for heavily filtered 280 kV X-rays. This recommendation was made in the absence of a primary calibration for iridium-192. It was also suggested that the measurements should be made with an NE 2 MV buildup cap, or a Perspex sheath around the source to remove photoelectrons emitted from the source capsule. The recommended values for electron filter corrections are 1.017 for the NE 2 MV build-up cap, or 1.004 for a 1 mm thick Perspex sheath around the source; more generally, for small thicknesses of low atomic number filter material, the recommended correction is 3% g-1 cm-2. It is estimated that, whichever method is used to ascertain the chamber factor, the difference between the 'energy response curve' method, the two-point method, or the simpler 250 kV factor method is less than 1%. Typical exposure times for an 'in-air' calibration at 100 mm using a nominal 10 mGy s-1 source will be about 300 s. If the mean reading is R then the RAKR, Kr in mGy s-1 is derived as follows:

Fc Figure 3.8 Energy response (E) of the NE 2571 (S/N 1436) with build-up cap. The error bars indicate two standard deviations. The line is the polynomial fit used to determine the response at the iridium-192 spectrum energies. (Reproduced with permission from Grimbergen and van Dijk, 1995 [31].)

uncertainty in the calibration factor for iridium-192 determined with the energy response curve method was estimatedat l%fortheNE2561 and l.l%for the NE 2571. It is concluded by Grimbergen and van Dijk [ 31 ] that, with respect to the chambers considered, the two-point method is a reasonable alternative to the energy response method. More recently, Ferreira et al. [33] have performed Monte Carlo calculations of chamber wall correction factors for 51 commercially available ionization chambers

F.c Ftp

Fs

Fg

Fe Fis

is the air kerma calibration factor for the secondary standard; is the intercomparison ratio between the field instrument and the secondary standard; is the temperature/pressure correction factor (= TIP x 1013/293.2), where T is the temperature in Kelvin and P the pressure in millibar; is the correction for room scatter and scatter produced in the jig and its support (= 0.998 for the Royal Marsden jig and support system); is the dose gradient correction factor for the ion chamber (= 1.009 for a 0.6 cm3 Farmer-type chamber at 100 mm); is the electron filter correction (= 1.017 for an NE build-up cap); is the inverse square scaling from 100 mm to 1 m

(= 10-2);

Fm is the gray to microgray conversion (= 106); t is the time, in seconds, for each reading.


In principle, there should also be corrections for air attenuation and scattering and for the source transit time, but both of these are taken as unity. RE-ENTRANT IONIZATION CHAMBER MEASUREMENTS

The most convenient means of measuring the strength of an HDR iridium-192 source is to use a re-entrant ionization chamber. The Standard Imaging HDR 1000 Ion Chamber is designed specifically for high strength sources [14]. The well of the chamber consists of a 35 mm diameter x 122 mm deep cavity into which a holder can be inserted to carry a catheter or rigid applicator for positioning the radioactive source. The responsivity of the chamber is affected by source position, but the variation is only ± 0.5% over a range of 25 mm near to the center of the chamber axis. Jones [34] used a modified Standard Imaging chamber with an NE 2571/1 electrometer as part of a qualityassurance programme for checking iridium-192 source strengths. The chamber measurements were found to correlate well with 'in-air' calibration measurements made over a 3-month source-decay period; the maximum discrepancy between the 'in-air' measurement and the re-entrant chamber measurement was 0.9% (Figure 3.9). A further investigation with a Nucletron Source Dosimetry System (PTW-Freiburg re-entrant ion chamber) calibrated at NIST and a modified Standard Imaging chamber showed that, over a 4-month period, 13 comparative measurements made with both chambers were found to be within 0.18% (1 SD). The air kerma strength measured using the NIST traceable Nucletron PTW chamber was found to agree within 0.3% of the 'in-air' calibration measurement. Goetsch et al. [29] also report measurements using three re-entrant ionization chambers manufactured by

Figure 3.9 The relative source strength of an iridium-192 source as a function of time measured with a modified standard imaging HDR WOO chamber over a 3-month period. The line corresponds to the decay curve; the points correspond to chamber measurements [34].

three different manufacturers. Agreement was found to be within 1%. In order to obtain maximum reproducibility, measurements in a re-entrant chamber should be made with the aid of a Perspex insert. For definitive calibration measurements, the chamber should be located away from objects that might cause radiation scatter (such as a laboratory wall). Consistent readings are obtained best when the chamber is used each time in the same position and in a reproducible manner. SOLID PHANTOM (OR WATER PHANTOM) MEASUREMENTS

The underlying principle of this type of measurement has been described in section 3.4.3, except that in the case of a single HDR source, the dose gradient through the centrally placed ion chamber has to be corrected for [18]. The method has been described by Ezzell [29], and Krieger [35]. Measurements in a phantom require corrections to be made for attenuation and scatter. Usually, the effective distance between the source and the attenuation is determined using a formula that applies to the condition of full scatter. Generally, the small dimensions of the solid (acrylic) phantom do not fulfil this requirement and a correction factor has to be applied to compensate for this lack of scatter. Ezzell [29] measured this to be 1.079 for a 130 mm diameter x 130 mm long acrylic cylinder. 3.4.6.

Pulse dose-rate sources

Pulse dose-rate (PDR) sources are of lower activity than HDR sources and are of different physical construction. PDR sources are typically 18-37 GBq in activity. In the case of iridium-192, the active length of a 37 GBq PDR source is 0.5 mm. The most convenient method of calibrating such a source is to use a re-entrant ion chamber. It will be necessary to ensure that the chamber has been calibrated for PDR sources rather than, or as well as, HDR sources. The strength of the source is such that an 'in-air' calibration with a 0.6 cm3 Farmer ion chamber is achieved best at a distance of about 50 mm; greater distances would require extended exposures. At this short distance, it is important to ensure precise alignment between the source and the chamber center. The location of the source center should be ascertained (by autoradiography) so that alignment can be achieved reproducibly. It is necessary to use a build-up cap (or a Perspex sheath over the source), as described in the section on HDR source calibration, to remove electrons emitted from the source capsule. A correction for the finite size of the chamber must be applied: this increases significantly at short distances. Tolli [18] has shown that, for a chamber of the same dimensions as a 0.6 cm3 Farmer chamber, the correction factor is 1.026. Exposure times to accumulate sufficient charge will be

References 33

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calibration of iridium-192 high dose rate sources. Int. J. Radial Onc. Bio/. Phys., 24,167-70. 15. Baltas, D., Geramani, K., lonaddis, G.T. et al. (1999) Comparison of calibration procedures for 192lr high dose rate brachytherapy sources. Int.J. Radial Oncol. Bio/. Phys., 1,43(3), 653-61. 16. Williamson, J.F., Morin, R.L and Khan, F.M. (1983) Dose calibrator response to brachytherapy sources: a Monte Carlo and analytic evaluation. Med. Phys., 10(2), 135-40. 17. AAPM Report No. 13 (1984) Brachytherapy. In Physical Aspects of Quality Assurance in Radiation Therapy. New York, American Institute of Physics, 38-9. 18. Tb'lli, H. (1997) Ionisation chamber dosimetry for brachytherapy. Doctoral dissertation. University of Goleborg, 15-31. 19. Schaeken, B., Vanneste, F., Bouiller, A. et al. (1992) 192Tr brachytherapy sources in Belgian hospitals. Nucl. Insl Methods Phys. Res., A312,251 -6. 20. Steggerda, M.J. and Mijnheer B. (1994) Replacement

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cobalt-60, radium-226and caesium-137. IntJ.Appl. Radial /sof.,29,21-7.

calibration of Cs-137and lr-192 sources in a solid

5. Rossiter, M.J., Williams, T.T. and Bass, G.A. (1991) Air kerma rate calibrations of small sources of cobalt-60, caesium-137, radium-226and iridium-192. Phys. Med. fi/o/., 36(2), 279-84. 6. Williamson, J.F. and Nath, R. (1991) Clinical implementation of AAPM Task Group 32

phantom. Radiother. Oncol., 31,76-84. 21. Aukett, R.J. (1991) A technique for the local measurement of air kerma rate from small caesium-137 sources, fir. J. Radiol., 64,918-22. 22. Meertens, H. (1990) In-phantom calibration of SelectronLDR sources. Radiother. Oncol., 17,369-78. 23. Mijnheer, B.J., Aalbers, A.H.L, Visser, A.G. and

recommendations on brachytherapy source strength

Wittkamper, F.W. (1986) Consistency and simplicity in the

specification. Med. Phys., 18(3), 439-48.

determination of absorbed dose to water in high-energy

7. IAEA-TECDOC-1079 (1999) Calibration of Brachytherapy Sources. Vienna, International Atomic Energy Agency. 8. Mcjury, M., Tapper, P.D., Cosgrove, V.P. et al. (1999) Experimental 3-D dosimetry around a high dose rate 192lr source using a polyacrylamide gel (PAG) dosimeter. Phys. Med. fi/o/., 44(10), 2431-44. 9. Berkley, L.W., Hanson, W.F., and Shalck, R.J. (1981)

photon beams: a new code of practice. Radiother. Oncol., 7,371-84. 24. Meisberger, LL, Keller, R.J. and Shalek, R.J. (1968) The effective attenuation in water of the gamma rays of gold 198, iridium 192, cesium 137, radium 226, and cobalt 60. Radiology, 90,953-7. 25. Jones, C.H. (1991) Quality assurance in brachytherapy

Discussion of the characteristics and results of

using the Selectron-LDR/MDR and microSelectron-HDR.

measurements with a portable well-ionisation chamber

Activity, 5(4), 12-15. Leersum, The Netherlands,

for calibration of brachytherapy sources. In Recent Advances in Brachytherapy Physics, ed. D.R. Shearer, Monograph No. 7. New York, AAPM, 38-48. 10. Weaver, K.A., Anderson, LL and MeliJ.A. (1990) Source calibration. In Interstitial Brachytherapy: a Report by the Interstitial Collaborative Working Group, ed. L.L. Anderson, New York, Raven Press. 11. Flynn, A. and Workman, G. (1991) Calibration of a microSelectron HDR iridium-192 source. Br.J. Radiol., 64, 734-9. 12. Goetsch, S.J., Attix, F.H., Pearson, D.W. and Thomadsen, B.R. (1991) Calibration of Ir192 high dose rate afterloading systems. Med. Phys., 18,462-7. 13. Jones, C.H. (1988) Quality assurance in gynaecological brachytherapy. In Dosimetry in Radiotherapy Vol. 1, Vienna, IAEA, 275-90. 14. Goetsch, S.J., Attix, F.H., Dewerd, LA. and Thomadsen, B.R. (1992) A new re-entrant ionisation chamber for the

Nucletron BV. 26. Chenery, S.G.A., Pla, M. and Podgorsak, E.B. (1985) Physical characteristics of the Selectron high dose rate intracavitaryafterloader. Br.J. Radiol., 58,735-40. 27. Messina, C.F., Ezzell, G.A., Campbell, J.M. and Orton, C.G. (1988) Commissioning the Selectron HDR cobalt-60. Activity, 2, 5-10. Leersum, The Netherlands, Nucletron. 28. Aird,E.GA, Jones, C.H.,Joslin,C.A.F.efo/. (1993) Recommendations for brachytherapy dosimetry: Report of a Joint Working Party of the BIR and IPSM. London, BIR, 1-17. 29. Ezzell, G. (1989) Evaluation of calibration techniques for the microSelectron HDR. In Brachytherapy2, ed. R.F. Mould. Leersum, The Netherlands, Nucletron, 61 -9. 30. Piermattei, A., Azario, L, Soriani,A. et al. (1995) Reference air kerma rate determination for iridium-192 brachytherapy sources. Phys. Med. 9-15. 31. Grimbergen, T.W.M. and van Dijk, E. (1995) Comparison of

34 Calibration of sources methods for derivation of iridium-192 calibration factors for NE2561 and NE2571 ionisation chambers. Activity, Special Report No. 7, 52-6. Leersum, The Netherlands, Nucletron BV. 32. Biiermann, L, Kramer, H.M. and Selbach, H.J. (1995) Reference Air Kerma Rate Determination of an Iridium-192 Brachytherapy Source. Activity: Special Report No. 7. Nucletron-Oldelft, Leersum, The Netherlands, 43-47. 33. Ferreira, I.H., Marre, D., Bridier, A., Marechal, M.H. and de Almeida, C.E. (1999) Personal communication.

34. Jones, C.H. (1995) HDR microSelectron quality-assurance studies using a well-type ion chamber. Phys. Med. Biol., 40,95-101. 35. Krieger, H. (1991) Messungder Kenndosisleistung punktund linien-formiger HDR iridium-192 Afterloadingstrahlermiteinem PMMAZylinderphantom.Ze/f. Med. Physik., 1,38-41.

4 Systems of dosimetry ANNE WELSH AND KAREN D'AMICO

4.1

INTRODUCTION

Brachytherapists have always aimed to deliver the optimum treatment to the patients in their care. In order to achieve this ideal, the introduction of brachytherapy was soon followed by the development of dosimetry systems which were based on clinical experience. A paper on the physics of brachytherapy was published in 1923 by Coliez [ 1 ] and this was followed by many other publications. The well-known Manchester System [2] was published in 1934, followed by the Quimby System in 1944 and 1953 [3,4]. The early systems were designed for radium. Subsequently, the Paris System [5,6] was published as a modern dosimetry system which allows the brachytherapist to take full advantage of the technological improvement in source production, in particular the use of iridium-192 flexible wire sources. The aim of all the published dosimetry systems is simple: to provide a set of guidelines for the brachytherapist which, if followed, enable a prescribed dose to be delivered to the patient as accurately as possible. This chapter contains brief descriptions of the systems most commonly used and some sample data to enable a limited number of practical calculations to be performed. It is recommended that the original works describing the dosimetry systems are consulted before any of the systems described are set up for clinical use for the first time.

4.2 NON-GYNECOLOGICAL TREATMENT SYSTEMS 4.2.1

The Paris System

BASIC PRINCIPLES

The first account of this system was published in 1966 [5] and was followed by several more detailed publications, e.g., in 1978 and 1987 [6,7]. The Paris System is designed for modern sources, particularly iridium-192 wires, which have narrow diameter, are flexible, and may be formed to any length required. The system requires the brachytherapist to distribute sources over a predetermined target volume in accordance with the system rules. Dose rates are then calculated at defined points, known as basal dose-rate points, within the target volume. The isodose that closely envelopes the target volume may be found by calculating 85% of the average basal dose rate. The basic rules for positioning the sources are as follows: • Each source must be implanted parallel to the others. • Each source must be equidistant from adjacent sources. • The reference air kerma per unit length of source is constant for all the sources used in the implant. • Ideally, the centers of all the sources are contained in a single plane which perpendicularly bisects the

36 Systems of dosimetry

sources. This plane is called the central plane of the implant. If such a plane cannot be defined, the central plane is that plane perpendicular to the sources which passes as closely as possible to the source centers. The perpendicular distance between two adjacent sources is referred to as the source separation in this chapter. The source separation must lie in the range 8-15 mm for short wires (i.e., 50 mm or less) and 8-22 mm for long wires (greater than 70 mm). If the source separation exceeds the maximum permitted, there will be an unacceptably large high dose area around each source. This is illustrated in Figure 4.1. If the wire separations are less than 8 mm, it is difficult to implant the wires in a parallel fashion and the implant may not conform to the requirements of the Paris System.

Figure 4.1 Two implants each showing the area receiving the prescribed dose and twice the prescribed dose. The diameter of the high dose area is considerably larger for the implant with

POSITIONING THE SOURCES

the greater wire separation.

The first planning consideration is the size of the target volume. The target volume has three dimensions, which are usually referred to, in the Paris System, as the length, the width, and the thickness (Figure 4.2). The sources are positioned parallel to the length dimension and may be implanted in one or more planes, depending on the thickness of the treatment volume. Practical planning commences by determining the number of source planes and the source separation necessary for the satisfactory treatment of the patient. • For a single plane containing only two sources, the source separation is given approximately by: wire separation = thickness x 2.0

Figure 4.2 The relationship between the wire positions, the

• For a single plane implant containing three or more sources, the source separation is given approximately by:

safety margins, and the target volume dimensions.

wire separation = thickness x 1.7

The number of sources needed to implant a target volume can then be calculated from: width = wire separation x (number of wires - 1) + safety margin x 2

The safety margins for the different wire arrangements are summarized in Table 4.1. Some brachytherapists prefer to omit the safety margin from their planning calculations and implant the sources up to the

edge of their planned volume. The safety margin then fulfils the purpose of its name and provides a small additional margin around the volume. If the calculated wire separation exceeds the maximum permitted value, the implant cannot be carried out as a single plane of sources and two or more planes must be implanted. In multi-plane implants the sources may be implanted on a square lattice ('in squares') or an equilateral triangular lattice ('in triangles') (Figure 4.3).

Table 4.1 Safety margins as fractions of wire separations for implants planned in accordance with the Paris System rules

0.37

0.27

0.15

Non-gynecological treatment systems 37

source length = 1.4 x target volume length All the formulae given above are approximate, but are sufficiently accurate for clinical use. Detailed tables may be found in reference [7].

CALCULATION OF THE DOSE

Figure 4.3 Cross-sections through two double-plane implants, one implanted 'in triangles' and one implanted 'in squares'. The dots indicate the wire positions and the crosses indicate the basal dose points.

• For an implant in squares, the wire separation can be calculated from: thickness = wire separation + safety margin x 2 • For an implant in triangles, the wire separation can be calculated from: thickness = wire separation x 0.87 + safety margin x 2 • The width of an implant in squares is given by: width = number of squares x source separation + safety margin x 2 • The width of an implant in triangles is given by:

The isodose that encloses the target volume is known as the reference isodose. It is calculated from the basal doserates, which are the lowest dose rates found within the central plane. For a single-plane implant, the basal doserate points are positioned at the midpoint of each gap between the sources. The basal dose-rate points for an implant in squares are at the center of the squares, and for implants in triangles the basal dose rates are calculated at the points where the perpendicular bisectors of the sides of the triangles intersect. The dose rates can be calculated by entering the source position data into a suitable computer program, which is likely to be available in most oncology centers, or by hand calculation using graphs or tables of dose rate against distance from the source for unit activity. The dose rates taken from graphs or tables must be corrected to values for the actual mid-implant source strength. This will involve obtaining the source strength from the supplier's measurement certificate and correcting it for radioactive decay to the date of the middle of the implant. Sample data are given in Tables 4.2a and 4.2b. A simple example of an application of the Paris System is shown below.

EXAMPLE

width = number of triangles x source separation x 0.5 + lateral safety margin x 2 The length of the sources required to treat a target volume is almost independent of the other parameters and is given approximately by the expression:

A target volume 55 mm long, 8 mm thick, and 35 mm wide is to be given a dose of 30 Gy. Calculate the source lengths required and the dose rate assuming an air kerma rate source strength of 800 nGy h-1 mm-1 at 1 m halfway through the implant.

Table 4.2a Sample dose rates for iridium-192, 0.3 mm diameter wire sources, calculated according to the recommendations of the Joint BIR/IPSM Brachytherapy Working Party [8]

20 10 20 30 40 50 60 80 100 120

350 489 547 577 595 606 619 627 631

104 176 219 246 262 275 290 299 305

48.0 88.3 118 138 153 164 179 188 194

27.7 52.4 72.6 88.4 101 110 124 132 138

100

12.5 24.3 35.0 44.4 52.3 59.1 69.5 76.9 82.3

7.1 13.9 20.3 26.3 31.6 36.3 44.2 50.2 54.9

4.5 8.9 13.2 17.2 20.9 24.3 30.3 35.1 39.0

3.1 6.2 9.2 12.0 14.7 17.3 21.8 25.7 28.9

1.7 3.4 5.1 6.7 8.2 9.3 12.6 15.1 17.3

1.0 2.0 3.1 4.1 5.1 6.1 7.9 9.6 11.1

Dose rates a re in mGyh-1 for an air kerma rate source strength of 1 mGy h-1 mm-1 at 1 m. All the dose rates are for crossline = 0, i.e., in the plane through the center of the wire and perpendicular to it.

38 Systems of dosimetry

Table 4.2b Sample dose rates for iridium-192, 0.3 mm diameter wire sources, calculated according to the recommendations of the Joint BIR/IPSM Brachytherapy Working Party [8]

0 10 20 30 0 30 50

50 50 50 50 100 100 100

595 581 487 139 627 606 319

262 251 200 98.9 299 278 157

153 145 116 71.4 188 170 103

101 95.2 78.0 53.9 132 117 74.9

52.3 49.9 43.0 22.7 76.9 66.9 46.8

31.6 30.4 27.2 22.8 50.2 43.8 32.7

20.9 20.3 18.7 12.1 35.1 30.9 24.2

14.7 14.4 13.5 9.3 25.7 22.9 18.6

8.2 8.1 7.8 7.3 15.1 13.8 11.8

5.1 5.1 4.9 4.7 9.6 8.9 7.9

Dose-rates are in mGy h-1 for source strengths of 1 u.Gy h-1 mm-1 at 1 m. The dose rates are for different crosslines, i.e., in different planes perpendicular to the wire and at the crossline distance from the wire center.

Single plane implant. Source separation = 1.7 x thickness = 1.7x8 = 14 mm Width =2 x 0.37 x 14 +14 x (number of wires -1) = 2 x .37 x 14 + 14 x 2 = 38 mm This is the closest width to the required value and requires three wires to be used. Wire length = 1.4 x 55 = 77 mm - use 80 mm. The details of the distances and dose rate calculations for this calculation are given in Table 4.3. The mean basal dose rate for a source strength of 1 1-iGy h-1 mm-1 at 1 m, from Table 4.3, is

0.5 x (943 + 943) = 943 mGy h-1 Correcting this to true source strength available for use:

Reference dose rate

_ 85

~100 X

Treatment time may be calculated from this dose rate and the prescribed dose.

The isodose distribution for this implant is shown in Figure 4.4. PROBLEMS It is unlikely that an implant that conforms perfectly with the Paris rules can be achieved without the use of a template to aid the source positioning. If the implant does not comply precisely with the rules, the Paris System may still be used providing none of the individual basal dose rates differs from the mean basal dose rate by more than 10% and if, when using the triangular formation of sources, none of the triangles is obtuse (Figure 4.5). Further information on dealing with variants in source position which may be needed in practice may be found in the book Modern Brachytherapy [7].

average basal dose rate

Table 4.3 Dose rates calculation for sample iridium-192 imnlnnt

1 2 3

7 7 21

412 412 119 943

Dose rates in mGy h-1 calculated for wire of air kerma rate source strength 1 mGy h-1 mm-1 at 1 m.

Figure 4.4 The dose distribution for the example of the Paris implant showing isodoses of 60 Gy, 30 Gy, 22.5 Gy, and 15 Gy.

Non-gynecological treatment systems 39

4.2.2

The Manchester System

The first widely available set of rules that could be used to deliver a uniform dose to a target volume is often referred to as the Manchester System, after its place of origin and is fully described in the book Radium Dosage, The Manchester System [9]. Excluding gynecological treatments, three different types of brachytherapy implant were considered: moulds, interstitial planar implants, and volume implants. The systems used to distribute sources and calculate treatment times need to be discussed separately for each of these cases. MOULDS

The term mould is used to describe the situation in which the radioactive sources are positioned external to the patient, usually at a distance from the patient's skin known as the treatment distance and represented by the letter d (Figure 4.6). The treatment dose is prescribed to the plane which is at distance d from the sources and the dose in this plane will be delivered with a 10% accuracy if the rules are followed. The sources may be arranged over the treatment area in circles or squares, circles being the preferred arrangement. In both cases the target area should be bounded with radioactive sources arranged in the required shape. Ideally, the sources should be laid in a continuous line around the periphery, but gaps not exceeding d are acceptable. For small circular treatment areas, the sources around the periphery will treat the target area adequately, but large circles may require additional sources in the interior. A circle may be deemed to be small if the ratio of the

Figure 4.6 Source arrangement for a Manchester-type mould arrangement. Source positions are indicated by dots on the cross-section and lines on the wire positions viewed from above.

circle diameter to the treatment distance (d) is less than 3. The distributions required for larger circles are given in Table 4.4. Squares will be adequately treated by the peripheral sources only if the side of the square does not exceed twice the distance d. If the square does not meet this requirement, supplementary lines of sources, parallel to the side of the square, will be needed in the interior. The distance between the lines of sources must not exceed twice the distance d. If only one additional line of

Table 4.4 Distribution of total source activity for circular moulds Ratio of Diameter to Treatment Distance

q 0 ) - reference point on the transverse axis of the source; P(r,q) = point to calculate the dose at; (3 = angle subtended by the active length L.

Note that Sk is the air kerma rate at 1 cm on the transverse axis of the source as if the source is a point source. SkA is the real dose rate in tissue at 1 cm on the transverse axis of the source. From this follows that A is also a function of the active length of the source.

Calculating of dose by computer 51

53

CALCULATING OF DOSE BY COMPUTER

To calculate dose to points around an HDR source, either equation (5.1) or (5.3), or a mixture of both, can be used by computer algorithms. The orientation of the source in free space must be known in order to apply the geometry factor G(r,q) and the anisotropy factor F(r,q). Localization techniques that supply this information are an essential part of any brachytherapy treatment planning system and are discussed in section 5.4. In this section, the different dose calculation parameters are discussed, with emphasis on sources used in afterloading.

53.1

Source strength

Typically, the source strength is derived from the measured air kerma rate at 1 m, a distance much larger than 1 cm, at which distance a source is practically a point source. The reference air kerma rate kk, defined at 1 m, is obtained directly from this measurement. The air kerma strength Sk is derived from Kk using Sk = 104 Kk for both a point source and a line source. Thus, Sk is the air kerma rate at 1 cm on the transverse axis of the source, as if the source is a point source. The apparent activity (Aa) follows from Kk using equation (5.2), Aa = 104 Kk/[(Gd)xf]. For iridium-192 sources, Kk or Sk values should be entered into the planning program instead of the derived Aa values, as there are different values published for (Gd)x. If a planning system requires the entry of apparent activity, then the same (Gd)x must be used when converting measured air kerma rate to apparent activity as when calculating dose values. Otherwise, a serious error in the dose given to the patient may occur.

53.2

Specific dose-rate constant (A)

The specific dose-rate constant (A) is defined as the dose rate in tissue per unit air kerma strength at 1 cm from the source center along the transversal axis of the source. It depends upon the physical configuration of the source, i.e., its active length, and upon the radiation spectrum. The latter influence is due to the tissue scattering and absorption factor at 1 cm, T(r0), which depends on the radiation spectrum. Thus, there will be different dose rate constants for identical isotopes in sources with different physical configurations.

533

Geometry factor, 6(r,q)

Depending on the active length of a source, either a point source or a line source should be assumed. For a point source, G(r,q) = 1/r2 and for a line source with active length I, G(r,q) = b(I r sin 0) with (3 the angle

subtended by the active length L at point (r,q). The modeling as a line source is of importance when calculating dose rates at distances shorter than 2 L. If HDR stepping sources with an active length of 3 mm or more are not modelled as a line source, doses calculated at distances shorter than 6 mm are less accurate [9-11].

53.4

Dose anisotropy function, F(r,q)

The dose anisotropy function, F(r,q), accounts for the anisotropic behavior of the dose distribution around the source, due to the self-absorption in the active material and the attenuation in the encapsulation of the source. The value of the anisotropy function at the distance r from the source along the transversal axis, F(r, 90°), is defined as 1.0. The anisotropy correction can be handled in several ways, depending upon the radiation spectrum of the isotope and the physical form and encapsulation of the source. Measured F(r,q) values, stored in tables, are often fitted to functions that are used in computer algorithms. For sources emitting high energy radiation, such as a cesium-137 source, the anisotropy correction for a point P(r,q) can be calculated by subdividing the active material in the source in small volume elements Da. For each element Da the path ra through the active material itself and the path rw through the source wall are determined. This gives a correction factor exp [-(ma ra + mw rw ], with ma the linear attenuation coefficient for the active source material and |iw the linear attenuation coefficient for the encapsulation material. By summing over all active volume elements Da, the correction factor C(r,q) for point P(r,q), is found. NowF(r,q) = C(r,q)/C(r,90°). In the traditional approach of dose calculation around radium and cesium tubes, the interval method is used. This method divides the source in a large number of point sources and calculates the attenuation of the rays from each point source by the source encapsulation [12,13]. Thus, there is no strict separation between the geometry factor and the anisotropy factor. For sources with medium or low range energies, an analytical correction is not possible due to the dependence of the tissue scattering and absorption on the radiation spectrum. For such a source, a table with measured values of F(r,0) or a function fitted to these values is used. The AAPM Task Group 43 report [7] gives tabulated values of -F(r,q) and G(r,q) for iodine-125, iridium192, and iridium-103 seeds, currently in use. Some authors present tables which are corrected for the inverse square law only and normalized to 1 at 1 cm distance from the source center on the transversal axis, thus representing F(r,q) g(r) values. The multiplication factor to the dose in the point (1 cm, 90°) to obtain the dose in point (r,0) then becomes F(r,q) g(r)/r2 [14]. For sources of medium range energies, such as iridium-192, there is less variation in the values of the

52 Computers in brachytherapy dosimetry

anisotropy function with distance r from the source. Therefore, the anisotropy function in some older planning systems is taken as F(q), with F(90°) again defined as 1. It is usually implemented as F(q)/r2, with F(q) a table with values for 0 between 0° and 180° [15]. Accurate dose values around an HDR source with an active length of 3.5 mm are obtained by using F(q) G(r,q), with G(r,q) applied for a line source of 3.5 mm. These dose values are even valid for short distances up to 1 mm to the source center [9]. If the orientation of an HDR stepping source in space is not known, then only the inverse square law with a fixed anisotropy factor, the anisotropy constant (jan, can be applied. The value of (jan is less than 1.

53.5 Tissue attenuation factors, T(r) andg(f) The tissue attenuation function, T(r), and the radial dose function, g(r), both account for the effects of absorption and scatter in tissue along the transverse axis of the source. In most computer algorithms, the tissue attenuation function is applied to represent the dose fall-off along the transverse axis, due to tissue absorption and scattering. The function T(r) is normally expressed as a polynomial in the form of:

The parameters a; most often used are those of Meisberger et al. [8], which are valid for the range of 1 cm through 8 cm. At depths beyond 8 cm, the above expression decreases sharply and, at those depths, T(r) is usually approximated by exp(m t r). A fit function with the least number of parameters is the modified Van Kleffens and Star function [16]:

For indium-192 the parameter a equals 0 and equation 5.8 reduces to T(r) = d(l + b r2) with 8 = 1.008 and b = 0.0012 cm-2. Equation 5.8 coincides with the Meisberger relation within 0.5% for sources with medium and high range energies, such as iridium-192, cesium-137, and cobalt-60. At depths beyond 8 cm, equation 5.8 decreases gradually and a separate exponential attenuation function is not needed when calculating clinical dose distributions around implants or applications.

5.4 RECONSTRUCTION OF SOURCE LOCALIZATION In order to obtain the dose distribution around an implant or application, the exact position of each source or dwell position in space must be known. For the reconstruction of the source localizations by a treatment planning program, different techniques are available.

5.4.1

Specification of coordinates

If the three-dimensional coordinates of the sources or dwell positions are known, keyboard entry of these data can be used. This, of course, is the most accurate description of the source positions.

5.4.2 Localization using film imaging techniques If the absolute coordinates are not known, imaging localization techniques must be used. These imaging techniques utilize either plane radiographs taken from different directions, or computed tomography (CT)/ magnetic resonance imaging (MRI) images of the implant. If an afterloading technique is used, it is necessary to simulate the position of the sources or dwell positions utilizing localization markers. These X-ray markers must be (i) easily discernible on the radiograph or CT/MRI slice, (ii) accurately depicting the source or dwell position, and (iii) coded such that the user can determine which markers correspond to a given catheter or applicator. They usually consist of a thin, braided, metal wire with markers of high Z metal at every centimeter. By counting from the catheter tip, corresponding images of a given X-ray marker are easily found. The images of these markers are called catheter describing points as the corresponding images of two plane radiographs are projections of the same point in a catheter. In implants with many catheters close to one another, it is sometimes difficult to follow these X-ray markers. In this case high Z wires can be inserted in each catheter up to the catheter tip. The images of these wires, starting at the catheter tip, are digitized from two-plane radiographs. The localization in space of each catheter can be reconstructed from its images on the two radiographs by dedicated software. This technique is called catheter image tracking. The points describing the curvature of an image are called catheter image points. Contrary to the catheter describing points, there is no direct link between the catheter image points on the two radiographs. ORTHOGONAL RECONSTRUCTION METHOD

The most widely used radiographic method for source localization is the orthogonal reconstruction method [17]. Two-plane radiographs of the implant are taken in a lateral and antero-posterior (AP) orientation. Either a radiotherapy simulator is used or a localization box with cross-wires on the faces of the box is placed over the patient (Figure 5.2). In the latter case, the beams are aligned such that the X-ray images of opposing crosswires coincide. The advantage of this technique is that AP and lateral radiographs are easily interpreted by the physician. A disadvantage is, however, that sources or X-ray markers in the lateral X-ray film are often difficult

Reconstruction of source localization 53

Figure 5.2 Orthogonal reconstruction. The beam set-up is obtained by calculation of the localization of the AP and lateral X-ray foci from the cross-wire images on the radiographs. Instead of a reconstruction jig to adjust the AP and lateral beams, a radiotherapy simulator with gantry angles of 0° and 90° can be

Figure 5.3 Semi-orthogonal reconstruction. The beam set-up is obtained by calculation of the localization of the AP and the lateral X-ray foci from the size and the displacement of both cross-wire images on the radiographs. I = center of box; P - point to be reconstructed.

used. I - isocenter; P = point to be reconstructed.

ISOCENTRIC RECONSTRUCTION METHOD

to distinguish, particularly in the pelvic region, due to the thickness of tissue and the overlying bony structures. SEMI-ORTHOGONAL RECONSTRUCTION METHOD

Truly orthogonal orientations for the AP and lateral film are not easily obtainable with portable X-ray units. In the semi-orthogonal reconstruction method, a localization jig with AP and lateral cross-wires is placed over the patient and two radiographs (a lateral and AP) are taken [18] (Figure 5.3). It is not necessary for these to be truly orthogonal, because the set-up information will be determined by the computer from the size and the relative distances of the cross-wire lead marker images on each of the two films. This method, therefore, accepts X-ray beams whose central axes do not intersect and are not perpendicular to one another. The only requirement is that the projections of the crosswires on the two corresponding box faces are visible on the radiographs. The semi-orthogonal reconstruction method has proven to be particularly advantageous in HDR endobronchial applications. Directly after insertion of the catheters, a portable radiographic X-ray unit can be used with the localization box to obtain the radiographs for localization of the catheters. This will shorten the time between the insertion of the catheters and the treatment of the patient considerably, because there is no localization session on a radiotherapy simulator required.

With an isocentric X-ray unit, such as a radiotherapy simulator, two images of the X-ray markers in each catheter can be obtained on a single, large-size radiograph [17] (Figure 5.4). The gantry angle of the first X-ray beam is -a and of the second beam is +a, with the

Figure 5.4 Isocentric reconstruction, a - reconstruction angle; FID -focus to isocenter distance; IFD = isocenter to film distance; I = isocenter; P=point to be reconstructed. This method requires an isocentric X-ray unit such as a treatment simulator. A large-size film is placed under the patient. The beam set-up is obtained by rotating the gantry over an angle of +a and -a, with a preferably in the range of 15°-30°.


total angle (2a) between the central axes of the projecting beams taken as large as possible. In order to visualize both images on this radiograph, it is essential that the isocenter is placed in the center of the implant and that the X-ray field is defined such that the two images on the radiograph do not overlap. Due to the equal angles between the left and right central axes with respect to the normal to the radiograph, lines between corresponding points on the left and right image all run parallel. This aids in the determination of individual seed or dwell positions from one image to the other. Usually, the gantry angle of each image with respect to the normal of the radiograph is between 15° and 30°, depending on the extension of the implant and the distance between the isocenter and the X-ray film. STEREO-SHIFT RECONSTRUCTION METHOD

The set-up is similar to that of the isocentric method, but, instead of the X-ray tube rotating, it is moved laterally over a given distance [ 17]. This method is applicable, for instance, with a ceiling-mounted X-ray unit where such a lateral movement is available. Usually, the angle between the two projecting beams is very small, typically 7°, which makes this method very sensitive to even small errors in the measuring of the source images or a small movement of the patient between the taking of the radiographs. If possible, this reconstruction method should be avoided. VARIABLE ANGLE RECONSTRUCTION METHOD

This method reconstructs the localization of the catheters from two radiographs taken with a therapy treatment simulator [19] (Figure 5.5). The only limitation is that the central axes of the projecting beams are not coinciding or opposing. The reconstruction algorithm requires that the angle, focus-isocenter distance, and isocenter-film distance of each radiograph are accurately known. The advantage of this technique is that the implant can be observed fluoroscopically at various gantry angles to define the two gantry angles that display the sources or localization dummies with the highest clarity and least obstruction. It is preferred that the total angle between the two projecting beams lies between 60° and 120°. Of course, the greatest accuracy is obtained when this total angle is 90°. The orthogonal reconstruction method is a special case, e.g., with gantry angles 0° and 90°. RECONSTRUCTION METHODS USING CORRESPONDENCE LINES

A digital image can be obtained by scanning a radiographic film with a film scanner or, in real time, by a portal imaging device mounted on the X-ray equipment. These images are then displayed on the treatment planning computer which has options to enhance them to

Figure 5.5 Variable angle reconstruction. ®a=gantry angle beam 1; b=gantry angle beam 2; FID 1 -focus to isocenter distance beam 1; IFD 1 = isocenter to film distance beam 1; FID 2 =focus to isocenter distance beam 2; IFD 2 = isocenter to film distance beam 2; I = isocenter. The two gantry angles a and b are determined such that the catheters are clearly visible on the image intensifier. The total angle a+b should preferably lie

between 60° and 120°. The radiographs are made with the film in the cassette holder on top of the image intensifier.

better delineate the source or X-ray marker positions, the target volume, and the surrounding organs. A problem exists with imaging equipment such as image intensifiers, where the image may be distorted by the cushion effect and the influence of the earth magnetic field, which will change with the gantry angle. To minimize these effects, the implant should be kept in the center of the image. Of course, the reconstruction methods based on two radiographs taken at different directions can still be used by replacing the digitizer with the mouse. However, if both digitized films can be displayed together on the monitor, an extension of the variable angle reconstruction method becomes possible. By pointing with the mouse to a point on one of the digitized films, the planning program can draw the ray from the corresponding X-ray focus to that point. The other X-ray focus will project that ray to the other film as a line over it. This line on the second film is called the correspondence line to the point on the first film (Figure 5.6). Thus, by moving the mouse over one of the digitized films to the image of an X-ray marker, the correspondence line moves over the other film until it intersects the other image of this marker. In this way the corresponding images in both radiographs are easily found and reconstruction methods based on catheter describing points can be used.

5.43

Tracking of catheter images

Sometimes, visually matching of X-ray markers on the two localization radiographs is not easily done, as in the

Reconstruction of source localization 55

Figure 5.6 Reconstruction using correspondence lines. C1 and C2 are images of the same X-ray marker in the catheter. [1] and [2] are the films obtained by variable angle reconstruction. They are digitized by a film scanner and displayed on the monitor. After entering marker image C2 on film 2, the ray of focus 2 to C2 is projected to film [1] as the correspondence line of C2. The intersection of this projection with the catheter image on film 7 gives the point C1. The intersection of the rays focus 2-C2 and focus 1-C1 gives the reconstructed localization of the marker in the catheter. Similarly, if C1 is entered, the corresponding image C2 on film 2 can be found. With this method, corresponding image points can be found without the use of an X-ray marker in the catheter.

case of implants with many catheters. In a lateral radiograph only a cloud of X-ray markers is visible, but not the braided metal cables. In such an implant, continuous radio-opaque wires should be used instead of the X-ray markers. As stated earlier, the isocentric reconstruction method connects corresponding catheter describing points between the two X-ray images with parallel lines. The localization of a catheter in space from its two images on the isocentric film is reconstructed as follows. First, the two X-ray images of the catheter are described with catheter image points. If on both X-ray images the catheter tip is clearly visible, the line connecting these tips is taken as the horizontal base line. This corrects for any patient movement between the taking of the two exposures. Otherwise, the line connecting the images of the isocenter is taken as the horizontal base line. With appropriate software, any set of variable angle radiographs taken with the same focus isocenter distance can be converted to a computer-generated isocentric 'radiograph' (Figure 5.7). Then each point with which a catheter image is described can be connected by the planning software to its corresponding point on the other image by a line parallel to the one connecting the images of the catheter tip. This conversion of the variable angle reconstruction to the isocentric one is not possible with the semi-

orthogonal reconstruction method. In the case of afterloaded sources or of stepping source dwell positions in a catheter, image tracking reconstruction can still be used [ 19]. Again, the tip of each catheter needs to be visible on both images. Subsequent points on each image are placed such that they describe the curvature of the image. Each one of the two catheter images is then digitized, starting with the tip, until a point beyond the last source or dwell position is entered. The advantage of this technique is that the points depicting the image on the first radiograph are not corresponding to the ones on the second radiographic image. Thus, any radio-opaque marker (e.g., any flexible metal cable) can be used to depict the catheter. This technique simplifies the data entry into the planning system, but is less accurate in handling any patient shift between the taking of the two radiographs, as is discussed in the section on reconstruction accuracy below. Digital images from CT or MRI scanners are also used for treatment planning. Usually, a series of parallel, transverse slices through the treatment volume and its surroundings is obtained. The digital images are displayed on the monitor of the treatment planning computer, which has options to enhance them to better delineate the source or X-ray marker positions, the target volume, and surrounding organs. They are distinguished by their position along the caudal-cranial axis along the CT table top. The coordinates of an image of a source or X-ray marker can be obtained with a pointing device such as a mouse. Reconstruction of the localization is straightforward; the x-coordinate and y-coordinate are obtained directly from the mouse coordinates and the 2-coordinate is given by the table position of the slice.

5*4.4

Reconstruction accuracy

ACCURACY OF THE DIFFERENT RECONSTRUCTION METHODS

The most accurate reconstructed catheter or source coordinates are obtained when the central axes of the two projecting beams are perpendicular to each other. This is achieved by the orthogonal reconstruction method or by the variable angle method when the gantry angles differ by 90° (or 270°). The accuracy remains high if the angle between the two beams lies in the interval (60°-120°). A reconstruction set-up which uses an angle outside that interval, thus smaller than 60° or between 120° and 180°, becomes sensitive to patient shifts between the taking of the radiographs and to digitizing errors. The stereo-shift reconstruction method is extremely sensitive to digitizing errors, due to the small angle between the two projecting beams, up to 10°, and should be used with great care [17]. The reconstruction accuracy depends also on the use of X-ray markers.


Figure 5.7 Variable angle reconstruction using isocentric pseudo-film. The intersections of the rays to the catheter image points with a computer-generated isocentric plane are determined. Corresponding images on the pseudo-film are all connected by parallel lines. This method is suitable for reconstruction of implants with flexible catheters using a therapy simulator. If the patient shifts between the taking of the radiographs, lines between corresponding images are parallel to the line connecting the images of the catheter tip.

RECONSTRUCTION USING a OR MRI SLICES

The main factor determining the accuracy of the reconstructed localization is the slice spacing, the distance between consecutive slices. A typical value of 4 mm results in an accuracy of 2 mm in that direction. The choice of the material for the catheters and the X-ray markers is also essential because dense high Z material will introduce artifacts in the scan. RECONSTRUCTION USING CATHETER DESCRIBING POINTS

The localization in space of a catheter describing point from its two X-ray images is defined by constructing the two rays projecting the catheter describing point to its X-ray images. These two rays will not intersect because there will always be some movement of the patient between the taking of the two radiographs. The reconstructed localization of the catheter describing point is taken halfway on the line connecting the two rays along their shortest distance (Figure 5.8). Thus, if the patient

moved a certain distance between the taking of the two radiographs, the resulting error in localization of the catheter describing point is only half that distance. RECONSTRUCTION USING CATHETER IMAGE TRACKING

The accuracy of image tracking reconstruction depends strongly on any movement of the patient between the taking of the two films. Because the projections of the tip of a catheter on both radiographs are usually visible, the shift of this catheter due to a patient shift between the taking of the two radiograph images can be determined. One of the images can then be adjusted by the planning system such that the rays from the X-ray foci to these first image describing points intersect. However, a rotation of the patient cannot be taken into account and will result in an error in the reconstructed localization of the source or wire. With catheter image tracking, the error in catheter localization due to a given patient movement is about twice the error obtained with catheter describing points.

Optimization techniques in stepping source brachytherapy 57

rithms with varying user-defined constraints may all deliver different dose distributions. Therefore, clinical experience will always be needed to judge the mathematically optimized dose distribution for actual patient treatment. Based on that judgement, changes may be made in the optimization constraints, resulting in a new optimized dose distribution, before the final dose distribution will be accepted for clinical use. 5.5.1

Figure 5.8 Correction for patient shift between thetakingof radiographs 7 and 2. To find the localization of an X-ray marker, the shortest distance between the rays to the corresponding images of this marker is determined. The reconstructed localization of this marker is placed midway on the line along this shortest distance.

5*5 OPTIMIZATION TECHNIQUES IN STEPPING SOURCE BRACHYTHERAPY Once the catheters are placed in the patient, stepping source brachytherapy offers two degrees of freedom: the dwell position and the dwell time. Usually, the dwell positions are placed in the sections of the catheters that are inside the target volume. Then optimization of the dose distribution is performed by manipulation of the dwell times either by the user or by dedicated software. Most optimization procedures do not determine the absolute dwell times for each dwell position. Instead, they result in a set of relative values for the dwell times in the range 0.0-1.0 with a corresponding set of relative dose values in the dose points. Another module of the treatment planning program calculates the absolute dwell times for the stated mean dose in these dose points. There are several factors which influence a mathematically optimized dose distribution. For example, due to the radial nature of radiation from a point source, it is not possible to obtain along the axis of a catheter a prescription isodose curve in the shape of a box. Also, if the placement rules for the catheters of a given target volume are not adhered to, it is difficult, if not impossible, to obtain a good dose distribution. Or, if an implant is not covering the target volume geometrically, manual changing of relative dwell times may be required to cover the target volume with the prescription isodose surface. Thus, a mathematically optimized dose distribution does not always represent the best possible one in and around an implant. Finally, different types of optimization algo-

Distance and volume implants

In mathematical optimization, two types of implants are distinguished: distance implants and volume implants. In a distance implant, dose points are placed at a given distance around the catheters. The mathematical optimization aims at determining the dwell positions and relative dwell times such that the prescription isodose surface passes through these dose points [ 16,20,21]. This is called 'optimization on distance.' Examples of distance implants are single catheters, double catheters, and single-plane implants. If digital imaging with transverse slices is used, these so-called dose points can be placed equidistantly on the target contours in the displayed cross-sections of the patient. With reconstruction by radiographic films, dose points can be placed only relative to the catheters. A volume implant contains one or more planes of catheters. Series of dose points are placed inside the target volume midway between the catheters and throughout the implant. In a volume implant, the relative dwell times are optimized to the same dose in these dose points. This is called 'optimization on volume' [16,21]. The prescription dose is defined as a given percentage of the mean dose in these dose points, with the prescription isodose surface encompassing the target volume as closely as possible. However, the above definition of optimization of volume is a gross simplification. The placement of dose points midway between the catheters alone is not sufficient for optimization (Figure 5.9). In cases in which dose point placement is complicated due to irregularities in the distances between implanted catheters, the dwell positions themselves can act as dose points for optimization. This technique is called 'geometric optimization' and can be performed either on distance or on volume [16,23]. 5.5.2

Rules of optimization

Once a stepping source implant is optimized, it can be evaluated by the following rules. Rule 1. The optimized isodose distribution should match the requirements specified by the physician. In the case of a distance implant, the prescription isodose surface should pass as closely as possible through each of the defined dose points. For a volume implant, the


Figure 5.9 Distance optimization of a volume implant. A two-plane implant with five parallel catheters is optimized to the same dose in rows of dose points, placed midway between the catheters. A perfect fit is obtained by only activating the central catheter. If the sum of the squares of the dwell times is minimized, the central catheter is switched off. Dwell positions 1-13 in each catheter; step length 0.5 cm; reference air kerma rate 4.0682 cGy h-1 m2, i.e., 10 Ci iridium-192. •: Active source dwell position; O: Inactive source dwell position; •: Dose points, midway between catheters along 6 cm active length.

dose in the volumes midway between the catheters should be as homogeneous as possible throughout the implant. Rule 2. The shape of the isodose surface close to the applicator or catheters should be smooth and resemble as closely as possible the shape of the isodose surfaces at distances further from the catheter. Rule 3. Active dwell positions should not extend outside the target volume. Rule 4. Optimization algorithms should be fast enough to keep the time between the application and treatment to a minimum. The first rule of optimization addresses the optimization goals of a distance and a volume implant. The second rule aims at the minimization of hot or cold spots in the implant, especially close to the active dwell positions. The third rule requires the active dwell positions to remain within the target volume, because extending beyond this boundary would increase dose to healthy tissue. To satisfy this rule, the most distal dwell positions must be increasingly weighted to account for the lack of contributions of dose from adjacent dwell positions. The fourth rule minimizes the hardship to the patient by keeping the time that the catheters or applicators remain in the patient to a minimum.

5.53 Optimization of distance implants by least square minimization The aim in optimization of a distance implant is to have the prescription isodose surface pass at a given distance from the dwell positions along the catheter(s). To accomplish this, dose points are placed at this distance from the implant, relative to the successive dwell positions. To obtain the best combination of dwell positions and relative dwell times, a mathematical object function must be minimized. This consists of the difference between the actual dose calculated at each dose point and the ideal dose requested. Usually, this optimization problem is addressed by least squares minimization. In that case, if there are N dose points, each receiving a dose contribution from M sources (active dwell positions), then the following least squares function is to be minimized [16,21]:

where N is the number of dose points, Dpi is the prescribed dose to point i, and Dci is the calculated dose to point i. (See the equations representing the prescribed doses, Dpi, in Figure 5.10.)


Figure 5.10 Optimization on distance of the dwell times in a straight catheter to prescribed doses in dose points along the catheter. Dpi=prescribed dose in dose point i; Dcj = calculated dose in dose point i; Au = dose in point if mm dwell position] for tt = 1, see equation 5.10. The Chi-square function x2 is minimized by setting the derivatives 8%V8f,for each dose point i to 0 and solving the resulting set of equations.

The dose Dci to a dose point i from each source j is calculated by using equation 5.3 for a point source:

where Sj is the source strength of source j: Sj = (Sk A)j tj is the time that source j stays at distance ri,j C( r i,qi,j) combines the radial dose function and the anisotropy function:

Ai,j

is the dose contribution in point i from dwell position j for tj = 1.

In the case of a stepping source implant, the source strength Sj for all j sources is the same. Thus, the only variable that can be altered to minimize equation 5.9 is the dwell time tj at each dwell position j. x2 can be minimized by setting its derivative to each tj toO:

In this way, M equations are obtained which are linear in their M unknown tjs. There are a number of mathematical procedures available to solve these equations. This results in a set of values for the tp. A problem arises when there are fewer dose points than dwell positions. Then, the set of equations is underdetermined and many mathematical solutions exist. To arrive at a unique solution, an additional criterion must be supplied. Intuitively, a suitable criterion would be to minimize the sum of the squares of the relative dwell times,

thus

suppressing wildly varying values. The method of singular value decomposition (SVD) contains this additional criterion [24]. The SVD method minimizes the least square differences between prescribed and calculated dose in the dose points. If there are fewer dose points than relative dwell times (i.e., fewer equations than variables), SVD also minimizes the sum of the squares of the relative dwell times in order to arrive at a unique solution. DWELL TIME GRADIENT

When a set of equations linear in tj is solved, negative relative dwell times may result. For example, in Figure 5.11 (a), an endobronchial application is simulated by a single catheter with 25 dwell positions. It is optimized using 25 corresponding dose points at a lateral distance of 1 cm from each dwell position. The solution which gives exactly the prescribed dose to the dose points results in large positive and negative values for the relative dwell times in adjacent dwell positions. This is unacceptable because large fluctuations will cause hot and cold spots (a violation of the second rule of optimization) and negative relative dwell times are a physical impossibility. An unacceptable solution to this problem is to set all negative relative dwell times to zero. In doing so, the calculated dose in the dose points changes considerably, which will offset the requirement of an equal dose to each dose point. A solution to prevent these negative and strongly fluctuating relative dwell times was developed by Van der Laarse et al. [16,19-21]. By gradually suppressing large fluctuations of dwell times in adjacent dwell positions, the negative relative dwell times must eventually all become positive, because in the limit situation where all dwell times are equal, they are positive (Figure 5.1 Ib). To


dwell time gradient restriction is applied to equation 5.9 as follows:

where w is the weighting factor for the dwell time gradient restriction. This expression remains linear in tj so x2 can be minimized as given by equation 5.11. By increasing the weighting factor, w, the dwell time gradient in adjacent dwell positions is reduced. This, in turn, reduces the likelihood and magnitude of negative relative dwell times (Figure 5.lib). The minimum value for the weighting factor is the one that makes all values of the relative dwell times positive or zero. As previously stated, the concept of the dwell time gradient is based on the second rule of optimization, which requires that the isodose surfaces remain as close in shape as possible as they get closer to the catheters. Thus, by requiring a smooth transition of relative dwell times along the catheters, smooth isodose surfaces will be obtained with a minimum of hot and cold spots close to the catheters. POLYNOMIAL OPTIMIZATION

Figure 5.11 The influence of the dwell time gradient restriction on the dwell times of a straight catheter implant optimized on distance. By restricting the difference between the dwell times of adjacent dwell positions, an optimized solution with positive or zero dwell times is obtained, (a) Optimized relative dwell times where there is no dwell time gradient restriction (DTGR) imposed on dwell times of adjacent dwell positions. The maximum

Optimization of a distance implant by setting the derivatives of x2 to each tj to 0 results in M equations with M unknown tp. Thus, in an M x M coefficient matrix, with M being the number of active dwell positions, large implants may exceed the available memory of the planning computer. For example, an implant with 500 active dwell positions requires the planning computer to solve 500 equations with 500 unknown tjs. Also, the computation times may become unacceptably long. The dwell time gradient also offers a solution to this problem. Because the differences between successive relative dwell times are smoothed, the relative dwell times in a given catheter can be approximated by a continuous function t(x) with x the distance to the catheter tip [16]. Thus, the relative dwell time at dwell position j with a distance xj from the tip, is given by tj = t(xj). For t(x), a set of polynomial functions, Pm(x), to the order m can be taken, similar to describing a continuous curve by a Fourier series expansion to a given order. Thus:

difference of successive dwell times is nearly 2, the limit value. (b) Optimized relative dwell times with a small DTGR of 0.01. The maximum difference of successive dwell times is reduced to 1.2. (c) Optimized relative dwell times with a DTGR of 0.18. The maximum difference of successive dwell times is 0.4. All dwell times are positive or zero, so this represents the best possible fit of an isodose line through the dose points.

implement this limitation of the variance of relative dwell times between adjacent dwell positions, the socalled dwell time gradient restriction was developed. The

where m is the index, indicating the order of the polynomial Pm(x), am is the mth parameter, Pm(x) is the polynomial of order m, and p is the number of parameters required for an adequate approximation of tj by t(xj at all dwell positions x}. By inserting equation 5.13 into equation 5.12, x2 is now expressed as a function of the p parameters am instead of the M relative dwell times tj. Minimizing of x2 is again obtained by setting the derivatives dx2 da m to 0. This leads to a p x p coefficient matrix instead of the M x M one when the derivatives of x2 to tj are taken.


Figure 5.12 Relative dwell times as in Figure 5.Tib, with just sufficient dwell time gradient restriction but now parameterized in terms of distance along the catheter. t(x) is approximated by polynomials P(x) to the degree m with m<M.

Take as an example a catheter with 33 active dwell positions (Figure 5.12). The value of p will be much smaller than 25 because, due to the dwell time gradient, the dwell times are interrelated. A suitable value of p is given by p = 2 m - 1. Thus, the set of 25 tjs can be described by nine parameters, am. This reduces the memory requirements by a factor of 8, from 25 x 25 to 9 x 9.

5.5.4 Optimization of distance implants by linear programming Linear programming, as applied to stepping source brachytherapy, solves the problem of minimizing a function linear in the dwell times, subject to a finite number of constraints. These constraints are again linear in the dwell times. The problem is formulated mathematically as follows [25]:

mized to the shortest overall time possible, with positive or zero dwell times and with the doses in the dose points at least equal to the prescription dose [26]. A disadvantage of this technique is that the dose distribution is solely defined by these dose points, with no regard to the dose distribution close to the catheters. This may conflict with rule 2 of optimization, which states that isodose surfaces near the catheters should be smooth and resemble as closely as possible the shape of the isodose surface through the dose points. Thus, implants optimized by equation 5.14 often show the occurrence of hot and cold spots at distances close to the catheters. Of course, this is not a problem when optimizing a vaginal cylinder application, where the dose inhomogeneities are within the plastic of the applicator. However, for an endobronchial implant, these volumes with high and low doses are within the target volume. Note. The concept of minimum dose points on circles with a given radius around the dwell positions can also be applied using least squares optimization. First, evenly spaced dose points are constructed on the circle around each dwell position, perpendicular to the catheter. The radius of the circle is the distance to the prescribed dose. Then, all relative dwell times of the active dwell positions are set to unity and the doses in these dose points are calculated. Finally, for each circle around an active dwell position, the point with the minimum dose is found and stored. These points with minimum dose will always lie in the area of lowest dose, even after optimization. They define the surface of the treatment volume. The points with minimum dose are now taken as dose points for the polynomial optimization technique, previously described. This technique has the advantage of minimizing the effort of placing the dose points, like in the linear programming approach, but overcomes the problem of irregular isodose surfaces close to the catheter by applying the dwell time gradient restriction.

5.5.5 Optimization of distance implants by simulated annealing In the case of a distance implant, one can construct circles with a given radius around each dwell position which are perpendicular to the catheter. The radius of the circles is the distance to the prescribed dose. Dose points are placed on the circles at equal angle intervals, e.g., every 15°. The calculated dose, Dci, in each dose point i is required to be at least equal to the stated prescription dose Drep thus Dci > Dref. Using equation 5.10, this translates in equation 5.14 to ay= C(r i,j qi,j) and b = Dref, again M being the number of dwell positions and N the number of dose points. If as object function M

is minimized, taking cj = 1, the treatment is opti-

Another optimization technique suitable for brachytherapy treatment planning is simulated annealing. This technique solves the optimization problem in a stochastical way, using a directed random search for the dwell times to seek the lowest value for an object function such as defined in equation 5.14 [27]. Simulated annealing proceeds iteratively as follows: 1. An initial solution (set of dwell times and/or source positions) is chosen and evaluated using the objective function. 2. A new solution is constructed from the current one by varying the dwell times in a random direction and by an amount which is initially large but decreases sufficiently slowly so that a global minimum can be found. If the new solution is


better, it replaces the current one. If it is worse, it is accepted with a probability that depends on the difference from the current one and on the size of the change in dwell times. 3. The process iterates with the amount of change in dwell times being reduced sufficiently slowly such that the system can search out the region in solution space containing the global optimum and converge to it. This method has been applied by Sloboda [28,29] for planning low dose-rate treatments with trains of active and non-active pellets in the catheters. In this case, a step is performed by switching an active position to an inactive one, or the reverse. An evaluation of different implementations of simulated annealing in brachytherapy is given by Wehrmann et al. [30].

5.5.6

Optimization of volume implants

A volume implant is any implant with two or more planes. Polynomial optimization of a volume implant aims to make the dose in the volumes midway between the catheters as homogeneous as possible. This optimization cannot be based on dose points alone. If dose points are placed only outside a volume implant, the inner part of the target volume will be underdosed because the outer dwell positions will be used mainly to deliver the required dose to these dose points. This is due to the inverse square dependency of the dose on the distance and to the minimization of the overall time by the optimization procedure. It is explained in a similar way: that the periphery will be underdosed if points were placed midway between the catheters. Of course, it is possible to place dose points inside the implant and around it at a given distance. However, except for very regular implants, it is not possible to determine the relation between the doses in the inner points and in the outer ones. It is obvious, therefore, that in optimization

of volume implants additional constraints are required. These are provided by applying polynomial optimization with constraints obtained by geometric optimization. GEOMETRIC OPTIMIZATION ON AMERICAN VOLUME IMPLANTS Geometric optimization is an alternative approach to optimization on dose points. It is based solely on the dwell positions on the assumption that they represent the target volume. Originally, it was applied only to those stepping source implants for which the spacing between the dwell positions (the intracatheter spacing) is about equal to the spacing between the catheters (the intercatheter spacing), typically 1-1.5 cm [16,23]. This type of implant is performed mainly in the USA. It results in an equidistant, three-dimensional grid of dwell positions in the target volume (Figure 5.13). The basic assumption underlying geometric optimization is that the dwell time in a dwell position is inversely related to the dose given in that position by the other dwell positions [23]. Take, for example, a dwell position at the border of the target volume. It requires a larger dwell time than a dwell position in the center, because it is further away from the other dwell positions which all contribute according to the inverse square of their distance (Figure 5.13). Geometric optimization in treatment planning software is based on the following two suppositions: (1) the dwell time at a dwell position is inversely proportional to the dose delivered by the other dwell positions; and (2) the dose given by another dwell position is inversely proportional to the square of its distance. So the influence of source geometry and tissue scatter is disregarded, i.e., the factor C(ri,j, qi,j) in equation 5.10 is assumed to be constant. Thus, the dose in a given dwell position i is inversely proportional to the sum of the inverse square of the distances from that point to all

Figure 5.13 Geometric optimization (GO) of a two-plane American-type implant with six catheters. Separation between the sources in the catheters is about equal to the distance between the catheters. Calculation is midway between the planes, (a) No optimization. Note the hot spot where the catheters converge, (b) Geometric optimization.


other dwell positions j. So the relative dwell time tt at position i becomes

(I)

with ri,j the distance between dwell positions i and j, and M the number of dwell positions. Note the following: Figure 5.14 Geometric optimization on distance. The relative

1. Using the inverse square of distances as doses in equation 5.15 is a simplification, but acceptable for iridium-192 or cobalt-60 sources. Of course, the sum of the actual dose contributions from the other dwell positions can also be used. 2. The optimized dwell time in a given dwell position is mainly determined by the dose contribution from its nearest neighbors. 3. Only relative dwell times are determined and one or more dose points are still required to define the prescription dose. An obvious advantage of this technique is its simplicity. However, this algorithm relies on good geometry of the implant itself and on the intracatheter spacing being about equal to the intercatheter spacing. When catheters converge, the algorithm tends to overcompensate by reducing the dwell times too much. Therefore, the contribution from any dwell position at a distance less than a given threshold distance is ignored. On the other hand, when the intercatheter distance is larger than the intracatheter one, the intracatheter distances dominate the dwell time calculation and the separation between the catheters is insufficiently taken into account. GEOMETRIC OPTIMIZATION ON EUROPEAN DISTANCE IMPLANTS Interstitial brachytherapy in Europe is based on continuous wires of iridium-192, usually with interwire spacing of 1.5-2 cm [3,4]. In stepping source dosimetry, these continuous wires are replaced by a source stepping in the catheters with a step length of 2.5 mm or 5 mm. Thus, in a European-type implant with intracatheter spacing of 5 mm, the intercatheter spacing is two to four times larger. If geometric optimization is used as described above, then the nearest dwell positions are always located in the same catheter unless another catheter approaches within the step length. Because the optimized dwell time in a given dwell position is mainly determined by the dose contributions from its nearest neighbors, this results in a cylindrical dose distribution around each catheter, similar to the ones obtained with polynomial optimization on distance with dose points placed laterally at 1 cm. So the geometric optimization procedure as performed on a USA volume implant results in optimizing on distance on a European implant. When applied on European-type implants, this technique is called geometric optimization on distance (Figure 5.14).

dwell time = 1/dosefrom all other dwell positions. (1) High dose contribution from both catheters. (2) High dose contribution, mainly from both neighboring dwell positions. (3) Low dose contribution, mainly from left neighbors. Thus, t1= t2 < t3. Geometric optimization on volume. The relative dwell time = 1/dosefrom dwell positions in other catheters. Dose contributions by other catheter (1) - high, (2) = medium, (3) low. Thus, t1< t2 < t3.

GEOMETRIC OPTIMIZATION ON EUROPEAN VOLUME IMPLANTS To optimize a European-type volume implant, a variation called geometric optimization on volume was developed [21]. This variation uses in equation 5.15 only the distances between the dwell position i in the current catheter k and all dwell positions j in the other catheters. If a given dwell position in a catheter is at a large distance from the ones in the other catheters, the dose contribution will be small, resulting in a large dwell time. This will substantially increase the dose in the volume between the dwell position and the other catheters (Figure 5.14). The consequences of geometrical optimization in pulsed dose-rate brachytherapy on European volume and distance implants are discussed in detail by Berns et al. [22] Although geometric optimization on volume does not require dose points, they are still required for the definition of the prescription dose. For a regular volume implant, the best position for the dose points is in the central transversal plane midway between the catheters. The prescription dose is then based on a given percentage of the mean dose in these dose points. A percentage of 90 is required for a distance of about 3 mm between the outer catheters and the prescription isodose line in the central transversal plane. A more detailed discussion about the prescription dose of an optimized implant is given in section 5.7.6. Geometric optimization alone of a European volume implant does not always suffice (Figure 5.15). It is not strong enough to keep all dwell positions inside the target volume. At the outer ends of the catheters, active dwell positions are needed on or even outside the target surface. In the next section, a combination of geometric and polynomial optimization is presented where all active dwell positions are located inside the target volume.


Figure 5.15 Intraluminal implant, optimized on distance, (a) Polynomial distance optimization on dose points placed at 1 cm distance in region of minimum dose, away from the other catheter. Note that the WOO cGy prescription isodose runs through all dose points, (b) Geometric optimization on distance of a European-type implant. The 1000 cGy prescription isodose is taken as the mean of the dose values in the dose points. Note that the geometric optimization undercorrects when catheters coincide.

POLYNOMIAL OPTIMIZATION ON VOLUME As previously stated, European volume implants cannot successfully be optimized based on dose points midway between the catheters alone. However, if an additional constraint, supplied by geometric optimization on European volume implants, is added to the least squares function x2 in equation 5.12, optimization on volume is achieved [21]. This two-step process is called polynomial optimization on volume. In the first step, the geometric optimization on volume is used to obtain the total relative dwell time for each catheter. The additional constraint now requires that the total relative dwell time for each catheter remains equal to the one obtained by geometric optimization. Thus, the total dwell time in each catheter, determined by geometric optimization, is redistributed by polynomial optimization in such a way that the dose points midway between the catheters all receive the same dose. Polynomial optimization on volume is an essential part of the Stepping Source Dosimetry System, which is presented in the next section.

5.6 THE STEPPING SOURCE DOSIMETRY SYSTEM Before the use of computers in brachytherapy, the Paris Dosimetry System was developed as a low dose-rate dosimetry system using afterloading of iridium-192 wires with equal linear activity into thin flexible catheters or rigid needles [3,4]. For a given target volume, the Paris System gives rules on how to implant a

target volume V = L x W x T a s a function of L, W, and T, with L the length, Wthe width, and T the thickness of the target volume. The active lengths extend outside the target to correct for the bending of the prescription isodose surface in between the catheter ends. This is because the Paris System applies wires of constant linear activity and does not place a crossing catheter at the end of the implant, as is done, for instance, in the Manchester System with a needle implant. As already described, the high dose-rate treatment of volume implants is performed with a source stepping through a set of catheters or needles. Thus, the Paris Dosimetry System can easily be adapted to high dose rate by applying equidistant dwell positions with equal dwell times. If, however, the dwell times at the longitudinal ends of the catheters are increased by polynomial optimization on volume, the active dwell positions, even at the longitudinal ends, are kept inside the target volume. This adaptation of the Paris System is called the Stepping Source Dosimetry System (SSDS) [16,31]. The SSDS uses the same rules for implantation as the Paris Dosimetry System, except that the active lengths in the catheters remain within the target surface, even at the longitudinal ends. Dose points are placed midway between the catheters over the whole length of the implant. When an implant is very regular, for example when templates are used to maintain the prescribed distances between the catheters, the first and the last dose point of each row midway between the catheters should be discarded. The SSDS applies polynomial optimization on volume to obtain the same dose in these dose points. Originally, the SSDS defined the prescription dose as 85% of the mean dose in these dose points [16,31]. As

Dose-volume histograms 65

discussed in section 5.7.6, where non-optimized and optimized implants are compared, the prescription dose is best defined as 90% of the mean dose in the dose points.

5.6.1 Summary of the Stepping Source Dosimetry System

A comparison of an isodose distribution for a breast implant using the Paris System and the SSDS is shown in Figure 5.16. The optimized dose distribution shows a more homogeneous dose distribution inside the target volume and an appreciable dose reduction outside it. A more graphical and quantitative approach for the evaluation of a dose distribution is given by its differential or natural volume dose histogram, presented next.

The following parameters are used in the SSDS: L T S M

= = = =

length of the target volume thickness of the target volume spacing between the catheters the safety margin around an implant: it is the distance between the prescription isodose and the active lengths in the outer catheters in the central transversal plane AL = active length in a catheter: it is the distance between the first and the last active dwell position inside the target volume. The SSDS implantation rules are as follows. • For a short target volume, L < 5 cm, the catheter spacing S varies between 8 mm and 15 mm; for a long volume, L > 5 cm, S varies between 15 cm and 22 cm. • For a target thickness T < 12 mm, single-plane implants are applied, with the catheter spacing S T/0.6, which gives M 0.35 S. • For a target thickness T > 12 mm, double-plane implants are used. A double-plane implant with a catheter pattern in triangles must conform to S 271.3. The safety margin Mbecomes M 0.2 S. For a double-plane implant with a catheter pattern in squares, S 271.6 and M 0.3 S. • The active dwell positions at the longitudinal ends of the catheters are placed inside the target volume using the safety margin as given above, AL = L — 2M. • The dwell position spacing is 5 mm. • The dwell times are obtained by polynomial optimization on volume, using dose points midway between the catheters along their whole active lengths. The first and the last dose point of each row midway between the catheters are usually discarded. • The prescription dose is defined as 90% of the mean dose in these dose points. As they are all optimized to the same value, this definition is equivalent to 90% of the mean basal dose points in the central transversal plane. The above rules are guidelines on how to implant a given target volume. The resulting dose distribution must be evaluated by assessing the isodose lines in several transversal and longitudinal planes. In order for the prescription isodose surface to encompass the target volume as closely as possible, dwell positions may have to be activated or deactivated and dose points to be added or removed, both near the longitudinal ends of the catheters.

5.7

DOSE-VOLUME HISTOGRAMS

Dose-volume histograms (DVHs) play an important role in evaluating the dose distribution in and around an implant [32,35,36]. A DVH of a dose distribution is represented as a graph with a series of dose intervals on its horizontal axis, and, on the vertical axis, for each dose interval, a volume related to that dose interval. Such a dose interval in a histogram is called a bin. For example, if 1000 bins are taken for a dose range of 500-2500 cGy, the first bin, DD1 will be 499-501 cGy, the second bin, DD2, will be 501-503 cGy, etc., with the bin width AD being 2 cGy. A differential DVH is a graph with dose intervals ADj on the horizontal axis and on the vertical axis, for each dose interval DDi the ratio AV/AD with DVi the volume receiving a dose between Di - 0.5 AD and Di + 0.5 AD. In a clinically useful histogram, AD is much smaller than Di. Then the volume with a dose between Di and Dj is given by the area under the histogram between Di and Dj If a volume implant is optimized to the same dose midway between the catheters, all the volumes midway between the catheters will obtain that dose and the differential DVH will show a sharp peak for that dose. Based on this behavior, a differential DVH can be used to assess the homogeneity of the dose distribution of a volume implant. A cumulative DVH has the same horizontal axis of dose intervals Di;, with bin width AD, as the differential DVH. On the vertical axis, however, is given the volume receiving at least the dose Di - 0.5 AD for each DDi. In a clinically useful histogram with AD much smaller than Di, the histogram presents for each Di the volume encompassed by the isodose surface(s) of that dose. Thus, the cumulative DVH of the target volume can be used to determine those parts of the target volume that are either underdosed or overdosed. In a clinical case, the dose distribution around an implant is so complex that a DVH can only be determined numerically, thus a discretization of the threedimensional dose distribution in and around the implant must take place. It is common practice to construct a grid of equidistant dose points inside a rectangular box, placed around the implant with a given margin. A sufficient number of grid points is placed inside the box and the dose in each one of them is


Figure 5.16 Two-plane breast implant with seven catheters. The length of the target volume is 8 cm. The active length, i.e., distance between first and last dwell position, is 10cm for Paris System implant, and 7 cm for SSDS implant. Step size is 5 mm. The 500 cGy lines are the prescription isodose lines determined according to the rules of the Paris System and the SSDS System, respectively, (a) Dose distribution in the central transversal plane. The solid HneZ=0 indicates the central longitudinal plane, midway between the two planes, (b) Dose distribution in the central longitudinal plane. The solid line indicates the central transversal plane, (c) Comparison of the dose distributions in three longitudinal planes of the Paris-type and the SSDS implant. PlaneZ=0is the central longitudinal plane; plane Z=-8 is the plane through needles 4, 5, 6, and 7; plane Z=+8 is the plane through needles 1,2, and 3. The upper part of each dose distribution is given by the SSDS implant, the lower part by the Paris implant.


voxels ni with a dose value between Di — 0.5 AD and Di + 0.5 AD, multiplied by the voxel volume v; thus DVi = n- v. A cumulative DVH gives for a given dose interval (Di — 0.5 AD, Di + 0.5 AD) the corresponding volume Vi, defined as the sum over all voxels with a dose equal to or exceeding Di - 0.5 AD, thus Vi = When a three-dimensional equidistant grid of points over the implant is used, a large number of grid points, between 50 000 and 200000, is needed for an accurate DVH. This is due to the application of an equidistant grid over the regular geometry of the implanted catheters, which leads to a large redundancy of grid points. It can be proven statistically that a more efficient grid over a set of regularly implanted catheters is a grid where the x, y and z coordinates of each point are determined randomly [16,33]. The voxel size is then equal to the volume of the rectangular box around the implant, divided by the number of grid points inside the box. The number of randomly placed grid points needed for an accurate DVH lies between 10 000 and 50 000. The target volume is defined by the tumor and the margin around it. The minimum peripheral dose (MPD), is defined as the dose of the isodose surface that just encompasses the target volume, thus the highest dose still encompasses the target volume. The treatment volume is defined by the prescription isodose surface which is selected by the radiation oncologist when viewing the dose distribution. The prescription dose (PD) is the dose prescribed to the prescription isodose surface. If CT or MRI images with the contours of the target volume are not available, the target volume is considered to coincide with the treatment volume and the MPD is taken to be equal to the PD.

5.7.1 Differential dose-volume histogram of a single point source

Figure 5.16 cont.

calculated. Each grid point is the center of a cubical volume element, a voxel. The whole voxel is considered to receive the same dose as the grid point. When a threedimensional equidistant grid with spacing s is applied, the voxels are cubes with edge s, which are centered around the grid points. More explicitly, a differential DVH gives, for a given dose interval (Di - 0.5DD,Di+ 0.5 DD), the corresponding ratio DV/DD, with DVi the volume with a dose value in that interval. DVi is obtained from the number of

Understanding of the properties of a DVH of a single point source is essential for the evaluation of implants with more sources. If a point source is ideal, i.e., tissue scatter and absorption can be ignored, then D = S/r 2 , with D the dose at distance r from the source. The values of the differential DVH for an ideal point source can be calculated directly [16], because the isodose surfaces are spheres with the source as center, of which the volumes are easily calculated by V= (4/3) p r3. For an ideal point source with D = S/r2, Vcan be written as a function of D:

The numerical and analytical value of (DV/DD) for D = 1000 cGy will be calculated for an ideal point source with S = 1000 cGy cm2. The numerical calculation requires the distance r at which D = 1000 cGy: r = s/D = 1 cm. The value of (AWAD) for D = 1000 cGy is found by calculating D and V for r equal to 0.99 cm and 1.01 cm. For


r = 0.99 cm, D099 = 1000/0.992 = 1020 cGy and V099 = (4/3) n 0.993 = (4/3) p 0.997 cm3. For r = 1.01 cm, D101 = 1000/1.012 = 980 cGy and V,01 = (4/3) p 1.013 = (4/3) p 1.03 cm3. Thus, DD = D1.01 - D099 = -40.0 cGy and DV = Voi -V0.99= 0.08 p cm3 This results in (DV/DD) = -0.002 p = -0.0063 cm3 cGy-1 for D = 1000 cGy. Analytically, the differential DVH for an ideal point source with D = S/r2 is given by, using equation 5.16: For S = 1000 cGy cm2 and D = 1000 cGy, dWdD = -2p 10003/2 1000'5/2 = -0.0063 cm3 cGy-1. See reference 16 for more details. A differential DVH of an iridium-192 point source is given in Figure 5.17. As in the above example, the dose at 1 cm given by this source is 1000 cGy. At such a short distance, the tissue scatter and absorption factor is near unity. From the dependence of dWdD on 1/D5/2, it is clear that, as the dose decreases, dV/dD increases more than quadratically.

5.7.2 Differential dose-volume histogram of multiple point sources A differential DVH of a volume implant behaves as a single point source for very low doses and for very high doses. This is illustrated in the case of an implant consisting of N identical point sources each with strength S (Figure 5.18). Points far away from the implant receive

very low doses from the sources, and essentially respond to all sources as a single source with strength N S. Correspondingly, for these distant points the histogram is dWdD = -2 7p(NSY3/2 D 5/2 . For points of very high doses, thus very near to a source, only the dose contribution of that source will be seen, due to the inverse square dependence of the dose on distance. Now the histogram shows the behavior of N times that of a single source: dV/dD = - 2 p N S3/2 D-5/2, which equals, of course, the DVH of a single point source with strength N2/3 S. For a large number of sources, this strength is much smaller than that at a large distance from the implant (Figure 5.18). Consequently, the influence on the dose distribution of the catheter placement and the dwell time optimization is reflected most strongly in the middle section of the differential DVH, which lies between about 75% and 200% of the PD which encompasses the target volume. Visual evaluation of this influence is difficult because of the underlying inverse square law influence. In Figures 5.18 and 5.19, the differential DVH of a point source located in the center of the implant is also given. The difference between the point source curve and the implant curve indicates how much better the implant is compared with a single source. The strength of this point source is defined such that the dose value of the spherical isodose surface that just fits inside the rectangular grid box equals that of the similarly fitting isodose surface given by the implant. The margin of the grid box around the implant is 1 cm. To determine the dose value of that spherical isodose surface, the maximum dose occurring on the

Figure 5.17 Differential dose-volume histogram of an iridium-192 point source which delivers WOO cGy at 7 cm in tissue. The influence of tissue scattering and absorption is hardly visible, as is indicated by the histogram value for D = 300 cGy and the theoretical value, using dV/dD = -2p S3/2 D- 5/2 for an ideal point source. A shaded area between two dose values represents the volume between the corresponding three-dimensional isodose surfaces. For a discussion of the three shaded areas of equal size, representing three equal volumes, see 'Natural dose-volume histogram,' p.69.


Figure 5.18 Differential dosevolume histogram of the twoplane breast implant of Figure 5.16, according to the Paris Dosimetry System. The lower peak is related to the volumes between the outer catheters, the higher peak to the volumes between the inner catheters. The underlying curve is the histogram of the point source in the center of the rectangular box around the implant. The strength of the point source is such that the same maximum dose on the grid surface is obtained as given by the implant. Note that the peak of this histogram is not well defined and the location of the 85% peak dose value D85 is not at the base of the peak.

rectangular box surface must be found. From that maximum dose value on the box surface, the source strength of the point source in the center of the box is calculated. This explains why both curves in Figures 5.18 and in 5.19 start with the same dV/dD value for the minimum dose of 40.0 cGy. Figures 5.18 and 5.19 present various dose values around the peak dose D100 to judge the implant. D100 is defined as the largest difference between the dose histogram of the implant and that of the ideal point source. So D100 is the dose under the peak after correction for the slope by the ideal point source. D85, D95, D105, and D115 are dose values of 85%, 95%, 105%, and 115% of D100. Note that D100 is located in the center of the implant and that the dose range where the implant differs from the point source extends only about 15% from the peak dose D100. D85 is usually taken as the PD for an implant which is not optimized. Figure 5.19 indicates that, for an optimized implant, the implant histogram value for DS5 already approaches the point source histogram. As discussed in section 5.7.6, the PD for an optimized implant should be taken as 90% of the peak dose D100. It is possible to evaluate an implant by its differential DVH. In addition, figures of merit based upon DVHs

have been developed [39]. However, to evaluate an implant implies evaluating the differences between the histogram of the implant and that of the corresponding point source in its center (see Figures 5.18 and 5.19). To address this problem, Anderson [34] in 1986 developed the concept of the natural DVH and derived the Uniformity Index (UI) as a figure of merit of the implant. Based on the natural DVH, a new figure of merit was defined, the Quality Index (QI) [22,35,36].

5*73

Natural dose-volume histogram

Because the inverse square law has such a detrimental effect on interpretations of the differential DVH, Anderson [34] introduced a new dose unit, u, for the horizontal axis: u(D) = D-3/2. Now, for an ideal point source, using equation 5.17 and dV/dw = (dV/dD)/ (dD/dw), it follows:

which is independent of dose D, thus the natural histogram of a point source is a horizontal line (see Figure

70 Computers in brachytherapy dosimetry Figure 5.19 Differential dosevolume histogram of the twoplane breast implant of Figure 5.16, optimized according to SSDS. The single high peak is caused by the optimization to the same dose of all volumes midway between the catheters. The underlying curve is again the histogram of the point source in the center of the rectangular box around the implant (see Figure 5.18). Note that the 85% peak dose value D85 is not located at the base of the peak and therefore is unsuitable as prescription dose.

5.20). Note that the horizontal axis is linear in u, thus linear in D-3/2. Also, that for increasing dose, u decreases. Thus, when expressed in dose D, the low dose section of this axis is expanded and the high dose section is compressed. The area under the curve between Dl and D2 is proportional to the volume between the Dl isodose surface and the D2 isodose surface. Note the difference in appearance of three equally sized volumes in the differential DVH of Figure 5.17 and the natural DVH of Figure 5.20. The natural DVHs of the unoptimized and optimized two-plane breast implants discussed in section 5.6 are given in Figures 5.21 and 5.22. The peak of the histogram represents the volumes, midway between the catheters, that receive an approximately uniform dose. The narrower the peak, the more uniform the doses in the volumes between the catheters. The narrowest peak is obtained by an equidistant three-dimensional grid of dwell positions over the target volume with the dwell times optimized to the same dose in dose points between the dwell positions. The broader the peak, the less desirable the implant, until finally a horizontal line remains which represents a single point source in the center of

Figure 5.20 Natural dose-volume histogram of an iridium-192 source which delivers 1000 cGy at 1 cm in tissue. The - sign of dV/du is disregarded.

indicates the actual histogram.

indicates the theoretical value of 132.5 using equation 5.19. The three equal volumes of Figure 5.17 now show up as areas with equal base, indicating the compression of the dose axis for high dose values and the expansion for low dose values.


Figure 5.21 Natural dose-volume histogram of the two-plane breast implant of Figure 5.16, according to the Paris Dosimetry System. (See legend of Figure 5.18 for explanation of the occurrence of two peaks.) Line (3) represents the theoretical limit, (4/3) p (nS)3/2 of dV/du at a large distance from the implant, with n the number of dwell positions and S = D(r) r2 the source strength of the ideal point source. Line (2) lies midway between lines (1) and (3) and defines the so-called 'low dose.' Line (5) represents the theoretical limit (4/3) p p S3/2 of dV/du for very high dose values. Line (4) lies midway between line (1) and (5) and defines the so-called 'high dose.' The prescription dose (PD) is defined as 85% of the mean dose in the basal dose points. See p. 72 for explanation of the Uniformity Index and the Quality Index.

Figure 5.22 Natural dose-volume histogram of the two-plane breast implant of Figure 5.16, optimized according to the SSDS System. The prescription dose (PD) is defined as 90% of the mean dose in the basal dose points, i.e., 90% of the peak dose value. Note the relatively small change in the Uniformity Index compared to the unoptimized case (Paris System) in Figure 5.21 (2.26 versus 1.98). The horizontal tails at the left side (very low dose values) and the right side (very high dose values) are explained on p. 71. The prescription dose coincides with the natural prescription dose (NPD), which lies at the base of the peak at the LD side (see p. 74).

the target volume. It should be noted that only volume implants will show a peak in their natural histogram. As discussed in the section 'Differential DVHs of multiple point sources', the histogram behaves for very low

doses as if a single point source exists, and the natural DVH will thus display a horizontal line for these values. Also, for very high doses, the histogram behaves as if a point source, although with much less strength, exists


(Figure 5.22). Because of the strong contraction of the w-axis for high doses, the horizontal line at the high dose end is sometimes hardly visible and appears as if it runs straight down to this high dose limit value of dV/du (Figure 5.21). Anderson derived the Uniformity Index by taking the ratio of the volume under the peak, normalized to the w-scale, and the volume encompassed by the isodose surface of the target dose, again normalized to the w-scale. A related Figure of Merit is the Quality Index, which is independent of the target dose [22,35,36]. The quantities PD, LD, and HD are used in these indices. PD refers to the target dose prescribed by the radiation oncologist. Usually, it belongs to the isodose surface which encompasses the target volume with a margin of about 3-5 mm. LD refers to the dose value at the half height of the peak in the low dose region. This half height is measured from the limit value of the histogram for dose values approaching 0. HD refers to the dose value at the half height of the peak in the high dose region. This half height is measured from the limit value of the histograms for doses approaching infinity. UNIFORMITY INDEX The Uniformity Index is a quantitative index to assess how well the dose distribution covers the target volume. It is defined as the volume between the dose values of PD and HD, normalized to the w-interval between PD and HD, divided by the volume encompassed by PD, normalized to the w-interval between PD and infinity dose. Thus, the Uniformity Index is:

with V(PD) the volume encompassed by the prescription isodose surface, V(HD) the volume encompassed by the high dose isodose surface, w(PD) the w-value corresponding to the prescription dose, and w(HD) the w-value corresponding to the HD value. By substituting u = D-3/2 and using u( ) = 0, we get

The first term of the UI is the volume under the peak extended to the target dose, divided by the width of the peak extended to the target dose. The narrower the peak, the larger the first term will be. The effect of the second term is the opposite. For a single point source, there is no peak and the UI = 1. As already mentioned, the UI is dependent upon the PD chosen by the radiation oncologist. It is a measure of the quality of the dose distribution within the selected target dose. If a perfectly regular implant is not covering the target volume completely and therefore a lower PD must be selected, this is reflected by a lower value of the UI.

QUALITY INDEX To compare different geometries of implantation and different dwell time optimization schemes, another Figure of Merit is needed, which is independent of the PD. For this purpose, the Quality Index is introduced [ 16,39]. In the Quality Index, LD is substituted for PD in equation 5.20. Thus:

A detailed study of the differences between UI and QI in geometrically optimized breast implants is given in reference 22.

5.7.4

Cumulative dose-volume histogram

The cumulative dose-volume histogram (CDVH) presents for each dose value the volume encompassed by the isodose surface(s) of that dose [51,52]. It is widely used to determine if a part of the target volume is underdosed or if an organ at risk is overdosed. The CDVH of the target volume shows a distinct behavior (Figure 5.23). For dose values lower than the minimum peripheral dose, the complete target volume is covered and the CDVH runs horizontal. When the dose value exceeds the minimum peripheral dose, part of the target volume is not included by the isodose surface with that dose value, so the CDVH runs steeply downward with increasing dose. For high dose values, only the small volumes directly around the sources inside the target contribute and the CDVH value decreases slowly.

5.7.5 Evaluation of dose distributions with dose-volume histograms DVHs play an important role in evaluating the following aspects of dose distributions in brachytherapy [32]. • How homogeneous is the dose distribution of a volume implant? This can be assessed independently of the actual PD, either by visual inspection or by the QI of the natural DVH. Note that it is not possible to evaluate the homogeneity of a distance implant, because of the steep gradients around the catheters. The differential and natural DVHs assess the regularity of the catheters and the optimization of the dwell times, irrespective of the coverage of the target volume by the implant. • How well is the dose distribution covering the target volume? This depends on the PD selected. It can be assessed again by visual inspection. It is obtained from the CDVH of the target volume by looking at the amount of the target volume which is underdosed by a dose less than the PD. The cumulative DVH is also used to determine the amount of volume being overdosed by, for example, a dose greater than 2 x PD.


Figure 5.23 Cumulative dose-volume histogram of the target volume of a non-optimized prostate implant. On the horizontal axis is given the dose relative to the prescription dose (PD). On the vertical axis is given the encompassed volume for each dose value, relative to the target volume V. The minimum peripheral dose (MPD) is the highest dose still encompassing the target volume. If the PD was taken to be equal to the natural prescription dose (NPD), it is evident that the implant is not covering 10% of the target volume. Additional dwell positions must be activated in the missed volume (see p. 74). The dose/non-uniformity ratio for a non-optimized implant, defined as DNR(D) = V(1.5 D)N(D), will show a minimum for the PD in this histogram as the curve slope is the steepest in the dose range PD-1.5 PD (see p. 74).

The UI of the natural DVH, which is based on the PD, scores the combination of aspects (1) and (2) only if the PD equals the minimum peripheral dose of the target. Thus, much more detailed information is obtained when the dose homogeneity is evaluated with the QI of the natural DVH and the coverage of the target volume with the CDVH. • How much volume outside the target volume receives a high dose? If CT or MRI images of an organ at risk are available, the volume which receives a dose exceeding the maximum dose allowed in that organ can be determined. Then, a grid of dose points must be placed over the organ at risk and the CDVH of that organ be determined. Similarly, the difference between the treatment volume and the target volume can be assessed by the CDVH of the treatment volume. The last two aspects are strongly related to the value of the PD. In a volume implant with an optimized dose distribution, dwell time has been moved from the center of the implant to its periphery. This results in a steeper dose gradient around an optimized implant, which influences the definition of the PD and the treated margin around the outer dwell positions.

5.7.6 Definition of the prescription dose in non-optimized and optimized volume implants A non-optimized Paris-type dose distribution displays a low dose gradient which starts from the center of the

implant. The 85% of the mean basal dose in the central transversal plane coincides more or less with the minimum peripheral isodose, i.e., the isodose surface with the highest value, which still encompasses the complete implant. In the natural DVH of the unoptimized breast implant in Figure 5.21, the prescription dose PD lies about halfway on the left side of the peak. An SSDS implant shows a much more homogeneous dose distribution inside the implant, which corresponds to the pronounced peak in the natural DVH of Figure 5.22, and a steep inverse-square-law dose gradient around it, which corresponds to the horizontal histogram curves away from the peak (see, again, Figure 5.22). The mean basal dose is practically equal to the mean dose in all dose points midway between the catheters, because these points are all optimized to the same value. Figure 5.24 shows that the isodose surface with a dose value of 90% of the mean basal dose coincides with the highest dose value still lying in the steep dose gradient area around the outer needles of an implant, and maintains a margin of a few millimeters around the implant. Therefore, the PD of an SSDS implant is taken as 90% of the mean basal dose. This PD isodose surface shows a smaller margin around the outer dwell positions, due to the steeper dose gradient around an optimized implant and the higher percentage of the basal dose (see Figure 5.24). This margin is about 3 mm, whereas the treated margin around a non-optimized implant is about 5 mm. This definition defines a PD which for an optimized implant lies at the base of the peak of the natural DVH, at the LD side. To define the PD as the dose value at the base of the


Figu re 5.24 The definition of the prescription dose for an implant, according to the Stepping Source Dosimetry System. The 90% value of the mean basal dose (BD) in the central transversal plane is the highest percentage still lying in the steep dose gradient area around the implant, thus just at the base of the peak in Figure 5.22. The treated margin around the outer sources is about 3 mm. Note that the 95% isodose line shows deep bends between the catheter intersections.

peak of the natural DVH is generally valid for all volume implants. It is the value of the isodose surface inside which the optimized dose distribution lies and outside which the inverse square law predominates. This definition of PD is called the natural prescription dose (NPD). Note that this PD is defined on the dose distribution only. The PD that covers the target volume is the minimum peripheral dose (MPD). If the NPD is equal to the MPD, the implant is well placed over the target volume and the PD can be taken as equal to the MPD. The UI now correctly scores both aspects of the dose distribution, the dose homogeneity and the target coverage. If, in the natural DVH in Figure 5.22, the PD is taken with a value lower than 90% of the mean basal dose, the PD will shift more to the left on the horizontal tail for low dose values. This implies that the PD is taken at a distance so far away from the implant that the inverse square law dominates. The UI will decrease correspondingly. Thus, according to the dose distribution, the PD should coincide with the NPD at the base of the peak in the natural DVH (Figure 5.22). According to the target volume, the PD should coincide with the MPD, the highest dose value still encompassing the target volume. If the PD does not match these two requirements, the dose distribution does not cover the target volume adequately. This matching is evaluated by the natural dose ratio (NDR), which is defined as the ratio of the NPD and the PD:

In clinical practice, the PD is often taken as equal to the MPD. If the target volume is suitably covered by the implant, the NDR has a value nearly equal to one. If the target volume is not suitably covered by the implant, cold spots in the target volume will arise, around which the MPD runs. Or, stated differently, the volume encompassed by the NPD covers the target volume only partly. Thus, an ill-covered target volume prescribed to the same MPD as a well-covered target volume will receive an overall much higher dose. This translates into values of NDR greater than one. NDR equal to 1.4 means that the base of the peak of the natural DVH starts at 1.4 PD and the whole target will receive a 40% higher dose than when treated to the same PD but with an NDR equal to 1.0. The use of NPD, MPD, and NDR is of utmost importance for implants of the prostate [61]. If the NDR is larger than 1 or, stated differently, if the required prescription dose does not lie at the base of the peak of the natural DVH, a part of the target volume is not covered by dwell positions (or by seeds, in the case of permanent implants). All transverse slices should then be inspected visually for target areas with a dose lower than the NPD, and dwell positions in these areas should be activated (or seeds be placed).

5.7.7 Other methods for evaluation of dose distributions Another assessment of implant quality, utilizing only the CDVH, is given by the dose-non-uniformity ratio (DNR) [53,54] for the homogeneity of the dose distribution and the coverage index (CI) for the target coverage [38]. The DNR ratio is a graph for each dose value of the ratio of the volume receiving a dose larger by a given fraction, say 50%, to the volume enclosed by that given dose value. Thus, for a given dose value, D:

The behavior of the DNR versus dose plot can be correlated with implant quality in the target volume. For non-optimized implants, the fraction is usually taken as 50%. In Figure 5.23, it is indicated that the minimum value for DNR(D) is defined by the 50% dose range where the volume curve has the steepest slope and thus the difference between V(D) and V(1.5 D) is maximal. The steeper the CDVH curve between D and 1.5 D, the better the dose distribution and the smaller DNR(D) will be. However, the relation between the minimum value of DNR and the MPD is defined by the shape of the CDVH, and there is also no direct relation with the NPD, as the latter is based on the implant dose distribution and not on the target volume. DNR(PD) is also known as the Dose Homogeneity Index (DHI) [37].

Three-dimensional imaging techniques 75

For optimized implants, it is better to take the fraction as 25% [55]. This is explained as follows. The differential histogram in Figure 5.19 shows that the dose range where the optimized implant differs from a single point source in the center of the target is only ±15% of the peak dose. As discussed in section 5.7.6, the PD of an optimized implant is 90% of the peak dose; thus, the dose range PD-1.25 PD just covers the volume under the peak. From this follows that the DNR value will be smaller for dose values other than 90% of the peak dose, and the plot of DNR(D) versus D will show a minimum at D equal to 90% of the peak dose. (For more details, see reference 55.) When adapting the fraction to the amount of optimization performed, the minimum value of DNR(D) will not distinguish for different types of optimization. Depending on the regularity of the implant and the type of optimization performed, the differential (and natural) DVH will show different peak widths and, as a result, different fractions are required in relation (22), ranging from 25% for a regular, fully optimized implant to 50% for a non-optimized implant. A detailed discussion is given by Low and Williamson [55], in whose article different optimization schemes were applied to different implant types but a fixed fraction of 25% was taken. The Coverage Index (CI) scores the coverage of the target volume by the PD. It is defined as:

In the CVDH of the target volume, V(target) is equal to V(MPD). If PD is based on the minimum value of the DNR(D) plot, then CI will be less than 1, about 0.9 for a non-optimized implant [55] (see Figure 5.23). Thus, also the combination of the DNR for the dose distribution inside the target volume and the CI for the target coverage are not suitable, easy to apply, evaluation tools for HDR implants. Another index, based on the CDVHs of the target and critical structures, is the Conformal Index (COIN), which scores the target coverage together with the unwanted irradiation of normal tissues and parts or all of critical structures. (See reference 38 for an extensive discussion.)

5.8 THREE-DIMENSIONAL IMAGING TECHNIQUES CT-based brachymerapy treatment planning is based on the visualization of the tumor, the target volume, the catheters, and the surrounding anatomical structures in a series of two-dimensional CT slices or in three-dimensional views reconstructed from these CT slices

[40-3,51]. Unfortunately, compared to catheter and anatomical point reconstruction from two radiographs, the localization of catheters or individual source positions using their intersections with CT slices is more difficult. The entry of anatomical structures into the planning system is achieved either by digitizing these structures from a hard copy of the CT slices on a digitizer tablet or by delineating these structures by mouse on the computer display. Usually, only the target and critical structures are entered, because the other internal structures are of no clinical significance and are not taken into account by the dose calculation routines in brachymerapy. Reconstruction of source locations from CT images poses several problems, especially if the spacing between the slices is large. When an X-ray ruler is used to reconstruct a catheter, markers may fall between the slices and a high resolution scout view is then required to indicate which marker is visible in a given slice. For that reason, X-ray rulers are often used which consist only of a single radio-opaque wire. If the tip of such a marker wire falls between two slices, the intersections of the marker wire in the first two CT slices must be used to extrapolate the marker wire over the distance between the first slice and the tip of the marker wire. The reconstruction of a looping catheter requires the differentiation in several slices between the images of the two sections of the loop. In general, in order to get the best reconstruction of a looping catheter, a small interslice distance is required, resulting in the necessity of handling a large number of CT slices. Dwell positions in these needles are calculated by the planning system, using the distance of the first dwell position from the tip and the dwell step. If the patient can be reproducibly positioned on the treatment table of both a CT scanner and a treatment simulator, the localization of the target volume and critical organs can be obtained from the CT scans and the localization of the catheters from two radiographs. The intersection of the catheters reconstructed from radiographs can be displayed in the CT slices. In this way, any change in the patient localization between the CT session and the simulator session can be visually detected and corrected interactively. This method is of interest for HDR implants of the prostate. Ultrasound imaging and three-dimensional treatment planning tools have been used for evaluation of HDR prostate implants [51]. The dosimetric quality indicators are the CI, the MPD, and the HI, which is the fraction of the target volume receiving doses in the range of 1.0-1.5 times the PD. The combination of different imaging modalities in the treatment of prostate carcinoma with HDR iridium192 afterloading is becoming common practice [46]. The flexible HDR catheters are inserted under guidance of ultrasound imaging, but the treatment planning is per-


formed on the postneedle-placement CT images. The target MPD is optimized to conform to the prostate's peripheral shape as it changes from base to apex. The urethra's dose is limited to 120% of the MPD. MRI has excellent soft tissue imaging capabilities, but the alinearities in the image prohibit direct utilization in brachytherapy treatment planning. To get around this problem, the reconstruction of prostate implant catheters can be performed with radiography and the imaging of the prostate and the implant can be done with MRI [43]. In this paper, permanent seeds are implanted, but the technique is equally valid for HDR implants with catheters with X-ray rulers inserted for radiography and MR rulers for MRI. With radiography, the seed coordinates are reconstructed in the conventional manner from a pair of isocentric radiographs. The reconstructed seed distributions are verified on the AP and lateral radiographs. With MR scanning, a flat table top is used to allow reproducible patient positioning between MR scanning and radiography. After scaling of the MR dataset to the real-size seed distribution, corresponding seeds in the data set of reconstructed seed positions and signal voids in the MR images are interactively identified. These corresponding seeds are distributed over a cranial, central, and caudal transverse slice through the prostate. A total of about ten corresponding seeds is then used for matching with the corresponding signal voids in the MR images. The resulting rotation and translation to the MR images is then applied to all reconstructed seeds. Similarly, instead of radiography, CT imaging can be used for seed reconstruction, and image fusion is used for matching the MR images with the CT ones [44]. Summarizing, three-dimensional imaging of a brachytherapy implant is a valuable tool for reconstruction of target and organs, and for assessment of the resulting dose distribution with the differential or natural DVH. The CDVHs of the target and of the critical organs show quantitatively the part of the target volume which is underdosed, and the amount of the critical organ volumes which are overdosed. CT imaging can also be used to reconstruct the localization of the catheters or even sources, but only if proper software is available. Finally, the dose distribution in transaxial planes and even arbitrary user-defined planes can be displayed together with the patient structures, interpolated between the CT slices.

5.9 THREE-DIMENSIONAL DOSE CALCULATION ALGORITHMS Three-dimensional dose algorithms which incorporate the influence of tissue inhomogeneities and metal shields on the dose distribution around brachytherapy sources are just emerging. Promising approaches are the

Monte Carlo simulation of the radiation transport equation [47-50] and the convolution algorithms which are based on a scatter dose kernel calculated by Monte Carlo simulation [59]. An analytical approach is given by Daskalov et al [60]. The Monte Carlo aided three-dimensional dose calculations have become so accurate that they function as the standard against which other algorithms are compared. For example, recent data for the dose calculation around high dose-rate and pulsed dose-rate sources according to the AAPM TG43 formalism are based on Monte Carlo calculations [9,10,11]. The convolution algorithms are suitable for dose computations in heterogeneous geometries. They are similar in approach to the pencil beam modeling of external beams, but are much more complex. Current treatment planning computers are not yet fast enough to use these algorithms for clinical treatment planning. An overview of these algorithms is given by Williamson [59]. 5.10 DOSE SUMMATION OF BRACHYTHERAPY AND EXTERNAL-BEAM DOSE DISTRIBUTIONS In order for doses from brachytherapy and externalbeam treatments to be combined, both dose distributions must be based on the same patient localization in space. If the external beam and the brachytherapy treatment planning are both based on the same set of CT slices, the overlaying is straightforward. If this is not the case, common reference points in space must be defined for both modalities, or the brachytherapy patient orientation must be matched interactively to the external beam one. Once the matching is obtained, the proper spatial transformations can be performed and the summation of the doses simply becomes an additive process. Weighting factors based upon the biological effectiveness of each treatment modality must be applied. These weighting factors may be based upon radiobiological models, such as the linear-quadratic (LQ) model [56]. This model can be used for high dose-rate, low doserate, and pulsed dose-rate treatments [57,58]. The resulting dose distributions can be evaluated with the viewing techniques available with current treatment planning systems. Three-dimensional isodose surfaces can be viewed together with the target and critical anatomic structures [34]. For ease of viewing, the degree of transparency and color of each of these isodose surfaces can be adjusted. 5.11 RECENT DEVELOPMENTS IN BRACHYTHERAPY With all the computing power, display techniques, and optimization methods currently available, the degree to

Recent developments in brachytherapy 77

which a brachytherapy implant will be effective is determined not by how well the implant is optimized, but by how well the physician has physically placed the catheters or applicators. Simply stated, optimization software cannot provide a good dose distribution around a badly placed implant. Therefore, to assist in the correct implantation of the catheters or applicator, visualization of the target volume, the critical structures, and the catheters themselves is often essential. When a CT scanner with a gantry tilt option is available, a regular volume implant, such as a brain implant using a template and needles, can be performed interactively, with each row of needles fully displayed in a CT plane. Filmless planning is the integration of the X-ray or ultrasound imaging and the treatment planning process. In such an integrated brachytherapy unit, an isocentric radiographic localizer (such as a treatment simulator) with digital imaging capabilities is directly interfaced with the treatment planning computer. In the surgical theater, the localizer transfers on-line the image information to the treatment planning computer for reconstruction, optimization, and display of the dose distribution. However, if these digital images are obtained from an image intensifier, they must be corrected for the image distortion due to the curved surface of the image intensifier screen, the influence of the earth magnetic field, and any imperfections of the electro-optical system. As the required accuracy in reconstructing the catheters or sources is in the range of 0.5 mm, the distortion of a digital image must be corrected to the same extent. Such an integrated brachytherapy system, which corrects these image distortions to the required accuracy, is currently already available [45]. This allows an interactive assessment of a needle position during implantation, especially if, in the future, the localizer is also provided with a CT option for visualization of the target volume and the surrounding structures. Three-dimensional ultrasound-guided perineal implantation of the prostate, combined with real-time treatment planning using ultrasound images, is also becoming available [51]. Catheters, guided by a perineal template, are inserted into the prostate and connected to an HDR afterloader. The three-dimensional ultrasound unit provides real-time transverse and longitudinal slices through the prostate and its immediate surroundings. A longitudinal plane through the prostate and its surroundings can be oriented such that a catheter being inserted can be imaged real-time in that ultrasound plane. The ultrasound images with the catheters depicted are directly available to the planning computer, which is an integral part of the implantation system. The treatment planning process consists of three distinct stages, the preplanning, the live planning and the postplanning. In the preplanning stage, transverse ultrasound

images are used to determine the catheters to be placed through the template. Longitudinal ultrasound images are used to determine the depth of insertion. After the virtual catheters have been placed, the virtual dwell positions inside the target volume are activated by the planning system. Geometric optimization on volume is currently available to obtain a real-time optimized dose distribution. Dwell positions and dwell weights can be modified interactively to obtain the required dose sparing of the urethra, e.g., to 120% of the MPD. In the live planning stage, the virtual catheters are replaced one by one by the real inserted catheter. The real dwell positions are activated by the planning system and the dose distribution from the catheters already placed, and the virtual catheter left is displayed real time. In this way, deviations of the catheters from the planned position and the corresponding deviation from the planned dose distribution can be corrected with the catheters still to be placed. Finally, when all catheters have been placed and the dose distribution has been decided upon, the actual treatment can start. Postplanning is done one or more days after the actual treatment has started, to check the stability of the catheter positions in the target volume. A full, real-time optimization method for volume implants is still to be developed. Such a method should combine the ease of the geometrical method (no dose points to be placed midway between the catheters) with the full optimization quality of the SSDS and should allow one or more critical volumes inside and outside the target organ to be treated to a predefined value of the PD. This is important for the HDR treatment of the prostate, where the urethra is to be treated to a given fraction of the PD and where the rectal wall adjacent to the prostate is to be spared. Only when such a fast volume optimization is available, will realtime full optimization of HDR volume implants become possible. Considerable research is still to be conducted to develop a bioeffect dose model that can be applied clinically. Computer software to implement such a model in a computer planning system is readily available and will allow the display of radiobiological isoeffect distributions instead of physical isodose distributions.

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Van Hollebeke, L (1998) High dose-rate afterloading 192 lridium prostate brachytherapy: feasibility report. Int.J. Radial Oncol. Biol. Phys., 41, 525-33. Williamson, J.F. (1990) Dose calculations about shielded gynecological colpostats. Int.J. Radial Oncol. Biol. Phys., 19,167-78. Kirov, A.S., Williamson, J.F., Meigooni, A.S. and Zhu, Y. (1996) Measurement and calculation of heterogeneity factors for an lr-192 high dose-rate brachytherapy source behind tungsten alloy and steel shield. Med. Phys., 23, 911-19. Weeks, K.J. (1998) Monte Carlo dose calculations for a new ovoid shield system for carcinoma of the uterine cervix. Med. Phys., 25,2288-92. Watanabe, Y., Roy,J., Harrington, P.J.and Anderson, L.L. (1998) Experimental and Monte Carlo dosimetry of the Henschke applicator for high dose-rate192lr remote afterloading. Med. Phys., 25,736-45. Kini, V.R., Edmundson,G.K., Vicini, FA, Jaffray, DA, Gustafson, G. and Martinez, A.A. (1998) Use of threedimensional radiation therapy planning tools and intraoperative ultrasound to evaluate high dose rate prostate brachytherapy implants. Int.J. Radial Oncol. Biol.Phys., 43, 571-8. Narayana, V., Roberson, P.L, Winfield, R.J. and McLaughlin, P.W. (1997) Impact of ultrasound and computed tomography prostate volume registration on evaluation of permanent prostate implants. Int.J. Radial Oncol. Biol. P&ys.,39,341-6. Saw, C.B. and Suntharalingam, N. (1991) Quantitative assessment of interstitial implants. Int.J. Radial Oncol. Biol.Phys., 20,135-9. Saw, C.B. and Wu, A. (1991) Interpretation of the dose nonuniformity ratio for interstitial brachytherapy. Med. Phys., 18, 605. Low, DA and Williamson, J.F. (1995) The evaluation of optimized implants for idealized implant geometries. Med. Phys., 22,1477-84. Orton, C.G. (1994) Mathematical models. In Brachytherapy from Radium to Optimization, ed. R.F. Mould, J.J. Battermann, A.A. Martinez etal. Veenendaal, The Netherlands, Nucletron International B.V., 34-8. Bleasdale, C. and Jones, B. (1994) Mathematical model for the time interval between external beam radiotherapy and brachytherapy. In Brachytherapy from Radium to Optimization, ed. R.F. Mould, J.J. Battermann, A.A. Martinezef al. Veenendaal, The Netherlands, Nucletron International B.V., 39-48. Deehan, C. and O'Donoghue, J A (1994) Biological equivalence of LDRand HDR brachytherapy. In Brachytherapy from Radium to Optimization, ed. R.F. Mould, J.J. Battermann, A.A. Martinez etal. Veenendaal, The Netherlands, Nucletron International B.V., 19-33. Williamson, J.F. (1995) Recent developments in basic brachytherapy physics. In Radiation Therapy Physics, ed. A.R. Smith, Berlin, Springer Verlag, 247-302.


60. Daskalov, G.M., Kirov, A.S. and Williamson, J.F. (1998) Analytical approach to heterogeneity correction factor calculation for brachytherapy. Med. Phys., 25,722-35.

Wijrdeman, H.K., Battermann, J.J. (2000) The combined

61. Moerland, M.A., Van der Laarse, R., Luthmann, R.W.,

prostatic seed implants. Radiother. Oncol., 57,279-84.

use of the natural and the cumulative dose-volume histograms in planning and evaluation of permanent

6 Dose specification and reporting:the ICRU recommendations ANDRE WAMBERSIE AND JAN J.BATTERMANN

6.1

INTRODUCTION

This chapter addresses the problem of dose specification for reporting in brachytherapy. It is based on the recommendations of the International Commission on Radiation Units and Measurements (ICRU), mainly ICRU Report 38, 'Dose and volume specification for reporting intracavitary therapy in gynecology' (1985) [ 1 ]1,and ICRU Report 58, 'Dose and volume specification for reporting interstitial therapy' (1997) [2] 2 . Exchange of clinical information between radiation oncology centers requires uniformity and agreement on the methods used to specify the doses and the volumes to which these doses are delivered. To avoid confusion, an agreement has also to be reached on definitions of the terms and concepts necessary for reporting treatments. Due to the limitations of the irradiation techniques, the doses delivered to the target volumes are in general not homogeneous. In external-beam therapy with pho-

1. The Reporting Committee for ICRU Report 38 was the following: D Chassagne and A Dutreix (Co-Chairmen), P Almond, JMV Burgers, M Busch, and CA Joslin (Members), M Cohen and T Landberg (Consultants). 2. The Reporting Committee for ICRU Report 58 was the following: D Chassagne and A Dutreix (Co-Chairmen), D Ash, WF Hanson, AG Visser and JF Wilson (Members).

tons and electrons, the differences between the maximum and the minimum doses in the target volume often reach 10%, 15%, and even 20%. Therefore, one can introduce large discrepancies, and thus confusion, depending on the criteria (or the dose levels) used for prescribing, recording, and reporting the treatment, e.g., maximum, minimum, or any mean dose or 'weighted' mean dose. Such discrepancies are in general much larger than the current dosimetric uncertainties. On the other hand, a difference in dose of 5% can be detected clinically for some radical treatments [3,4]. The ICRU recognized the importance of the problem many years ago and, in 1978, published Report 29, 'Dose specification for reporting external beam therapy with photons and electrons' [5]. This report was superseded, in 1993, by ICRU Report 50, 'Prescribing, recording and reporting photon beam therapy' [6]. A 'Supplement to ICRU Report 50' appeared recently [7]. In brachytherapy, the situation is even more difficult because very high doses are always obtained close to the sources, and there are actually no large volumes for which the dose is nearly homogeneous (reaches a kind of plateau), as in external-beam therapy. The problem is addressed in ICRU Reports 38 and 58. In order to retain as much consistency as possible, it is desirable to use, the same terms and wherever possible, in concepts and the same approach as in external-beam therapy. In particular, the definitions of the volumes are therefore the same for the two techniques. It is, however,

82 Dose specification and reporting: the ICRU recommendations

recognized that brachytherapy raises some specific problems which have to be taken into account. Other ICRU reports dealing with dose specification for reporting special techniques, such as electron, proton, and neutron beam therapy, are in preparation. For reporting in external-beam therapy, the dose is specified first at the ICRU reference point, which is located (always) in the central part of the clinical target volume, and (when possible) at, or near, the intersection of the beam axes. The maximum and the minimum doses to the planning target volume (or their best estimation) should also be reported. In brachytherapy, there are high dose gradients within the clinical target volume and the use of a single reference point is not, therefore, sufficient. It is, however, appropriate to consider the dose at points where plateaus of dose occur in the central part of the clinical target volume and where the bulk of the malignant cell population is generally located. This leads to the concept of the mean central dose. In addition, the whole of the clinical target volume must receive a certain minimum dose in order to achieve the desired clinical effect. It is therefore also important to record the minimum dose at the periphery of the clinical target volume, i.e., the minimum target dose. Several systems of brachytherapy have developed historically. Best known and most widely used (with or without modification) are the Manchester, Quimby and Paris systems [8-14]. The term 'system' denotes a set of rules which takes into account the source types and strengths, geometry and method of application to obtain suitable dose distributions over the volume(s) to be treated. The system also provides a means of calculating and specifying dose. It is important to remember that, whereas an implant may follow the source distribution rules of a system, it does not comply with the system unless the method of dose prescription and specification are also followed. In addition, if the implant rules are modified, the dose uniformity intended by the system may be compromised. The situation is more difficult in intracavitary therapy due to the steep dose gradient in the vicinity of the sources, i.e., throughout the target volume. Therefore, the specification of the target absorbed dose in terms of the absorbed dose at specific point(s), in the vicinity of the sources, becomes less meaningful and a different approach is required. Instead of a target-dose specification, a volume specification is an alternative and, in that respect, specification of an intracavitary application in terms of the 'reference volume' enclosed by a reference isodose surface of 60 Gy has been proposed in ICRU Report 38. The problems of interstitial therapy (and of brachytherapy in general) are discussed first. The specific problems encountered in intracavitary therapy, and especially in gynecology, are dealt with in section 6.6. Over the last two decades, technological developments in brachytherapy have seen the introduction of minia-

turized and highly flexible sources which can be used in afterloading devices with radionuclides of different activities that can produce a wide range of dose rates. At the same time, sophisticated three-dimensional source localization methods have been developed and can be linked to computerized methods of dose calculation and representation of dose distribution. These developments have led many clinicians to depart from the longestablished implant systems and it is for this reason that a common language is valuable to provide a method of dose specification for reporting which can be used and be common for all types of brachytherapy applications. It should be stressed from the beginning that it has not been the intention or the role of the ICRU to encourage users to depart from their current practice of brachytherapy and from their method of dose prescription. The aim of the ICRU recommendations is to develop a common language for reporting a treatment, based on existing concepts. The description of the treatment and the method of dose specification for reporting should be presented in a way that can be easily understood and closely related to the treatment outcome.

6.2

DEFINITION OF VOLUMES

The definition of volumes is of utmost importance, both in external-beam planning and in brachytherapy planning. The process of determining volumes for the treatment of a malignant disease consists of several distinct steps, during which different volumes may be defined. 6.2.1

Gross tumor volume

The gross tumor volume (GTV) is the gross palpable or visible/demonstrable extent and location of the malignant growth. The GTV may consist of the primary tumor ('GTV primary'), metastatic lymphadenopathy(ies) ('GTV nodal'), or other metastases. The GTV almost always corresponds to those parts of the malignant growth where the tumor density is largest. Due to the high density of the cancer cells in the GTV, an adequate dose must be delivered to the whole GTV in order to achieve the aim of therapy in radical treatments. According to the above definition, there is no GTV after complete 'gross' surgical resection. There is no GTV when there are only a few individual cells or 'subclinical' involvement (even histologically proven). From the origin of medical terminology, the latin word tumor was used to designate a swelling, which could be of various types. The shape, size, and location of the GTV may be determined by means of different diagnostic methods such as clinical examination (e.g., inspection, palpation, endoscopy), and various imaging techniques (e.g., X-ray,

Definition of volumes 83

computerized tomography (CT), digital radiography, ultrasonography, magnetic resonance imaging (MRI), and radionuclide methods). The methods used to determine the GTV should meet the requirements for scoring the tumor according to the TNM [15,16] and American Joint Committee on Cancer (AJCCS) [17] systems, and the definition of the GTV is then in full agreement with the criteria used for the TNM classification. The GTV (primary tumor, metastatic lymphadenopathy, other metastases) may appear to be different in size and shape, sometimes significantly, depending on what examination technique is used for evaluation (e.g., palpation versus mammography for breast tumors, CT versus MRI for some brain tumors). Therefore, the radiation oncologist should, in each case, indicate which method has been used for the evaluation and delineation of the GTV. A GTV may be confined to only part of an organ (e.g., a Tl breast cancer), or involve a whole organ (e.g., multiple metastases of the brain). The GTV may or may not extend outside the normal borders of the organ tissue involved. For reporting, the GTV should be described in standard topographical or anatomical terms, e.g. '18 x 12 x 20 mm3 tumor in the left lobe of the prostate adjacent but not reaching the capsule.' In many situations, a verbal description might be too cumbersome and, therefore, for the purpose of data recording and analysis, a classification system is needed. Several systems are proposed for coding the anatomical description, some of them are mentioned in ICRU Report 50 [6]. There are at least three reasons for identifying the GTV. First, accurate description of the GTV is needed for staging (e.g., TNM). Second, identification of the GTV is necessary to allow for recording of tumor response in relation to the dose and other relevant factors. It can be used (carefully) as a prognostic factor. Third, an adequate dose must be delivered to all parts of the GTV in order to obtain local tumor control in radical treatments.

6.2*2

Clinical target volume

Clinical experience indicates that around a GTV there is generally subclinical involvement, i.e., individual malignant cells, small cell clusters, or microextensions, which cannot be detected by the staging procedures. The GTV, together with this safety margin consisting of tissues with presumed or proved subclinical involvement, is defined as the clinical target volume (CTV). The tissues immediately surrounding the GTV usually have a high malignant cell density close to the edge of the GTV; the cell density decreases toward the periphery of the CTV (often a safety margin of about 1 cm thick is taken). This CTV is usually denoted CTV-T. If the GTV has been removed by radical surgery, but it

is still thought that radiotherapy is needed for the tissues that remain close to the site of the removed GTV, this volume is also usually designated as CTV-T (e.g., in breast-saving procedures). Additional volumes with presumed subclinical spread (e.g., regional lymph nodes) may also be considered for therapy. They are also defined as CTVs and may topographically be designated CTV-N1, CTV-N2, etc. The CTV is a tissue volume that contains a gross tumor volume and/or subclinical microscopic malignant disease. This volume has to be treated at an adequate dose level (and time-dose pattern) in order to achieve the aim of therapy - cure or palliation. Delineation of a CTV will require consideration of factors such as the local invasive capacity of the tumor and its potential to spread to, for example, regional lymph nodes. The CTV, like the GTV, is a purely clinical-anatomical concept. It must always be described, independently of the dose distribution, in terms of the patient's anatomy and the tumor volume. As a minimum recommendation, the physical dimensions of the clinical target volume are described in terms of its maximum diameters (cm) in three orthogonal directions. For reporting, the CTV must be defined in plain topographic terms and/or according to a corresponding code in conformity with the recommendations for the GTV. If different dose levels are prescribed, different CTVs have to be defined. This is the case, for example, in 'boost' therapy where the 'high-dose' volume (often containing the GTV) is located inside the 'low-dose' volume. It must be stressed that the descriptions of the GTV(s) and CTV(s) are based only on general oncological principles, and are independent of any therapeutic approach. In particular, they are not specific to the field of radiation therapy. For example, in surgery, a safety margin is taken around the GTV according to clinical judgement, and this implies the use of the same CTV concept as in radiation therapy. In brachytherapy, as in external-beam therapy, volumes to be irradiated are defined, and thus the same concept of CTV is applied. Furthermore, the CTV concept can be applied to other modalities, e.g., regional chemotherapy, hyperthermia, and photocoagulation. The definitions of GTV and CTV in brachytherapy are thus identical to the definitions given for external-beam radiotherapy in ICRU Report 50 [6] and Supplement to Report 50, ICRU Report 62 [7].

6.2.3

Planning target volume

In external-beam therapy, to ensure that all tissues included in the CTV receive the prescribed dose, one has, in principle, to plan to irradiate a volume geometrically larger than the CTV. This is the planning target volume (PTV).


The additional safety margin included in the PTV results from a number of factors: expected physiological movements (e.g., with respiration) and variations in size, shape, and position (e.g., stomach, bladder, rectum) of the CTV; all variations and uncertainties in beam geometry and patient-beam positioning. The PTV is a geometrical concept, used for treatment planning, and it is defined to enable selection of appropriate beam sizes and beam arrangements, taking into consideration the net effect of all the possible geometrical variations, in order to ensure that the prescribed dose is actually absorbed in the CTV. The dose distribution to the PTV has to be considered to be representative of the dose distribution to the CTV. As indicated in ICRU Report 50 for external-beam therapy, when delineating the PTV, consideration may also be given to the presence of any radiosensitive normal tissue (organs at risk) as well as to other factors such as the general condition of the patient. Delineation of the PTV is a matter of compromise, implying the judgement and thus the responsibility of the radiation oncologist. In brachytherapy, the PTV is in general identical to the CTV. There are only very few exceptions. For instance, with some techniques in which there are uncertainties of consistency of source position (high dose rate, moving sources, fractionated techniques) or alteration of source position (intracavitary applications, permanent implants) during the application, the PTV may be larger than the CTV to take these factors into account. In this chapter, as in ICRU Report 58 [2], the term clinical target volume is used rather than planning target volume. In external therapy, the two steps localization of CTV and treatment planning can always be dissociated and therefore checked separately. However, in interstitial therapy, the CTV is finally decided upon by the clinician at the time of implantation on the assumption that it is contained within the minimum target isodose surface (see section 6.4.4). This procedure cannot be recommended, and the CTV should be clearly described in the patient chart before the implant is planned.

6.2*4

Treated volume

The treated volume is that volume of tissue, based upon the implant as actually achieved, which will receive at least a dose selected and specified by the radiation oncologist as being appropriate to achieve the purpose of treatment (e.g., tumor eradication or palliation). The treated volume is thus encompassed by an isodose surface corresponding to that dose level, which is the minimum target dose (see section 6.4.4). This isodose surface should, ideally, entirely encompass the CTV.

6.3 TECHNIQUES OF BRACHYTHERAPY: CLASSICAL SYSTEMS The Paterson-Parker or Manchester System was developed to deliver a reasonable dose uniformity (±10%) throughout a region implanted with radium needles [10]. The system specifies rules for the geometrical arrangement of the sources, and for the linear activity required in order to cover a PTV with a sufficiently homogeneous dose (Figure 6.1). The system includes tables of milligram-hour needed to deliver specified doses for different sizes of implants or moulds. The proportion of activity on the periphery is specified according to the size of the implant; it is larger for smaller implants. The system is still used for single-plane and double-plane implants in many centers. The Quimby System is characterized by uniform source spacing and uniform source activity [11]. Consequently, this arrangement of sources resulted in a non-uniform dose distribution, higher in the central region of the implant (as in the Paris System; see Figure 6.2). This system was particularly used in the US centers. The Paris System of implant planning has been developed mainly with iridium-192 wire sources [13,18]. The sources are of equal linear activity, parallel, placed at equal distances, and arranged in such a way that their centers are in the same plane perpendicular to the direction of the lines (Figure 6.2a and b). This plane, called the central plane, is the midplane of the application (Figure 6.3a, b, and c). If the volume to be treated is large, more than one plane containing wires is used. Again, equidistance of the radioactive lines is required. This means that their intersections with the central plane are arranged according to the apices of equilateral triangles or squares (Figure 6.3b and 6.4a and b). This regular distribution of the wires results in a slight overdose at the center of the target volume. The dose rate at a point in the middle of a group of sources is called the basal dose rate (BD). This BD is always calculated from the position of the sources in the central plane and is the minimum dose rate between a pair or group of sources. The values of the isodose curves are expressed as a percentage of the BD. The reference dose rate is derived from the BD and is equal to 85% of the BD. It is used for calculating the total treatment time of the implant. Because the ends of the active wires are not crossed, as in the Manchester System, the active sources should be 20-30% longer than the target volume at both ends. The minimum thickness of a treated volume is 50-60% of source separation for single planes and 130-150% for two planes. Dosimetry according to the Paris System has many advantages. The use of equal linear activity, equal distance between the sources, and the fact that no cross

Techniques of brachytherapy: classical systems 85

Figure 6.1 Manchester System for application of radioactive sources with different loading. As an example, (a) is the localization film for a bladder implant with radium needles of different activity. Although the Manchester System was designed for radium sources, it can be used with other radionuclides as well, such as cesium-137 needles or iridium-192 wires. As an example of the application of the Manchester System with radioactive sources other than radium, (b) and (c) give the distribution of dose rates for a single-pi one implant with iridium wires of unequal linear activity in order to ensure dose uniformity throughout the implanted region. Wires 1, 4, 5, and 6 (peripheral) contain a linear activity of 60 MBq (1.6 md) per cm; wires 2 and 3 contain a linear activity of 37 MBq (1 md) per cm. Wires 1, 2, 3, and 4 are 6 cm long; wires 5 and 6 are 3.5 cm long, (b) The dose rates in the plane containing the wires; (c) the dose rates in a perpendicular plane.

needles are used make the application itself relatively easy. The relationship between the geometry of the implant, and the dimensions of the target volume can easily be determined. The dose rate can be quickly controlled with a planning computer, even in complicated implantations. Nowadays, most of the implant techniques are based on the original Paris System. For rapid planning, in some institutes, normograms have proven useful as approximate planning guides. Both for removable iridium implants and for permanent iodine implants, normograms were developed at the Memorial Sloan Kettering Institute [19]. However, individualized computer planning, in general is superior to

the above-described techniques, because the isodose lines generated by the computer allow a far more complete evaluation of the treatment plan. Both orthogonal and isocentric techniques are used to reconstruct the source coordinates. The isocentric reconstruction method is a variation of the stereo-shift method. With isocentric equipment, like a treatment simulator, the angle between the central axes of the projecting beams can be enlarged up to 60°, still obtaining two projections of the sources (carriers) on the same radiograph (Figure 6.5 a, b, and c). With the simulator, variable angles can also be chosen, such that sources are not obscuring one another.


Figure 6.2 lridium-192 wire implant according to the Paris System (single-plane implant). The wires are of equal linear activity, parallel, and arranged in such a way that their centers are in the same plane perpendicular to the direction of the wires (i.e., the central plane, see Figure 6.3). Figure 6.3 Central plane. In an implant where the source lines are rectilinear, parallel, and of equal length, the central plane is perpendicular to the direction of the source lines and passes throughout their centers. The mean central dose (DJ is the arithmetic mean of the local minimum doses D, (i = A, B ...) in the plateau region, (a) A single-plane implant; (b) a twoplane implant; (c) an actual single-plane implant where sources are not rectilinear: the central plane can be defined as in (a). (From ICRU Report 58 [21)

6,4 DESCRIPTION OF DOSE DISTRIBUTION IN INTERSTITIAL THERAPY

regions of high dose surrounding each source. However, within the volume of the implant there are regions where the dose gradient approximates a plateau (Figure 6.6).

6.4.1

1. In an interstitial implant, the regions of plateau dose are equidistant between adjacent neighboring sources, for sources of identical activity. They are regions of local minimum doses.

General concepts

In interstitial therapy, the dose distribution is nonhomogeneous and includes steep dose gradients and

Description of dose distribution in interstitial therapy 87

Figure 6.4 Dose planning for implants with iridium-192 wires contained in two parallel planes, following the Paris System. Examples of a breast implant in two planes, (a) The seven wires are equidistant and arranged in triangles (length of the wires 7 cm for the upper row and 8 cm for the lower row), linear activity 52 MBq cnr1 (1.4 md cnr1), application time 43.32 h for a reference dose of 20 Gy. (b) The six wires are equidistant and arranged in squares (length of the wires 6 cm for the upper row and 7 cm for the lower row), linear activity 52 MBq Cm-1 (1.4 mCi cm-1), application time 42.91 h for a reference does of 20 Gy.

2. Variations between these local minimum doses can be used to describe the dose uniformity of an implant. 3. A region of plateau dose is the place where the dose can be calculated most reproducibly and compared easily by different departments. Although in modern computer systems the threedimensional dose distribution can be computed and presented as isodose surfaces, these facilities are not yet available in all departments. In order to provide the minimum of information needed about the dose or dose rate distribution, the calculation of isodose curves in at least one chosen plane is necessary. If only one plane is chosen for isodose calculation, the central plane of the implant (as defined in section 6.4.2) should be chosen for this purpose. In order to assess the dose distribution in other areas of the implant, multiple planes for isodose calculation can be chosen, either parallel or perpendicular to the central plane.

6.4.2

The central plane

In source patterns in which the source lines are straight, parallel, of equal length and with the centers which lie in a plane perpendicular to the direction of the source lines, this plane is the central plane (see Figure 6.3a and b).

In an actual implant, all source lines may not necessarily be straight, parallel, and of equal length. In such cases, the central plane should be chosen perpendicular to the main direction of the source lines and passing through the estimated center of the implant (see Figure 6.3c). For more complex implants, it may be necessary to subdivide the target volume into two or more subvolumes for dose evaluation. In this event, a central plane may be defined for each of these subvolumes (Figure 6.7). The calculation of dose distributions in multiple planes throughout the target volume shows that a variation of a few millimetres in the position of the central plane is not critical.

6.43

Mean central dose

In interstitial therapy, the mean central dose is taken to be the arithmetic mean of the local minimum doses between sources in the central plane (or in the central planes if there are more than one). In the case of a single-plane implant, the mean central dose is, in the central plane, the arithmetic mean of the doses at mid-distance between each pair of adjacent source lines, taking into account the dose contribution at


Figure 6.5 Orthogonal AP (a), lateral (b) and isocentric (c) radiographs of Fletcher-Suit rigid applicator. Note lead wire in vaginal packing, contrast medium in balloon of Foley catheter, and air in distal rectum.

that point from all sources in the pattern (see Figure 6.3a). In the case of an implant with line sources in more than one plane, the mean central dose is the arithmetic mean of the local minimum doses between each set of three adjacent source lines within the source pattern (see Figure 6.3b). As seen in Figure 6.4a, the minimum dose lies at the intersection of perpendicular bisectors of the sides of the triangles (geometric center) formed by these source lines. This point is equidistant from all three source lines. In some complex implants, a single central plane may not bisect or even include all the sources. In these cases, a mean central dose based on one plane can be misleading and it is advisable to subdivide the volume and to choose a separate central plane for each sub volume (see Figure 6.7). Three practical methods are acceptable for determining the mean central dose: 1. If parallel lines are used, one can identify triangles consisting of three adjacent source lines for all the sources, so that the triangles formed constitute as

Figure 6.6 Plateau dose region between radioactive sources. In a plane perpendicular to linear and parallel sources, the dose distribution shows a plateau region of low dose gradient. In this example of three sources, 6 cm long and with 1.5 cm spacing, the dose varies by less than 2% in the gray region between the sources. (From Dutreix et a I. [18].)


Figure 6.7 Central planes in a complex implant. It is sometimes necessary to plan the treatment in terms of two or more subvolumes. In the example shown, where all source lines are not of equal length, two central planes are identified: (a) for the longest source lines and (b) for the shortest ones. Two mean central doses are determined in the two subvolumes Dma and Dmb, respectively. Open circles are the intersections of the sources with the central planes, and closed circles are the points where the local minimum doses are calculated. (From ICRU Report 58 [2].)

many acute triangles as possible. The intersection points of the perpendicular bisectors of each triangle are determined and the local minimum doses are calculated at each of these points. The mean of these local minimum doses is the mean central dose. This method is the most precise one when parallel lines are used. 2. Evaluation of dose profiles: the dose profiles are calculated for one or more axes through the center of the implant expected to pass through as many local minima as possible. The local minimum doses are determined by inspection. The mean of these local minimum dose values is the mean central dose (Figure 6.8). In a single surface implant performed following a curved surface, a profile may lead to an underestimation of the mean central dose. In a complex implant, it may be difficult to find axes passing through the minima and profiles may lead to an overestimation of the mean central dose. However, experience shows that the error lies within acceptable limits. This method is sometimes preferred for seed implants. In a seed implant, such as the one presented in Figure 6.9, the dose should be calculated along several random profiles passing through the implant. 3. Inspection of dose distribution: the dose

Figure 6.8 Evaluation of dose profiles. Three profiles (b) are drawn along two orthogonal directions through a two-plane implant (a) with eight parallel line sources, 10 cm long, 1.8 cm spacing. The profiles are calculated in percentage of the minimum target dose (thick line) along axes XX, YY and YY in the central plane. The profile along the axis YY is the most representative to estimate the mean central dose. The mean of the local minimum doses is the mean central dose. The mean central dose is equal to 7 78% of the peripheral dose. (From ICRU Report 58 [2].)


Figure 6.10

Determination of mean central dose from

inspection of dose distribution. Dose distribution in the central plane of an implant with six parallel iridium-192 line sources, 6 cm long, 1.5 cm spacing, reference air kerma rate 14.5 mGyh-1 at 1 m. The dose varies by 5% between plotted isodose lines in the region of interest. The idodose values are 16, 19, 22, 24, 26, 28, 30, 31.5, 33, 35, 40, and 45 cGy h-1 The local minima, A, B, C, and D, can be easily estimated by inspection. DA and DD approximate 31 cGy h-1 and D6 and Dc approximate 34 cGy h-1 The estimated mean central dose is Dm - 32.5 cGy h-1 (From ICRU Report 58 [2].)

Figure 6.9 Seed implant with 68 iodine-125 seeds of 19.2 MBq (0.52 md), total activity 1310 MBq (35.4 md). (a) Radiograph of implant, (b) Dose distribution in the central plane.

distribution is plotted in the central plane. With isodose lines varying by 5% (at most 10%) of the local dose in the central region, the local minima can be determined by inspection. The mean of these local minima is the mean central dose (Figure 6.10). This method is often preferred for complex implants with line sources. 6*4.4

Minimum target dose

The minimum target dose is the minimum dose at the periphery of the CTV. It should be equal to the minimum dose decided upon by the clinician as adequate to treat the CTV. The minimum target isodose surface is the isodose surface corresponding to the minimum target dose. As indicated above, it defines the treated volume and should entirely encompass the CTV (see section 6.2.2). The minimum target dose corresponds to the prescribed dose in many instances.

The minimum target dose is known in some American centers as the 'minimum peripheral dose' [20]. It is known as the 'reference dose' in the Paris System, and is equal to about 90% of the prescribed dose in the Manchester System for interstitial therapy. 6.4.5

High-dose regions

In order to correlate radiation dose with late damage, the high-dose regions around sources should be assessed (Figures 6.4 and 6.11). There will inevitably be a high-dose zone around each source. Although this zone is often small and well tolerated, the exact tolerance dose and volume for interstitial therapy are not known. However, it is necessary, for intercomparison purposes, to agree on a way to describe the high-dose volumes. It has been suggested that a dose of approximately 100 Gy is likely to be significant in determining late effects. In those patients who receive 50-60 Gy as peripheral minimum dose or 60-70 Gy as mean central dose, 100 Gy corresponds approximately to 150% of the mean central dose. It is therefore recommended in ICRU Report 58 [2] to report the size of the region receiving more than 150% of the mean central dose. The high-dose regions should be defined as the


Figure 6.11 Tongue implant, using five loops of 8 cm indium wires with activity of 68 MBq cm'1 (1.8 md cm-1). (a) Radiographs of the implant, (b) Dose distribution in the central plane of the implant.

regions encompassed by the isodose corresponding to 150% of the mean central dose around the sources in any plane parallel to the central plane where a high-dose region is suspected. The maximum dimensions of all regions in all planes calculated should be reported. 6.4.6

Low dose regions

A low dose region should be defined as a region within the CTV, encompassed by an isodose corresponding to 90% of the prescribed dose. The maximum dimension of the low dose region in any plane calculated should be reported. In implants for which the CTV is included within the minimum target dose isodose, the occurrence of a low dose region is exceptional. If the clinical target volume is not covered by the minimum target dose isodose, there will be low dose regions due to geographical miss. Low dose regions should be reported in order to correlate the local recurrence rate with the dose distribution.

6*4.7

Dose uniformity parameters

Several indices quantifying the homogeneity of the dose distribution have been proposed (see, for example, references 21-23).

Two parameters describing dose uniformity for interstitial implants are recommended in ICRU Report 58 [2]. They can be derived directly from the concepts of minimum target dose and mean central dose: 1. the spread in the individual minimum doses used to calculate the mean central dose in the central plane expressed as a percentage of the mean central dose; 2. the dose homogeneity index, denned as the ratio of minimum target dose to the mean central dose.

6*4*8 Additional representations of the dose distribution In order to obtain a full perception of the dose distribution of an implant, the use of volume-dose calculations has been advocated (see, for example, references 24-26). For this purpose, the CTV (or a larger volume including an additional margin) is subdivided in subvolumes (e.g., voxels) and the dose rate is calculated at the center of each subvolume. The volume receiving at least a specified dose is then defined as the sum of all subvolumes where at the center at least that dose is received. Examples of results are shown in Figure 6.12. Because of high dose gradients, significant differences in calculated volumes can be observed, depending upon the size of the elementary subvolumes. The size of the grid and of the


elementary subvolumes used in dose and volume calculations should be clearly stated. Volume-dose data can also be represented by means of histograms showing the distribution of fractions of the CTV receiving doses within chosen intervals, especially the natural volume-dose histogram (NVDH) as published by Anderson [27]. With this model, even small differences between implants can be revealed. The main characteristic of the NVDH is the peak that occurs with regular implant of several sources (see, for example, Figure 6.13). In fact, the peak dose reflects the basal dose of the Paris System. If the implant is less uniform, the peak is wider. So, the NVDH can be used for intercomparison between planned and realized source arrangements [28,29]. The value of these alternative representations of the dose distribution as a possible prognostic factor for treatment outcome has still to be established in clinical research.

6.5 RECORDING AND REPORTING INTERSTITIAL THERAPY Figure 6.12 Volume-dose curves. Volume (sum of subvolumes receiving at least a certain dose) versus dose, for two different patterns of parallel source lines: a two-plane implant with six sources 5 cm long (upper curve), and a cylindrical implant with seven sources 4 cm long (lower curve). The dose is expressed as percentage of the minimum target dose. The size of the voxel used for calculation is 1 mm3. For the upper curve, linear

Adequate information must be recorded in order to give a consistent description of any implant. The guidelines for reporting doses will make it possible to compare results of future brachytherapy practice and to better relate outcome to treatment. In order to report an implant, at least the following should be recorded [2].

sources are simulated by point sources (seeds) arranged in a linear fashion. (Bridier et al. [25])

Figure 6.13 Natural volumedose histogram of the tongue implant in Figure 6.11. Treatment dose rate of 1 Gy h-1 was chosen to deliver 60 Gy in 60 h. (From Anderson [27].)

Recording and reporting interstitial therapy 93

6.5.1

Description of volumes

6.5.4

Description of time-dose pattern

The description of volumes should include as a minimum the GTV, the CTV, and the treated volume.

The description of the time-dose pattern should include the type of irradiation with the necessary data on treatment and irradiation time, as described below. The information on dose and time should provide the necessary data to calculate instantaneous and average dose rates.

6.5.2

• Continuous irradiation: the overall treatment time should be recorded. • Non-continuous irradiation: both the overall treatment time and the total irradiation time should be recorded. • Fractionated, hyperfractionated, and pulsed irradiation: the irradiation time of each fraction, the interval between fractions, and the overall treatment time should be recorded. • When the irradiation times of the different sources are not identical, they should be recorded.

Description of sources

The description of the sources employed should include details of: • Radionudide used including nitration, if relevant. • Type of source used, i.e., wire, seed, seed ribbon, hairpin, needle, etc. • Length of each source line used. • Reference air kerma rate of each source (or source line): the reference air kerma rate of a brachytherapy source is the kerma rate to air, in air, at a reference distance of 1 m, corrected for air attenuation and scattering. The quantity reference air kerma rate is expressed in Gy s-1 at 1 m, or a multiple of this unit (in a convenient way, for low dose-rate brachytherapy, in microgray per hour, )m,Gy Ir1, at 1 m). The problem of specification of sources used in brachytherapy has been discussed by several authors, and the quantity reference air kerma rate has been increasingly adopted by different organizations or commissions [1,2,30-39]. • The distribution of the strength within the source should be described (uniform or differential loading, etc.) [40,41].

6.5.3 Description of technique and source pattern If the source distribution rules of a standard system have been followed, this must be specified. If it is not the case, the source pattern should be described completely and unambiguously. In addition, the following data should be recorded: • number of sources or source lines, • separation between source lines and between planes, • geometrical pattern formed by the sources with the central plane of implant (e.g., triangles, squares), where relevant, • the surfaces in which the implant lies, i.e., planes or curved surfaces, • whether crossing sources are placed at one or more ends of a group of linear sources, • the material of the inactive vector used to carry the radioactive sources, if any (e.g., flexible or rigid); whether rigid templates are used at one or both ends, • type of remote afterloading, if used.

Moving sources: • Stepping sources: step size and dwell time should be recorded if constant. Variation of the dwell times of a stepping source can be used for manipulating the dose distribution. If such a dose optimization is applied, this should be specified (e.g., optimization on dose points defined in the implant or geometrical optimization [42]. • Oscillating sources: speed in different sections of the vectors should be recorded.

6.5.5

Total reference air kerma (IRAK)

The total reference air kerma is the sum of the products of the reference air kerma rate and the irradiation time for each source. The TRAK is an important quantity which should be reported for all brachytherapy applications. It is a quantity that is simple to calculate and on which there can be no ambiguity. It is analogous to the milligrairrhour (mg.h) of radium. The conversion of the quantity mg.h to the TRAK is easy and straightforward (1 mg.h radium equivalent corresponds to 7.2 mGy h-1, at 1 m). In addition, the TRAK is proportional to the integral dose to the patient, and can also serve as a useful index for radiation protection of personnel. However, the simple determination of the TRAK does not allow one to derive, even approximately, the absorbed dose in the immediate vicinity of the sources (i.e., in the tumor or target volume).

6.5.6

Description of dose distribution

The following doses should be recorded. • Prescribed dose: if the dose is not prescribed at the level of either the minimum target dose or the mean central dose, the method of dose prescription should


be recorded. If, for clinical or technical reasons, the dose received differs from the prescribed dose, it should be noted. • Minimum target dose. • Mean central dose. The following additional information, when available, should be recorded: • • • •

Dimension of high dose region(s). Dimension of any low dose region. Any dose uniformity data. Additional representation of dose distribution, if any.

The above guidelines are based on the recommendations contained in ICRU Report 58 [2]. It should be stressed again that it is not the intention, or the role, of the ICRU to encourage radiation oncologists to depart from their current practice of dose prescription or technique of application. The ICRU reports aim to help radiation oncologists to report a given application in the same way, using the same definitions and concepts. One should avoid a situation in which the same application would be described differently in different centers or, conversely, in which the same reported dose would correspond to completely different actual dose distributions. For the purposes of this chapter, the prescribed dose is defined as the dose which the physician intends to give and which is entered in the patient's treatment chart. Depending on the system used, the approach for dose prescription in interstitial therapy may be different from center to center.

6.6 SPECIFIC PROBLEMS FOR INTRACAVITARY THERAPY IN GYNECOLOGY

6.6.1

Introduction

As the absorbed dose in soft tissues from intracavitary applications is so highly non-uniform throughout the target volume, the concepts of maximum, mean, median, and modal target absorbed dose, as defined in ICRU Report 50 [2], are not relevant. The minimum target absorbed dose is the only useful concept and is, by definition, equal to the treatment absorbed dose level. For external-beam therapy, it has been recommended that the target absorbed dose be defined as the absorbed dose at one or more specification points which are representative of the dose distribution throughout the target volume. These specification points could be established with respect to the target volume (center or central part) or to the beam axes, or both. In contrast, in intracavitary therapy, due to the steep dose gradient in the vicinity of the sources, i.e., throughout the target volume, the specification of the target absorbed dose in terms of the absorbed dose at specific

point(s), in the vicinity of the sources, is not at all meaningful and a different approach is required. Instead of a target-dose specification, a volume specification is recommended in ICRU Report 38 [1]. Specification of an intracavitary application in terms of the 'reference volume' enclosed by the reference isodose surface of 60 Gy is proposed. However, as the different isodose surfaces are close to each other, the indication of the reference volume must be supplemented, for safety reasons, by the indication of the TRAK. In addition, recording the absorbed dose at reference points related to organs at risk or to fixed bony structures is recommended. As for interstitial therapy, the ICRU recommendations contained in Report 38 [1] do not imply a modification of the method used for the calculation of the treatment duration, but they require the calculation of specific quantities for reporting. The recommendations presented in ICRU Report 38 [1] must be considered a minimum requirement for reporting. On the other hand, the reported parameters will be meaningful only to the extent that the technique of the particular intracavitary application has been completely described. ICRU Report 38 [1] deals mainly with the treatment of cervix carcinoma, for which the anatomical region of interest is similar for every patient and the possible variation in the position of the radioactive sources is limited. However, for other gynecological intracavitary applications, the same philosophy can be adopted, but some of the numerical values and definitions may need to be modified according to the type of application.

6.6.2

Description of the technique

It is recommended that the technique be described on the basis of the guidance given below. THE SOURCES

1. Radionuclide 2. Reference air kerma rates 3. Shape, filtration, etc. SIMULATION OF LINEAR SOURCES

When a linear source is simulated by a set of point sources, the activity of these point sources and their separation^) must be indicated [25,43]. When moving sources are used to simulate a set of different sources in fixed position, in order to produce an appropriate dose distribution, the following indications are required [44-47]: 1. type of movement (continuous or stepwise, step distance), 2. unidirectional or oscillating movement, 3. range of movement or oscillation,

Specific problems for intracavitary therapy in gynecology 95

4. speed in different sections of the applicator, or dwell times of the source at different positions. THE APPLICATOR

Reference to the applicator is sufficient when a complete description has already been published, provided that there is no significant difference between the applicator used and the one described in the literature. To avoid confusion, it is recommended that the applicator be described, including the name of the manufacturer. The description should include information on the following points: 1. rigid (or not), consequently with fixed known geometry (or not) of the complete applicator, 2. rigid uterine source with fixed curvature (or not), 3. connection between vaginal and uterine applicators, i.e., fixed, loose (semi-fixed), free, 4. type of vaginal sources, number and orientation of line sources, special sources (box, ring, etc.), 5. high atomic number shielding materials in vaginal applicator (or not).

6.63

Recommendations for reporting

Three sets of quantities are recommended in ICRU Report 38 [1] to specify intracavitary application for cervix carcinoma; they complement each other and should be combined. TOTAL REFERENCE AIR KERMA (TRAK)

The TRACK will always be reported (see section 6.5.5).

rates, the radiation oncologist has to indicate the dose level which he or she believes to be equivalent to 60 Gy delivered at the conventional low dose rate, and this should be clearly stated [48-50]. Reference volume: description of the pear-shaped volume

When the uterine source(s) is combined with vaginal sources, or when the uterine source is more heavily loaded at the lower end, the tissue volume to be described presents a pear shape, with its longest axis coincident with the intrauterine source (Figure 6.14). This reference volume is defined by means of three dimensions (Figure 6.15): 1. the height (dh)is the maximum dimension along the intrauterine source and is measured in the oblique frontal plane containing the intrauterine source; 2. the width (dw) is the maximum dimension perpendicular to the intrauterine source and is measured in the same oblique frontal plane; 3. the thickness (dt) is the maximum dimension perpendicular to the intrauterine source and is measured in the oblique sagittal plane containing the intrauterine source. The definitions of dh, dw and dt are proposed in order to minimize the number of calculations. These dimensions are usually expressed in centimeters. The volume estimated from the intersections of the surface of a pearshaped volume on two conventional planes does not necessarily represent the size of the true reference volume. However, for most applications they do not differ from the maximum dimensions of the reference volume by more than 1 or 2 mm.

DESCRIPTION OF THE REFERENCE VOLUME

The description of the reference volume, i.e., the tissue volume encompassed by a reference isodose surface, has been proposed for specification in reporting. The reasons for this approach are described in section 6.6.1. Dose level

An absorbed dose level of 60 Gy is widely accepted as the appropriate reference level for conventional low doserate therapy. When two or more intracavitary applications are performed, the absorbed dose to consider is that resulting from all applications. The time-dose pattern should be clearly stated. When intracavitary therapy is combined with external-beam therapy, the isodose level to be considered is the difference between 60 Gy and the dose delivered at the same location by external-beam therapy. For example, if a dose of 20 Gy were delivered to the whole pelvis by external-beam therapy, the isodose level to be considered would be 60 —20 Gy = 40 Gy. Nevertheless, it is recognized that the combined dose does not necessarily produce the same effect as a similar dose from intracavitary therapy alone. For intracavitary therapy at medium or high dose

ABSORBED DOSE AT REFERENCE POINTS

Several reference points are in current use. Some are relatively close to the sources and related either to the sources or to organs at risk; others are relatively far from the sources and are related to bony structures. The following definitions apply to the case where the doses are calculated from two perpendicular radiographs, anterioposterior (AP) and lateral. When other methods are used, such as stereographic X-ray films, oblique perpendicular radiographs or transverse sections (CT scans), the calculations need to be modified. Reference points close to the sources and related to the sources

As such points are located in a region where the dose gradients are high, any inaccuracy in the determination of distance results in large uncertainties in the absorbed doses evaluated at these points. Such calculated absorbed doses do not, therefore, seem an appropriate means of characterizing an intracavitary application and/or of reporting the target absorbed dose, particularly if rigid source combinations are not used. Such points are not recommended in ICRU Report 38 [ 1 ].


Figure 6.14 Dose distribution of Fletcher-Suit rigid applicator, as in Figure 6.5, using total activity of 606 MBq (16.4 md) cesium-137 and showing the pear-shaped tissue volume, (a) Plane perpendicular to Z-axis. (b) Plane perpendicular to X-axis.

Reference points relatively close to the sources but related to organs at risk

The determination and specification of the absorbed dose to organs at risk (bladder, rectum, etc.) are obviously useful with respect to normal tissue tolerance limits. However, such information will be meaningful only to the extent that it is obtained and expressed in precise and well-codified ways. • Calculated values: reference points for the expression of the absorbed dose to the bladder and the absorbed dose to the rectum (see Figure 6.16) have been proposed by Chassagne and Horiot [51]. The bladder reference point is obtained as follows. A Foley catheter is used. The balloon must be filled with 7 cm3 of radio-opaque fluid. The catheter is pulled

downwards to bring the balloon against the urethra. On the lateral radiograph, the reference point is obtained on an AP line drawn through the center of the balloon. The reference point is taken on this line at the posterior surface of the balloon. On the frontal radiograph, the reference point is taken at the center of the balloon. The point of reference for the rectal dose is obtained as follows. On the lateral radiograph, an AP line is drawn from the lower end of the intrauterine source (or from the middle of the intravaginal sources). The point is located on this line 5 mm behind the posterior vaginal wall. The posterior vaginal wall is visualized, depending upon the technique, by means of an intravaginal mould or by an opacification of the vaginal cavity with a radio-opaque gauze used for the

Specific problems for intracavitary therapy in gynecology 97

/

Figure 6.16 Determination of the reference points for bladder and rectum as proposed by Chassagne and Horiot [51].)

Reference points related to bony structures

Figure 6.15 Geometry for measurement of the size of the pearshaped 60 Gy isodose surface (broken line) in a typical treatment of cervix carcinoma using one rod-shaped uterine applicator and two vaginal applicators. Plane a is the 'oblique'frontal plane that contains the intrauterine device. The oblique frontal plane is obtained by rotation of the frontal plane around a transverse axis. Plane b is the 'oblique' sagittal plane that contains the intrauterine device. The oblique sagittal plane is obtained by rotation of the sagittal plane around the AP axis. The height (d J and the width (d J of the reference volume are measured in plane a as the maximal sizes parallel and perpendicular to the uterine applicator respectively. The thickness (dt) of the reference volume is measured in plane b as the maximal size perpendicular to the uterine applicator. (From ICRU Report 38 [1].)

packing. On the AP radiograph, this reference point is at the lower end of the intrauterine source or at the middle of the intravaginal source(s). Monitoring of the absorbed dose rate to the rectum: in addition to calculating the rectal dose, the dose, or dose rate, can be measured at different points along the anterior rectal wall to ensure that no area of the rectal mucosa receives a dose above the tolerance level. This type of measurement requires special care in positioning the measuring probe. An example is given in Figure 6.17.

• The lymphatic trapezoid is obtained as follows (Figure 6.18). A line is drawn from the junction of S1-S2 to the top of the symphysis. Then a line is drawn from the middle of that line to the middle of the anterior aspect of L4. A trapezoid is constructed in a plane passing through the transverse line in the pelvic brim plane and the midpoint of the anterior aspect of the body of L4 (from Fletcher [52]). A point 6 cm lateral to the midline at the inferior end of this figure is used to give an estimate of the dose rate to mid-external iliac lymph nodes. At the top of the trapezoid, points 2 cm lateral to the midline at the level of L4 are used to estimate the dose to the low para-aortic area. The midpoint of a line connecting these two points is used to estimate the dose to the low common iliac lymph nodes. • The pelvic-wall reference point [51] can be visualized on an AP and a lateral radiograph and related to fixed bony structures. This point is intended to be representative of the absorbed dose at the distal part of the parametrium and at the obturator lymph nodes (Figure 6.19). On an AP radiograph, the pelvic-wall reference point is intersected by the following two lines: a horizontal line tangential to the highest point of the acetabulum, and a vertical line tangential to the inner aspect of the acetabulum. On a lateral radiograph, the highest points of the right and left acetabulum, in the cranio-caudal direction, are joined and the lateral projection of the pelvic-wall reference point is located at the mid-distance of these points. Evaluation of the absorbed dose at reference points, related to well-defined bony structures and lymph node areas, is particularly useful when intracavitary therapy is combined with external-beam therapy. It is also useful in


Figure 6.17 Measurement of the rectal dose rate. The rectal dose is measured following the insertion of the source applicators, either preloaded (low-activity treatment) or manually loaded with low-activity sources identical in design to those used during highactivity afterloaded treatment. Method A: the measuring probe is moved relative to a rigid guide tube inserted into the rectum and held in position. The point of maximum rectal dose rate is noted and the distance d, in cm, from the anal verge deduced. Method B: the measuring probe is moved so that the tip of the probe is moved along the midline of the recto-vaginal septum until the point of maximum dose rate is reached. Distance is taken as a direct reading on the central tube and at the anal verge. The dose rate and distance are recorded. The major disadvantage of Method A is that the probe tip cannot follow the surface of the anterior rectal wall closely. However, a IIowa nee for the distance of the probe sensor from the vagi no-recta I septum needs to be taken into account. (From ICRU Report 38 [1].)

Figure 6.18 Determination of the lymphatic trapezoid. On the left is an anteroposterior view and on the right a lateral view (see text). (From Fletcher [52].)

helping to avoid an overdose when intracavitary therapy is to be followed by surgery. CALCULATION OF DOSE DISTRIBUTION

The present recommendations, in particular the description of the reference volume encompassed by the 60-Gy isodose surface, necessitate the computation of complete dose distributions in several planes.

The respective planes for which the dose distribution is to be computed will depend on the technique and the particular clinical situation. However, as a minimum requirement, it is recommended that the dose distributions be computed in two planes: the oblique frontal plane and the oblique sagittal plane, both containing the intrauterine source. When practicable, it is recommended that dose distributions be calculated in additional sets of planes and

Concluding remarks 99

Figure 6.19 Determination of the right (RPW) and left (LPW) pelvic wall reference points (see text). (From Chassagne and Horiot

[57].;

that these dosimetric data be correlated with those obtained from radiographs or CT sections, in order to determine the absorbed dose at any relevant anatomical point. While this additional information will be of value in assessing effects in any individual patient, it will also provide: 1. the possibility of comparing the methods of specification used in different centers and of evaluating their respective merits; 2. the possibility of comparing the methods of specification used in historical series (mg»h, points 'A' and 'B') with the methods recommended in ICRU Report 38 [1]; 3. the possibility of deriving new clinical and radiobiological data and correlations which could improve treatment techniques and develop further the method of specification. 6.6*4 Definition of the 60-Gy reference volume in special situations • One linear source only. In some situations, only one linear source is present: in the case of a narrow vagina with a uterine source protruding into the vaginal cavity, in the case of vaginal irradiation with a central source from a cylindrical applicator. In estimating the volume in this simple case, the width is equal to the thickness, as the dose distribution is symmetrical about the source axis. • Vaginal sources only. When only vaginal sources are present, width is the largest dimension from right to left in an oblique frontal plane through the main axis of the vagina. Thickness is the largest dimension in a direction perpendicular to the above oblique plane. Height is measured along the vaginal axis, and is commonly shorter than the other two dimensions. • Rigid applicator. Provided that there is a fixed connection between vaginal and uterine sources, pre-

calculated isodose surfaces can be obtained for given loadings of the applicator. Therefore, pre-calculated dimensions of height, width, and thickness can be given [53]. Uterine packing in endometrial carcinoma. In connection with uterine packing, the same definitions of height, width and thickness given in section 6.6.3 can be used. However, two facts need to be noted: width and thickness are usually located at the level of uterine fundus (the pear-shaped volume is reversed), height should be determined in the oblique frontal plane, which gives the maximum dimension.

6.7

CONCLUDING REMARKS

At the end of this chapter, it should be stressed again that the aim of the ICRU Reports 38 and 58 [1,2] is not to encourage the users to depart from their current practice in brachytherapy. Treatment prescription is the responsibility of the radiation oncologist (or team) in charge of the patient; it is based on the radiation oncologist's judgement and experience and implies his or her responsibility. Reporting a treatment is another issue. The aim of the ICRU efforts is to recommend a common language for reporting a treatment in such a way that the clinical information can be exchanged in a relevant way, avoiding misinterpretation and confusion between radiation oncologists and departments. However, the use of the same sets of definitions, concepts, and approaches for prescribing, recording, and reporting a treatment has obvious advantages in simplifying the issues and avoiding confusion. It could be a long term beneficial consequence of the ICRU efforts. ICRU Report 58 [2] on interstitial brachytherapy was published at the end of 1997, but Report 38 [ 1 ] was published in 1985. Significant changes took place during the 14 years in the field of brachytherapy, especially the development and dissemination of high dose-rate, and pulse dose-rate applications.


Revision of ICRU Report 38 [1] becomes necessary and is welcomed by the radiation oncology community, as indicated by a recent inquiry [54,55]. The ICRU initiated a revision of Report 38, in 1998, on the basis of the answers to a questionnaire sent to the ESTRO members and a large survey of the recent literature. The following topics are considered: HDR, MDR, PDR, exploitation of the patient data provided by the modern imaging techniques, localization of the different Volumes', and identification of the organs at risk, specification of dose, combination of external and intracavitary therapy, three-dimensional treatment planning, and radiobiological issues raised by the different dose rates which can now be applied. The use of the TRAK should be encouraged. The fact that several companies use this quantity to specify the sources they are manufacturing will certainly facilitate its general use (e.g., Amersham,1 CIS Bioindustries,2 Mallinckrodt Medical3). Finally, as in externa-beam therapy (see ICRU Report 50 [6]), several levels of complexity could be proposed for reporting the treatments in brachytherapy (see, for example, reference 56): • Level 1: basic techniques-minimum requirements. A standard applicator is used, with a fixed geometry. Unambiguous and simple definitions of reference points are required. Radiographs are taken to check the position of the applicator. • Level 2: advanced techniques-modern radiotherapy standards. An individual assessment of absorbed doses at reference points, in different volumes (GTV, CTV, PTV), organs at risk, and normal anatomy is needed, based on radiographs taken in well-defined geometry or CT sections. Computer-assisted dose calculations are performed in three planes at different levels/sections, indicating accurately the doses at the chosen reference points, reference volume(s), and other volumes of interest, e.g., high dose volumes. • Level 3: developmental techniques-clinical research. Planning and performance of brachytherapy according to proposed level 3 imply individualized three-dimensional, computer-assisted assessment of the patient anatomy based on sectional imaging (e.g., with CT, MRI, ultrasound). The different volumes, such as GTV, CTV, PTV, and organs at risk, can be identified and localized. This makes possible accurate three-dimensional dose computation at selected reference points and in different volumes of interest. Dose-volume histograms can also be computed.

1. Amersham International pic, Amersham Laboratories, White Lion Road, Amersham, Buckinghamshire HP7 9LL, UK. 2. CIS Bioindustries (Compagnie ORIS Industrie S.A.), CEN Saclay, 91190 Gif-sur-Yvette, France. 3. Mallinckrodt Medical B.V., Westduinweg 3, NL-1755 LE Petten, The Netherlands.

As in external-beam therapy, the limits between the three levels proposed for reporting in brachytherapy are not definitely fixed, but may vary, in time, with the development of the imaging, computation, and dosimetry techniques.

REFERENCES 1. International Commission on Radiation Units and Measurements (1985) Dose and Volume Specification for Reporting Intracavitary Therapy in Gynecology, ICRU Report 38,7910 Woodmont Avenue, Bethesda, Maryland 20814, USA. 2. International Commission on Radiation Units and Measurements (1997) Doseand Volume Specification for Reporting Interstitial Therapy, ICRU Report 58,7910 Woodmont Avenue, Bethesda, Maryland 20814, USA. 3. International Commission on Radiation Units and Measurements (1976) Determination of Absorbed Dose in a Patient Irradiated by Beams of X or Gamma Rays in Radiotherapy Procedures, ICRU Report 24,7910 Woodmont Avenue, Bethesda, Maryland 20814, USA. 4. Mijnheer, B.J., Battermann, JJ. and Wambersie, A. (1987) What degree of accuracy is required and can be achieved in photon and neutron therapy? Radiother. Oncol., 8, 237-52. 5. International Commission on Radiation Units and Measurements (1978) Dose Specification for Reporting External Beam Therapy with Photons and Electrons, ICRU Report 29,7910 Woodmont Avenue, Bethesda, Maryland 20814, USA. 6. International Commission on Radiation Units and Measurements (1993) Prescribing, Recording and Reporting Photon Beam Therapy, ICRU Report 50,7910 Woodmont Avenue, Bethesda, Maryland 20814, USA. 7. International Commission on Radiation Units and Measurements (1999) Prescribing, Recording and Reporting Photon Beam Therapy (Supplement to ICRU Report 50), ICRU Report 62,7910 Woodmont Avenue, Bethesda, Maryland 20814, USA. 8. Paterson, R. and Parker, H.M. (1934) A dosage system for gamma ray therapy. Br.J. Radio!., VII, 592. 9. Paterson, R. and Parker, H.M. (1952) A dosage system for interstitial radium therapy. Br.J. Radiol., 25,505-16. 10. Meredith, W.J. (1967) Radium Dosage: the Manchester System. Edinburgh, Livingstone. 11. Quimby, E.H. and Castro, V. (1953) The calculation of dosage in interstitial radium therapy. Am.J. Roentgenol., 70,739-49. 12. Pierquin, B. (1964) Precis de Curietherapie, EndocurietherapieetPlesiocurietherapie. Paris, Masson. 13. Pierquin, B., Dutreix, A., Paine, C, Chassagne, D., Marinello, G. and Ash, D. (1978) The Paris System in interstitial radiation therapy. Acta Radiol. Oncol., 17, 33^7.

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31. Dutreix, A. and Wambersie, A. (1975) Specification of gamma-ray brachytherapy sources. Br.J. Radiol.,48,1034.

15. International Union Against Cancer (1997) TNM Classification of Malignant Tumours, 5th edn, ed. L.H.

32. Comite Francais de Mesure des Rayonnements lonisants (1983) Recommendations pour la Determination des Doses

Sobin and C.H. Wittekind. New York, Wiley-Liss and Sons. 16. International Union Against Cancer (1990) TNM Atlas, Illustrated Guide to the TNM/pTNM, Classification of malignant tumours, 3rd edn, ed. 0. Spiessl et al. Berlin, Springer Verlag.

Absorbeesen Curietherapie, Rapport du Comite Francais 'Mesure des Rayonnements lonisants' No. 1. Paris, Bureau National de Metrologie. 33. BCRU (1984) Specification of brachytherapy sources, Memorandum from the British Committee on Radiation

17. American Joint Committee on Cancer (1988) Manual for Stagingof Cancer, 3rd edn, ed. O.H. Beahrs, D. Henson,

Units and Measurements. Br.J. Radiol., 57,941-2. 34. AAPM (1987) Specification of Brachytherapy Source

R.V.P. Mutter and M.H. Myers. Philadelphia, J.P. Lippincott. 18. Dutreix, A., Marinello, G. and Wambersie, A. (1982)

Strength, AAPM Report No. 21. New York, American Institute of Physics. 35. Netherlands Commission on Radiation Dosimetry (1991)

Dosimetrieen Curietherapie. Paris, Masson. 19. Anderson, LL, Hilaris, B.S. and Wagner, LK. (1995) A

Recommendations for Dosimetry and Quality Control of

normograph for planar implant-planning.

Radioactive Sources used in Brachytherapy, NCS Report 4,

Endocuriether./Hypertherm. Oncol., 1,9-15.

Netherlands Commission on Radiation Dosimetry,

20. AAPM (1993) Remote Afterloading Technology, AAPM Report No. 41. New York, American Institute of Physics. 21. Wu, A., Ulin, K. and Sternick, E.S. (1988) A dose homogeneity index for evaluating 192-lr interstitial implants. Med. Phys.,15,104-7. 22. Paul, J.M., Koch, R.F. and Philip, PC. (1988) Uniform analysis of dose distribution in interstitial brachytherapy dosimetry systems. Radiother. Oncol., 13,105-25. 23. Saw, C.B. and Suntharalingam, N. (1991) Quantitative assessment of interstitial implants. Int.J. Radial Oncol. Biol.Phys., 20,135-139.

Bilthoven. 36. British Institute of Radiology (1993) Recommendations for Brachytherapy Dosimetry. Report of a Joint Working Party of the BIR and the IPSM. London, British Institute of Radiology. 37. Nath, R., Anderson, LL, Luxton, G., Weaver, K.A., Williamson, J.F. and Meigooni, A.S. (1995) Dosimetry of interstitial brachytherapy sources: recommendations of the AAPM Radiation Therapy Committee Task Group No. 43. Med. Phys., 22,209-34. 38. Societe Francaise des Physiciens d'Hopital (1995) Controle

24. Neblett, D., Nisar Syed, A.M., Puthawala, A.A., Harrop, R.,

de Qua lite en Curietherapie par lridium-192 a Haul Debit

Frey, H.S. and Hogan, S.E. (1985) An interstitial implant technique evaluated by contiguous volume analysis. Hypertherm. Oncol., 1,213-21. 25. Bridier, A., Kafrouni, H., Houlard, J.P. and Dutreix, A.

deDose, Rapport No. 11, Commission de Curietherapie,

(1988) Comparison des distributions de dose en

Gamma-ray Sources, ICRU Report 18,7910 Woodmont Avenue, Bethesda, Maryland 20814, USA. 40. Bernard, M., Guille, B. and Duvalet, G. (1975) Mesure du

in Radiotherapy, IAEA SM-298/23, IAEA, Vienna.

debit d'exposition lineique nominal des sources a une

McCrae, D., Rodgers, J. and Dritschilo, A. (1987) Dose-

dimension, utiliseesen curietherapie./ Radiol. Electrol.,

volume and complication in interstitial implants for breast carcinoma. Int.J. Radial Oncol. Biol. Phys., 13, 525-9. 27. Anderson, LL (1986) A 'natural' volume-dose histogram for brachytherapy. Med. Phys., 13,898-903. 28.

Measurements (1970) Specification of High Activity

curietherapie interstitielle autour des sources continues et discontinues. International Symposium on Dosimetry 26.

Institut Curie, 26 rue d'Ulm, 75231 Paris Cedex. 39. International Commission on Radiation Units and

56,785-90. 41. Ling, C.C. and Gromadski, Z.C. (1981) Activity uniformity of 192lrseeds. Int.J. Radial Oncol. Biol. Phys., 7,665-9. 42. Kolkman-Deurloo, I.K.K., Visser, A.G., Niel, C.G.J.H, Driver, N. and Levendag, P.C. (1994) Optimization of interstitial

Laarse, R. van der and Prins, T.P.E. (1994) Comparing the

volume implants. Radioth. Oncol., 31,229-39.

Stepping Source Dosimetry System and the Paris System

43. Dutreix, A. and Wambersie, A. (1968) Etude de la repartition des doses autour de sources ponctuelles

using volume-dose histograms of breast implants. In Brachytherapy from Radium to Optimization, ed. R.F. Mould, J.J. Battermann,A.A. Martinez and B.L Speiser. Veenendaal, The Netherlands, Nucletron, 352-72. 29. Merrick, G.S., Butler, W.M., Dorsey, A.T., and Walbert, H.L (1997) Prostaticconformal brachytherapy: 125l/103Pd postoperative dosimetric analysis. Radial Oncol. Invest., 5,305-13. 30. National Council on Radiation Protection and Measurements (1974) Specification of Gamma-ray

alignees. Acta Radiol., 7,389--tOO. 44. Henschke, U.K., Hilaris, B.S. and Mahan, G.D. (1966) Intracavitary radiation therapy of cancer of the uterine cervix by remote afterloading with cycling sources. Am. J. Roentgenol.,96,45. 45. Joslin, C.A., Liversage, W.E. and Ramsay, N.W. (1969) High dose-rate treatment moulds by afterloading techniques. Br.J. Radiol.,42,108. 46. Joslin, C.A., Smith, C.W. and Mallik, A. (1972) The

Brachytherapy Sources, NCRP Report 41,7910 Woodmont

treatment of cervix cancer using high activity 60-Co

Avenue, Bethesda, Maryland 20814, USA.

sources., Br. J. Radiol., 45,257.

102 Dose specification and reporting: the ICRU recommendations 47. von Essen, C.F. (1980) Clinical application of the Brachytron: the San Diego technique for treatment of cancer of the cervix. In High Dose-rate Afterloading in the

48.

uterine cervix. In Textbook of Radiotherapy, ed. G.H. Fletcher. Philadelphia, Lea & Febiger, 720-851. 53. International Atomic Energy Agency (1972) Atlas of

Treatment of Cancer of the Uterus, ed. T.D. Bates and R.J.

Radiation Dose Distributions, Vol. IV, Brachytherapy

Berry. British Journal of Radiology Special Report 17, p. 117.

Isodose Charts. Sealed Radium Sources, ed. M. Stovall, L.H.

Hall, E.J. (1994) Radiobiologyfor the Radiologist,

Agency, Vienna.

Philadelphia, J.B. Lippincott Company. 49. van Limbergen, E., Chassagne, D. Gerbaulet, A. and Haie, C. (1985) Different dose rates in preoperative endocavitary brachytherapy for cervical carcinoma./ Eur. Radiother., 1,21-7. 50. Leborgne, F., Fowler, J.F., Leborgne, J.H., Zubizaretta, E. and Chappell, R. (1997) Biologically effective doses in medium dose rate brachytherapy of cancer of the cervix. Radial Oncol. Invest., 5,289-99. 51. Chassagne, D. and Horiot, J.C. (1977) Propositions pour une definition commune des points de reference en curietherapiegynecologique.y. Radiol. Electrol., 58,371. 52. Fletcher, G.H. (1980) Squamous cell carcinoma of the

Lanzl and W.S. Moos. Vienna, International Atomic Energy 54. Groupe Europeen de Curietherapie-European Society for Therapeutic Radiology and Oncology (1998) Workshop ICRU 38: The basis for a revision (Dir. R. Potter), Napoli, 11-13 May. 55. Potter, R., van Limbergen, E., Gerstner, N. and Wambersie, A. (2000) Survey of the use of the ICRU 38 in recording and reporting in brachytherapy of cervical cancer. Radiother. Oncol. 56. Potter, R., Kovacs, G. and Haverkamp, U. (1995) 3D Conformal Therapy in Brachytherapy, 8th International Brachytherapy Conference, Nice (France), 25-28 November 1995, Nucletron-Oldelft, PO Box 930,3900 AX Veenendaal, The Netherlands.

7 Afterloading systems A. FLYNN

7,1

INTRODUCTION

The aim of this chapter is to examine the various afterloading systems that are currently available and also some that are perhaps not strictly currently available but have been used in the recent past. It is not intended to be a complete itemization of the subject, but rather an overview of the main types of equipment and the uses to which they are generally put. It is anticipated that this chapter will help the newcomer to this field to see which systems are particularly suited to each treatment site and method of treatment. It is inevitable in an analysis of this nature that there will be omissions, as it is impossible to cover every aspect of each use of each piece of equipment or technique, and the writer apologizes in advance to any user of this equipment if his or her particular technique has been omitted. However, it is hoped that there is sufficient information for a user or potential user to perceive the relative clinical and technical advantages and disadvantages of each method or equipment. No attempt has been made to assess the relative costs of the equipment, as this will vary from one country to another depending on the local supply situation and servicing and delivery costs. However, it will become apparent that some types of equipment are designed to be specific for a particular site in the body, whereas others are more flexible in the way that they can be adapted for use in several body sites, and the financial considerations of whether a particular machine will be more or less cost-effective will depend, in part, on the anticipated number of applications and the case mix. It is stated at the outset that, whilst various suppliers of radioactive sources and manufacturers of brachyther-

apy equipment are mentioned, this should not be taken to imply any specific recommendation of the products of any individual company. The chapter does not make recommendations of the merits and demerits of similar treatment machines made by the different manufacturers. The reader will appreciate that machines which are similar (but not identical) in their mode of operation are available from different manufacturers and suppliers: an example of such a pair of similar machines is the microSelectron-HDR (supplied by Nucletron) and the Varisource (supplied by Varian). It is the responsibility of the prospective purchaser to decide which particular machine of a certain type is best suited to his or her purpose, bearing in mind the cost, safety aspects, supplier's service record, and all other appropriate considerations. The reader is referred to Chapter 1 for further details of the radioactive sources associated with these afterloading techniques, and to Chapters 8 and 9 for a full discussion of commissioning and quality assurance aspects of low, high, and pulsed dose-rate equipment. An excellent review of remote afterloading technology may be found in American Association of Physicists in Medicine (AAPM) Report No. 41 [1], and internationally agreed specifications for the safety requirements of remotely controlled afterloading equipment may be found in reference 2.

7.2 ADVANTAGES OF AFTERLOADING The accelerated development of afterloading from the 1960s onwards was initially driven by the desire to

104 Afterloading systems

improve the radiation protection environment of the staff involved in the provision of brachytherapy treatments. Readers of older textbooks will find pictures of implants using many radium needles, all of which were inserted manually in the operating theatre, with the consequent radiation exposure of the clinicians and other staff, and there are both documented and anecdotal reports of radiation injury to the fingers of radiotherapists. The technique of afterloading involves the placing of the non-radioactive needles, tubing, or applicators into the patient without the presence of the radioactive sources. Often, dosimetry radiography will be performed at this stage using non-radioactive marker inserts in the applicators. The radioactive material is inserted only when all of the preliminary procedures have been carried out and the operator is satisfied that the applicators are placed correctly within the treatment site. In the case of manual afterloading, the sources are introduced into the carrier needles or tubing directly by the operator, using forceps or other appropriate manipulation instruments. This may be done in the operating theatre (for example, in the case of iridium-192 hairpins) or perhaps on the ward (as may be the case for cesium-137 gynecological source trains or iridium-192 wires). In this way, the radiation exposure to operating room and radiography staff may be minimized. An important 'by-product' of the use of non-radioactive materials at this stage is that the radiotherapist is able to spend more time in the placing of the applicators and can therefore obtain an improved geometry within the implant site. Thus, afterloading confers a benefit to the patient, even with this minimal afterloading method. However, it is apparent that with manual afterloading the radiation protection advantage is gained only in the initial phases of the treatment and that, eventually, the sources themselves have to be inserted into the applicators by the operator and the patient has to be cared for by the nursing and clinical staff, with radioactive sources in position, for the duration of the treatment. The use of remote or machine afterloading extends the radiation protection advantage to the whole of the brachytherapy treatment in that not only are the sources placed initially in the applicators by the machine, but they may also be temporarily withdrawn from the patient into the machine's protected safe for the duration of any nursing procedures that the patient may require. In addition,.the treatment machine timer(s) controls the duration of the treatment to a high degree of accuracy. Whereas considerations of radiation protection were the main driving force for the development of afterloading, more recently other advantages have become apparent. For example, high dose-rate (HDR) and pulsed dose-rate (PDR) brachytherapy would not be possible (or would at least be highly inconvenient) without the use of afterloading devices. Also, the modern development of conformal brachytherapy using stepping or

oscillating source positions has been dependent on the availability of computer-controlled, accurate source positioning, which would not be possible without afterloading.

73 DEFINITION OF LOW, MEDIUM, HIGH, AND PULSED DOSE RATES There is no general agreement in the literature regarding the boundaries between low, medium, and high dose rate or even where the relevant dose rates are defined. Both the International Commission for Radiological Units (ICRU) [3] and the AAPM [1] base their definitions on the dose rate at the prescription point or prescription isodose. ICRU 38 is a document concerned solely with intracavitary therapy, so it may be reasonably assumed that it refers to the dose rate at or near point A of the Manchester System, but a similar inference cannot be made for the AAPM categories. The ICRU recognizes three categories: 0.4 Gy Ir1 to 2 Gy Ir1 2 Gy Ir1 to 12 Gy Ir1 greater than 0.2 Gy mhr1 (i.e., 12Gyh-') although it acknowledges that these definitions are debatable. On the other hand, the AAPM defines LDR in terms of '... conventional doses of about 10 Gy are delivered daily ...,' which implies a prescription dose rate of about 0.5 Gy Ir1. An HDR category is defined as having a prescription dose rate greater than 0.2 Gy min~', which is the same as the ICRU definition of HDR. MDR is defined as being 'between LDR and HDR,' but the boundary between LDR and MDR is not defined. It is interesting that the dose rate of about 1.5 Gy Ir1 that has been frequently used for cervix treatment since afterloading was introduced, and for which radiobiological considerations require a dose rate correction factor to be used, is actually less than the lower boundary for MDR as defined by the ICRU, and is therefore regarded as LDR by this authority, although it could be classed as MDR according to the AAPM definitions. However, this dose rate is often colloquially called MDR. Another definition may arise from the standpoint of radiation protection, where the interest is in the environmental levels of radiation around equipment rather than the clinical dose rates. For example, the Guidance Notes for the United Kingdom's Ionising Radiation Regulations [4] defines equipment giving a dose rate of less than 10 m Gy h-1 at 1 m as LDR; radiation levels greater than this are HDR. This boundary corresponds approximately to a dose rate at point A of 0.4 Gy mur1, which is not the same as the ICRU and AAPM boundary. In practice, these differences are somewhat academic, as HDR machines generally operate at dose rates well Low dose rate (LDR): Medium dose rate (MDR): High dose rate (HDR):

Manual afterloading systems 105

above these boundaries, typically at around 2 Gy mhr1, which is well within the HDR category as denned by all the aforementioned documents. The boundary between LDR and MDR is more questionable. In any event, the only safe practice when reporting radiotherapy is to state exactly the dose, dose rate, and fractionation used, as recommended in the ICRU Report 38 [3]. The idea behind pulsed dose-rate (PDR) brachytherapy is to replace continuous low dose-rate brachytherapy (CLDR) by a series of 'pulses' of higher dose-rate treatment. Brenner and Hall [5] and Fowler and Mount [6] have published analyses of studies of the radiobiology of these modalities, from which come recommendations that, to obtain equivalence to CLDR, the PDR should give the same overall dose in the same overall time, provided that the pulse interval is about 1 h, the length of each pulse should be not less than 10 min, and each pulse should give a dose of about 0.5 Gy, i.e., a dose rate of not more than about 3 Gy h-1 within the pulse. Some early studies of the use of PDR have been reported [7,8]. The main advantage of PDR is technical, in that it enables the equivalent of CLDR to be given with a single stepping source, thereby increasing the range of active lengths and dose distributions that may be obtained.

7A MANUAL AFTERLOADING SYSTEMS

7.4.1 Iridium wires Iridium wire has an external diameter of 0.3 mm and is generally supplied as a loosely wound coil containing a length of 500 mm, although other lengths may be available to special order. In cross-section there is a central 'core' of iridium/platimim alloy of diameter 0.1 mm, which is surrounded by a sheath of platinum of thickness 0.1 mm, giving the overall diameter of 0.3 mm, as stated above. It is available in a range of activities; for further details, the reader is referred to Chapter 1. In use, the wire is cut to the appropriate lengths required for the particular application. Before being afterloaded into the needles or 'outer' tubing implanted in the patient, it is normal practice for the wire itself to be encapsulated into the so-called 'inner' tubing. Once the wire has been fed into its encapsulating tubing, the latter is deformed slightly, either mechanically (for example by the Amersham crimping tool or the Amersham Iridium Wire Loader crimping tool) or by heat (for example, by the now obsolete TEM Iridium Wire Loader), to provide a seal in the tubing at each end of the wire which fixes the wire into the tubing. Nonactive ends of empty tubing may be left at each end of the wire and these may be used to control the position of the active material within the 'outer' tubing or needles. Equipment to facilitate the preparation of iridium wires is commercially available.

The implantation of the carrier tubing into the treatment site may be performed either with flexible nylon tubing or with rigid needles, depending upon the circumstances of the particular case. Surgical methods of placing the tubing in the implant site have been described by Pierquin et al. [9]. The encapsulated iridium wires are held in place for the duration of the implant by crimped lead discs separated from the patient's skin by nylon balls. These may be easily removed to allow removal of the wires from the patient at the end of treatment. The main problem with the use of these flexible tubes is that it is difficult to achieve good implant geometry, as the tubes do not generally remain straight in the patient. The use of rigid needles (and, where possible, templates) permits improved implant geometry: this method is preferred where possible.

7.4.2 Iridium hairpins These have a larger diameter than the wires and are therefore more rigid. The overall diameter is 0.6 mm, this being made up of a 0.4 mm diameter central 'core' of iridium/platinum alloy, surrounded by a platinum sheath of thickness 0.1 mm. They are available in a preformed 'hairpin' shape, as shown in Figure 7.1. The length of each 'leg' of a hairpin is 60 mm, and this may be cut down to the required length just prior to implantation. Single pins may be available to special order. Hairpins are implanted into the tissue with the aid of slotted hairpin guides. The guides are implanted and their positions checked by radiography. If they appear satisfactory, the hairpins are inserted into the guides, which are then removed, leaving the hairpins in the tissue. These are secured by a suture around the crosspiece of the hairpin.

Figure 7.1 Indium wire hairpin (courtesy Nycomed-Amersham pk).


Hairpins are particularly useful in head and neck implants where the implant site is often only accessible from one end. The radioactive 'bridge' across the top of the hairpin provides an effective 'crossing source,' which allows the reference isodose to be brought up to the level of the mucosa.

7*43 Iridium ribbons In North America, iridium-192 is available in the form of 'ribbons.' A ribbon consists of 12 seeds loaded into a nylon carrier, the seeds being placed at 10 mm intervals. They are used in a similar way to iridium wires in that the ribbon is afterloaded into previously positioned carrier tubing in the implant site. The ribbon may be shortened to the required active length by cutting between the seeds. One advantage over conventional wire is that it becomes unnecessary to cut through the active material itself when preparing the sources. Otherwise, the method of use is similar to that for the iridium wires already described. 7.4*4 Iodine seeds Iodine seeds are mainly used for non-afterloaded techniques and are therefore beyond the scope of this chapter. Examples of their use are for transperineal implantation of the prostate, which has been described by Blasko et al. [10], and for the manufacture of ophthalmic applicators. However, the treatment of brain lesions using removable afterloaded high activity seeds has also been described [11]. 7*4*5 Tantalum wire This material was similar in construction to iridium wire, which has now superseded it, owing to the latter's greater specific activity. It was used in the late 1940s and early 1950s as a source for interstitial implants.

the Manchester ovoids), but they are cylindrical in shape and incorporate tungsten rectal and bladder shielding. The colpostats are linked external to the patient and may move with a 'scissor' action to allow the separation between them to be varied. A further modification was reported and evaluated in 1985 [ 14] to enable the applicator system to be used with the Selectron-LDR afterloading unit. 7*4*7 Amersham Gynecological System A manual afterloading system is supplied by NycomedAmersham. The applicators are based on the Manchester System and are designed to allow the ovoids to be separated by a 'washer' or 'spacer' or be used 'in tandem.' There is a choice of three sizes of applicators. The applicators are made of semi-flexible plastic tubing and are supplied pre-sterilized and are intended to be disposed of after a single use. The uterine tube and ovoids are linked together, but they can slide longitudinally with respect to one another to accommodate differing anatomy. In contrast to the traditional Manchester System, the ovoids lie with their axes parallel to the vaginal axis. The source trains used with these applicators consist of a flexible helical spring, which is loaded with an arrangement of miniature cesium-137 sources and spacers. A number of standard source train arrangements are available and, if required, the supplier can make up trains to the customer's requirements at the time of purchase. Normally, therefore, a selection of trains would be needed to cover the variations in source requirements envisaged. The handle of each source train is marked with a code to aid identification, as shown in Figure 1.2 in Chapter 1. Figure 7.2 shows a typical applicator set. Other applicators are available based on the Fletcher and the Henschke systems, but these use the standard cesium-137 tubes. This system is described in more detail in Chapter 1.

7*4*6 Fletcher-Suit applicators These applicators for treatment of the uterine cervix developed from a non-afterloading system designed by Fletcher [12] and modified in the early 1960s by Suit [13]. Suit's modification allowed the use of afterloaded radium sources, now superseded by cesium-137 sources, held in a hinged carrier, which could be inserted into the tubes. The source arrangement has similarities to the traditional Manchester System (see Chapter 4) in that it employs a line source in the uterine canal and two vaginal sources, one placed in each lateral fornix. In the Fletcher-Suit system, the vaginal sources are called 'colpostats' rather than 'ovoids.' There are three sizes of colpostat, 20 mm, 25 mm, and 30 mm diameter (similar to

Figure 7.2 Amersham manual afterloading system for the uterine cervix; plastic applicator set (courtesy NycomedAmersham pic).

Lose dose-rate remote systems 107

7.5 LOW DOSE-RATE REMOTE SYSTEMS The reasons behind the introduction of remote afterloading systems are considered in section 7.2. However, it will also be apparent from the foregoing descriptions of manual afterloading systems using pre-prepared source trains that another significant disadvantage to this method is the limited availability of source arrangements. An institution would generally have only a small number of source trains, which limits the number of applicator combinations and dose distributions that may be employed. Remote afterloaders were therefore designed to attempt to overcome this restriction by increasing the number of available source patterns. In earlier machines, this was done by having a larger number of preloaded trains, whereas later machines allow the user to compose source trains in the required pattern at the time of use, or by using a single source whose movement through the applicators can be controlled to give the desired dose distribution. This section reviews some of the LDR afterloaders and their applications.

7.5.1 Curietron The Curietron is one of the older type of afterloaders. It was designed and manufactured in France and was used during the 1960s and 1970s, though it is now largely obsolete. The machine was used for the treatment of the uterine cervix. It employed pre-loaded flexible source trains, consisting of cesium-137 sources and spacers in various combinations. The trains were mechanically coupled to drive motors and up to three trains could be transferred to the patient applicators. The treatment exposure of each train could be independently timed and the treatment could be readily interrupted to allow for nursing care. The treatment unit contained a safe for the source trains, to which they were withdrawn during interruptions and at the end of the treatment. The capacity of the main treatment unit was limited to four source trains, so the Curietron also had a 'secondary' radiation sources safe, separate from the main treatment unit, which housed extra source trains, thereby increasing the range of treatment dose distributions that could be obtained. When the applicators and treatment requirements for a particular application were known, the appropriate source trains were transferred to the main treatment unit, from whence they were subsequently driven into the applicators, as described above. The radioactive sources were cesium-137 pellets of length 5.3 mm and diameter 1.8 mm. These were loaded into source holders, with spacers, to give a variety of active lengths. The use of this machine is described in reference 15.

7.5.2 Selectron-LDR/MDR Whilst a number of types of afterloading machines predate the Selectron-LDR (Nucletron), it could be argued that this machine was the first LDR afterloading machine to achieve worldwide acceptance. It was developed by Nucletron during the late 1970s and has been in extensive clinical use since around 1980. There are over 100 installations around the world and the reader will find numerous references in the literature relating to its clinical use. It was designed initially for the treatment of the uterine cervix [16], but it has also been used for intraluminal and surface applicator treatments. The Selectron-LDR was designed to circumvent the aforementioned difficulty by allowing the user the flexibility of being able to construct source trains as required for a particular insertion. To this end, it contains up to 48 cesium-137 sources of external diameter 2.5 mm (see Figure 1.3 in Chapter 1) and a large number of inactive spacers, also of diameter 2.5 mm. The sources and spacers are initially stored in their respective compartments of the main safe. When a source train is programmed and composed by the user, the machine selects sources and spacers in the correct order, as required, and places them in a vertical column in the so-called 'intermediate safe.' Three-channel and six-channel versions of the machine are available, so this process is repeated until all the required channels have been prepared. When all channels have been composed, they may be pneumatically driven through flexible transfer tubes into the treatment applicators. The trains may be withdrawn into the intermediate safe during planned treatment interruptions, under alarm conditions, and finally at the end of the treatment. Each channel may be independently timed. Source activities between 20 mCi (740 MBq) and 40 mCi (1480 MBq) are available. Most users opt for the higher activity sources, which typically give a dose rate to the Manchester Point A of about 1.5-1.7 Gy tr1, putting it in what might be called the MDR category. The gynecological applicators are constructed of stainless steel, the tubing being 6 mm external diameter. They are available in various configurations, including the Manchester set, the Fletcher set (which incorporates shielding in the ovoids), the Henschke set, and a ring applicator set in which the vaginal component is in the form of a ring of sources around the cervical os. There are also applicators for vaginal and endometrial treatments. The open ends of the applicators are mechanically coded to ensure that they connect to the correct transfer tubes. The Selectron-LDR has also been used for the treatment of the oesophagus [17] and nasopharynx [18].

7.5.3 microSelectron-LDR High dose-rate afterloaders have now mainly superseded this machine. It is an LDR system that can position


radioactive sources into up to 18 treatment catheters simultaneously, and has been typically used for LDR implant therapy. The catheters have an external diameter of 2 mm and may be either flexible tubes or rigid needles. Flexible transfer tubes connect the catheters to the treatment unit. As with most other afterloaders, each catheter may be timed independently. A choice of source systems is available. Originally, the microSelectron-LDR was used with iridium wires. These were made from the standard coils of iridium wire (as described in section 7.4.1) and had to be made up to the required lengths and attached to the drive cables, using a preparation station supplied with the machine. A range of lengths would be made up to ensure that wires suitable for any proposed treatments were available. The treatment unit itself could store up to 18 wires; any further lengths were stored in a separate sources safe, from where they could be transferred to the treatment unit when required, in a manner reminiscent of the Curietron. The main disadvantage of these was the short half-life of iridium-192, which meant that new sources had to be prepared every few weeks. Later, miniature cesium-137 source trains were introduced, which overcame this disadvantage. Reference 19 describes an example of the use of this system.

7*5.4 Buchler System This machine has been used in both low dose-rate and high dose-rate versions, and in single-channel and threechannel configurations, and is intended principally for the treatment of the uterine cervix. It uses either cesium 137 or iridium-192 sources. Each channel is treated by a single source, rather than a train of sources as used in the machines described above. All sources are mechanically afterloaded, but the central source of a three-channel unit (or the only source of a single-channel unit) is mechanically coupled to a drive system which controls the position of the source in an oscillating manner within its catheter, the range and pattern of movement of the source being used to provide the required dose distributions. An eccentric cam within the drive system, the shape of which determines the position of the source at any instant, controls the oscillating movement of this source. The main advantage of this system is its reproducibility, it being necessary only to select the appropriate cam corresponding to the dose distribution required. However, the cams have to be specially made for each dose distribution, so it is inflexible in use, as changes in dose distribution cannot be implemented at short notice. Typical source activities are 300 mCi (11.1 GBq) of cesium-137 for low dose-rate use, but activities up to 4Ci (148 GBq) of cesium-137 or 20 Ci (740 GBq) of iridium-192 were used in high dose-rate versions.

7.6 HIGH DOSE-RATE SYSTEMS High dose-rate afterloading has become increasingly popular in recent years. The main advantage is the increased rate at which treatments can be carried out, which is particularly important when a high patient throughput is required. Treatment may be given in minutes instead of several hours or days, and may be given on a day-case basis in many instances. The short treatment times allow rigid rectal retractors to be used, thereby reducing the rectal dose compared with LDR systems. However, these advantages must be offset to some extent by the fact that the treatment has to be fractionated, so a patient may need several of these, albeit shorter, treatments within a course of treatment. Also, there may be a clinical disadvantage in that a patient may need several anesthetic episodes during the course of treatment, depending on the insertion procedure being performed. Also, the treatment rooms required for HDR equipment need to be more substantial than for LDR equipment, due to the extra radiation protection required, making HDR installations generally more expensive. Reference is made in the clinical sections of this book to some of the treatment regimes used in HDR brachytherapy; these, of course, are very different from those used for the equivalent LDR therapy due to radiobiological considerations. Now that much experience has been gained in the clinical applications of HDR therapy, most new installations of afterloading equipment are of this type. The reader is referred to a recently published report of the AAPM Task Group 59, which considered the practice of HDR afterloading brachytherapy [20].

7.6.1 TEMCathetron Although most of these machines have now been decommissioned, the Cathetron is discussed here as it was the first HDR afterloader to be put into general use, particularly for the treatment of the uterine cervix, and considerable valuable data regarding treatment schedules for this condition were obtained using this machine. It was introduced in 1966 and its early clinical use is described by O'Connell et al. [21]. It consisted essentially of a spherical lead safe in which there were channels for nine source trains. The source trains were made up of cobalt60 pellets and inactive spacers; these were made up to the user's specification at the time of purchase and were therefore fixed for the useful life of the sources. The sources and spacers were held in helical steel springs (the source holders), which were welded on to the end of a Bowden cable, at the distal end of which was an 'eye' connector. When in the standby state, the sources rested close to the center of the safe, each in its own channel, with the end of the Bowden cable projecting from the rear of the safe.

High dose-rate systems 109

Outside the treatment room was the control and drive system. This provided three drive cables, each powered by its own electric motor and independently timed. These drive cables entered the treatment room (through a curved track or under the floor, to maintain radiation protection) and could be connected to up to three (of the nine) source trains required for use. At the front of the safe, three hollow transfer tubes were connected to the output ports of the appropriate source trains, and these transfer tubes led to the stainless-steel applicators in the patient. The three drive cables and the three transfer tubes were color coded to enable them to be matched throughout the system, and mechanical and electrical interlocks ensured that everything had to be connected correctly before a source transfer could be initiated. The safe was designed for a maximum content of 50 Ci (1850 GBq) of cobalt-60. Source trains would usually be made up to provide for the various lengths of intrauterine tube and ovoids sizes of the Manchester (cervix) System. Some users also used this machine for the HDR treatment of surface moulds and appropriate source trains would then be included, for example perhaps a single source pellet for use as the center spot of a mould.

7.6.2

Selectron-HDR

The Selectron-HDR (Nucletron BV) operates in a similar general manner to its stable-mate, the Selectron-LDR, in that source trains consisting of 2.5 mm diameter sources and spacers are composed at the time of use, and these are then transferred pneumatically to and from the applicators as required. However, there are differences in the source type and safe design, to accommodate the HDR requirements of this machine. In this case, the sources are cobalt-60 (see Chapter 1), each has a nominal activity of 500 mCi (18.5 GBq), and the machine can contain up to 20 such sources. There are three output channels, as the machine can only be used for one patient at a time. The system is controlled from the operator's desk situated outside the treatment room. The machine is designed specifically for gynecological treatments, and the treatment applicators are similar to (in fact, mechanically interchangeable with) those for the Selectron-LDR. However, for a busy center, much of the time advantage of HDR is lost if pre-treatment dosimetry has to be performed between performing the insertion and starting the treatment, and many users therefore use applicator systems whose geometry within the patient is predictable, allowing the use of pre-calculated treatment plans and standard treatment times. The Joslin-Flynn applicator (Figure 7.3) is an example of such an applicator system; this allows the operator to select one of two intrauterine tube lengths and one of two ovoid positions, and it also gives rectal dose sparing by means of a rigid retractor. Typically, dose rates of

Figure 7.3 Joslin-Flynn afterloading applicator (HDR) for the uterine cervix (courtesy Nucletron BV).

about 2 Gy min-1 at the Manchester Point A are obtained, and the rectal dose may be kept to less than 60% of the Point A dose. 7.63

Stepping source units

The availability of iridium-192 sources that are physically small but that contain typically an activity of 10-20 Ci (370-740 GBq) has led to the development of this type of treatment machine, in which a single source is sequentially stepped through a series of dwell positions in all the treatment applicators in turn, thereby removing the need for several sources or source trains to be present in the machine. There are several machines of this type now available; examples are the microSelectron-HDR (Nucletron), the Varisource (Varian), and various versions of the Gammamed (Isotopen-Technik Dr Sauerein). Whilst there are differences between the different system relating to source design, maximum catheter number and dimensions, number of dwell positions etc., they are sufficiently similar to be dealt with generically for the purpose of this present description. Generally, an encapsulated iridium-192 source is attached to the end of a drive cable. Usually, the machine also contains a 'check cable,' which is essentially a dummy source on its own drive cable. The purpose of the check cable is to be driven out through the transfer tubes and applicators before the source is transferred, in order to check the correct connection of all the components and also for obstructions or tight curves. The check cable may also be used as a simulated source for radiography in some systems. The source and check cable are driven out, when appropriate, by stepper motors to a claimed positional accuracy of ±1 mm. Each machine will treat a number of channels, for example up to 18 for the microSelectron-HDR and up to 24 for the Gammamed, and each channel may be 'treated' by a number of dwell positions, for example, up to 48 for the microSelectronHDR and up to 40 for the Gammamed. The interval


between the dwell positions depends on the type of machine, but is typically 2.5 mm, 5 mm, or 10 mm. The source diameter is small, typically about 1 mm, so the catheters through which it travels can also be narrow; an external diameter of 2 mm (6 French gauge) or less is common. Also, the length of travel of the source (and check cable) is long, from 1.5 to 2 m depending on the machine. The combination of these two features makes this type of machine very adaptable and it may be used for intraluminal, interstitial, and intracavitary therapy. Each of the individual dwell times in each of the catheters may in general be different, and this gives the user the opportunity to optimize dose distributions to suit the target volume. Optimization is dealt with more fully in Chapter 5. With older versions of these machines, data from the treatment planning computer had to be manually entered into the treatment unit; with multicatheter treatments and many dwell positions per catheter, this required a lot of data to be entered and was prone to errors. Later machines used a program card system to transfer the data, and the latest machines incorporate combined treatment planning and machine control systems into one computer. Iridium-192 has a half-life of 74 days, and source exchanges are required at (usually) 3-month intervals. Frequent source calibrations are therefore required - this and other quality assurance aspects are fully dealt with in Chapter 9. All the machines have various fail-safe systems built into them to reduce the possibility of errors and accidents. At the time of writing, machines of this type have been used experimentally for the emerging technique of intravascular brachytherapy. This is a developing field, so it is inappropriate to go into detail here, but the reader is referred to references 22 and 23 for further information.

2. BSI 5724 Section 2.17 (equivalent to IEC 602-1-17) (1990) Specification for Remote-controlled Automatically-driven Gamma-rayAfterloading Equipment. London, British Standards Institute. 3. ICRU Report 38 (1985) Dose and Volume Specification for Reporting Intracavitary Therapy in Gynecology. Bethesda, MD, International Commission on Radiation Units and Measurements. 4. N RPB (1988) Guidance Notes for the Protection of Persons against Ionising Radiations arising from Medical and Dental Use. Didcot, UK, National Radiological Protection Board. 5. Brenner, D.J. and Hall, E.J. (1991) Conditions for the equivalence of continuous to pulsed low dose rate brachytherapy. Int.). Radial Oncol. Biol. Phys.,20, 181-90. 6. Fowler, J.F. and Mount, M. (1992) Pulsed brachytherapy: the conditions for no significant loss of therapeutic ratio compared with traditional low dose rate brachytherapy. Int.J. Radial Oncol. Biol. Phys., 23,661-9. 7. Mazeron, J.S., Boisserie, G., Gokarn, N. and Baillet, F. (1994) Pulsed LDR brachytherapy: current clinical status. In Brachytherapy from Radium to Optimisation. Veenendaal,The Netherlands, Nucletron BV. 8. Swift, P.S., Fu, K.K., Phillips, T.L, Roberts, LW. and Weaver, K.A. (1994) Pulsed low dose rate interstitial and intracavitary therapy. In Brachytherapy from Radium to Optimisation. Veenendaal, The Netherlands, Nucletron, BV. 9. Pierquin, B., Wilson, J.F. and Chassagne, D. (1987) Modern Brachytherapy. New York, Masson. 10. Blasko, J.C., Ragde, H. and Schumacher, D. (1987) Transperineal percutaneous iodine-125 implantation for prostatic carcinoma using trans-rectal ultrasound and template guidance. Endocuriether. Hypertherm. Oncol., 3,

7.7 PULSED DOSE-RATE SYSTEMS The only commonly available PDR system is the microSelectron-PDR (Nucletron), which is an adaptation of the microSelectron-HDR machine. Its external appearance, mode of operation, and safety systems are similar. However, there are two major differences. First, the iridium-192 source contains less radioactivity, typically having an activity of 0.5 Ci (18.5GBq) to 1.0 Ci (37 GBq). Consequently, it is also physically smaller, having an active length of 0.5 mm and an overall length of 2.7 mm. Second, the operating software is different, allowing the source movement to be programmed for the pulsed nature of the treatment, as described in section 7.3.

131-9. 11. Liebel, S.A., Peschel, R.E., Hilaris, B.S., Gutin, P.M. and Wara, W.M. (1990) Principles of Implantation for Brain Tumours, Interstitial Collaborative Working Group. New York, Raven Press. 12. Fletcher, G.H., Shalek, R.J. and Cole, A. (1953) Cervical radium applicators with screening in the direction of bladder and rectum. Radiology, 60,77. 13. Suit, H.D., Moore, E.B., Fletcher, G.H. and Worsnop, B. (1963) Modification of Fletcher ovoid system for afterloading using standard radium tubes. Radiology, 81, 126. 14. Marbach, J.R., Stafford, P.M., Delclos, L and Almond, PR.

(1985) A dosimetric comparison of the manually loaded and Selectron remotely loaded Fletcher-Suit-Delclos utero-vaginal applicators. In Brachytherapy 1984. Veenendaal, The Netherlands, Nucletron BV.

REFERENCES

15. Jackson, A.W. and Davies, M.L (1983) In Radiation Treatment Planning, ed. N. Bleehan, E. Glatsein and J.

1. AAPM (1993) Remote Afterload ing Technology, AAPM Report No. 41. New York, American Institute of Physics, for The American Association of Physicists in Medicine.

Haybittle, New York, Marcel Dekker. 16. Wilkinson, J.M., Moore, C.J., Notley, H.M. and Hunter, R.D. (1983) The use of Selectron afterloading equipment to

References 111

17.

18.

19.

20.

simulate and extend the Manchester System for intracavitary therapy of the cervix uteri. Br.J. Radial., 56, 404-14. Rowland, C.G. (1985) Treatment of carcinoma of the oesophagus with a new Selectron applicator. In Brachytherapy 1984. Veenendaal, The Netherlands, Nucletron BV. Flores, A.D. (1989) Remote afterloading intracavitary irradiation for cancer of the nasopharynx. In Brachytherapy 2, Veenendaal, The Netherlands, Nucletron BV. de Ru, V.J., Hofman, P., Struikmans, H., Moerland, MA Nuyten-van-Deursen, M.J.H.and BattermannJ.J. (1994) Skin dose due to breast implantation for early breast cancer. In Brachytherapy from Radium to Optimisation. Veenendaal, The Netherlands, Nucletron BV. Kubo, H.D., Glasgow, G.P., Pethel, T.D., Thomadsen, B.R.

and Williamson J.F. (1998) High dose-rate brachytherapy treatment delivery: report of the AAPM Radiation Therapy Committee Task Group No. 59. Med. Phys., 25(4), 375-403. 21. O'Connell, D., Joslin, C.A., Howard, N., Ramsay, N.W. and Liversage, W.E. (1967) The treatment of uterine carcinoma using the Cathetron. fir. J. Radiol., 40,882-9. 22. Schopohl, B., Liermann, D., Pohlit, LJ. etal. (1996) 192lr endovascular brachytherapy for avoidance of intimal hyperplasia after percutaneous translumenal angioplasty and stent implantation in peripheral vessels: 6 years of experience. Int.]. Radial Oncol. Biol. Phys, 36,835-40. 23. Nath, R.,Amols, H.,Coffey, C.etal. (1999) Intravascular brachytherapy physics: report of the AAPM Radiation Therapy Committee Task Group No. 60. Med. Phys., 26(2), 119-52.

8 Quality assurance in low dose-rate afterloading ERICD.SLESSINGER

8.1

INTRODUCTION

The advent of remote afterloading brachytherapy devices has required that the scope of quality assurance in brachytherapy be broadened substantially. This is due to the fact that these devices are designed to perform the basic tasks that previously had been directly controlled by staff: source selection, transport and positioning in the treatment applicators, the monitoring of elapsed treatment time, and treatment termination. These remote functions should practically eliminate the radiation exposure to anyone involved in the treatment and care of brachytherapy patients. A comprehensive quality assurance program is necessary to verify that these devices perform in accordance with the manufacturers' specifications to deliver treatment accurately and safely [1]. This chapter describes the methodology for achieving those ends. The process starts with planning for the equipment and the treatment facility, the application for authorization to use the equipment, the coordination of the facility construction and the equipment installation. The facility and equipment must be thoroughly tested, new treatment procedures must be established, and personnel trained and an ongoing quality assurance and equipment maintenance program must be developed. A successful quality assurance program requires a team approach, incorporating the radiation oncologist, medical physicist, device manufacturer, brachytherapy technologist, nurse, dosimetrist, health physicist, and service technician. The experience of this author in low doserate (LDR) remote afterloading has been exclusively with

devices manufactured by the Nucletron Corporation BV, specifically the Selectron-LDR and the microSelectronLDR. The principles of quality assurance that have been applied for those devices serve as a basis for comparable systems.

8.2 PREPARATION FOR A LOW DOSE-RATE REMOTE AFTERLOADING PROGRAM 8.2.1

Equipment selection

The selection of appropriate equipment is one of the first steps toward the establishment of a remote afterloading program. The type of brachytherapy procedures to be performed (intracavitary, interstitial, intraluminal etc.) with remote afterloading should be determined and then matched to the most suitable device. These devices offer a variety of features for consideration, including source types and activities, applicator systems, the number of treatment channels, the means for programming treatment times, and the ability to customize source configurations. Other basic device design features include the mechanism for source transport, the monitoring of correct source positioning, the safety interlocks and fail-safe systems, and the shielded source storage containers. For a more complete description of remote afterloading systems, see Chapter 7. The review, selection, and specification of applicator designs must be done carefully, consistent with the anticipated treatments. This process will directly influence the selection of the source activities and possibly the

Preparation for a lose dose-rate remote afterloading program 113

selection of the treatment machine as well. If a radiation oncology department is converting from manual afterloading to remote afterloading, maintaining similar applicator styles and source activities is important. For example, if the Fletcher-Suit afterloading tandem and ovoid system had been used, then a comparable applicator set, compatible with the remote afterloading device, should be requested. In addition, applicators for treating the vagina, endometrium, oesophagus, bronchus, and nasopharynx should also be considered. With a remote afterloader like the Selectron-LDR, linear sources are replaced by uniform activity spherical sources configured with inactive spherical spacers. These spherical cesium-137 sources have an outer diameter of 2.5 mm and are available with a maximum activity of 40 mCi (1480 MBq or 115 U) per source. When specifying the source inventory for this type of remote afterloader, the following questions should be addressed: • What is the range of prescription dose rates for the different clinical applications that are anticipated? • How many channels may be in use at one time? • How will the active and inactive source pellets be configured to achieve suitable dose distributions? • What is the recommended maximum activity for the main and intermediate source safes? These questions should aid in deciding the total number of sources and the activity of each source. Combinations of eight sources and spacers can be used to compose 2-cm long sequences that can replace 2-cm linear sources. The medical physicist should determine the ideal source strengths to deliver the prescribed dose rates for each clinical application as specified by the radiation oncologist, and a treatment planning computer should be used to verify the design of the source-spacer configurations. At the Mallinckrodt Institute of Radiology, St Louis, Missouri, a six-channel device with a 36-source inventory (36 U/source) has proven to be adequate for enabling two simultaneous intracavitary treatments. Further discussion of spherical source configurations is presented in the clinical implementation section of this chapter. The specification of sources for a remote afterloader that uses drive motors to transport source-cable assemblies requires a different rationale, because the source trains usually cannot be easily reconfigured, if at all. A list of required source trains, their activities, and active lengths must be established that will satisfy most clinical situations. Certain applicators, such as the intrauterine tandem, may require source trains composed with differential linear activity. Their designs can be based on the non-uniform linear activities that had been used for the manually afterloaded treatments. The position of the source in the applicator can also be specified by the user, but the physical constraints of source rigidity and the curvature of the source transport channels may not necessarily allow ideal source alignment. In that case, dosimetric analysis should be used to evaluate the clinical

utility. Several papers [2-5] have reported on source inventory specification, source assembly design, and source-spacer configurations. For interstitial work, the user can select rigid metal needles or flexible plastic needles or catheters. The availability of templates from the manufacturer should be explored, as well as the compatibility of existing templates with the remote afterloading device. For interstitial applications, a permanent inventory of fixed cesium seed source trains or an inventory of temporary iridium wires or seed ribbons, or a combination of both, may be used. The purchase of cesium seed source trains is practical if one can anticipate an appropriate source inventory. The cesium seed source trains are expensive, but can be used over a long time period, whereas the iridium, though requiring frequent purchases, allows the user more options. A rationale for choosing a specific cesium seed ribbon inventory has been reported [6]. Whether cesium or iridium is used for interstitial application, the positioning of the active length within the needle or catheter must be well understood, because these techniques can use varied active and inactive source lengths as well as varied needle or catheter lengths. Special procedures must be established for iridium source preparation and for verification of accurate interstitial source placement. These procedures are reviewed in greater detail later in this chapter.

8.2.2

Site preparation

LOCATION

Careful planning for a remote afterloading facility is very important to achieve convenience and safety for the patient and staff, and to avoid unnecessary costs. Physicians, physicists, nursing personnel, and the manufacturer should all be involved in the planning. Typically, LDR brachytherapy is given in a private patient room on a surgical or cancer nursing division. It is ideal if the brachytherapy room is near to the nurse station and to the brachytherapy preparation laboratory, while being as far as possible from unrestricted patient rooms. Multiple LDR treatment rooms should be adjacent to each other. Figure 8.1 shows an example of a floor plan of an extensive LDR remote afterloading facility. SHIELDING CONSIDERATIONS

The shielding design must be based on the anticipated maximum source activity loadings and duration to limit exposure rates and total exposure in unrestricted areas to less than the maximum level allowed by the user's regulatory agency. In the USA, for example, the United States Nuclear Regulatory Commission (USNRC) limits the radiation exposure to 2 mrem

114 Quality assurance in low dose-rate afterloading

Figure 8.1 Floor plan for a four-treatment device remote afterloading facility at Barnes-Jewish Hospital in St Louis, Missouri. The equipment shown consists of two microSelectron-LDRsfor intracavitary applications, a six-channel Selectron-LDR for simultaneous treatments in two adjacent rooms, and a microSelectron-LDRfor interstitial Indium located in the room opposite to the source preparation laboratory where the two air compressors for the systems are housed.

(0.02 mSv) in an hour to any non-monitored person, with an annual limit of 100 mrem (1 mSv) [7]. The USNRC ALARA (as low as reasonably achievable) program limits exposure in restricted areas to 500 mrem (5 mSv) per year. For LDR brachytherapy rooms that were previously used for manual afterloading, it is possible to use rolling bedside shields to protect unrestricted areas on the same floor, but lead thicknesses in the range of 0.6-1.3 cm should be anticipated for the floors above and below. New construction is best served with shielded walls. The recommendations for room shielding should be made after studying appropriate blueprints and considering the actual location of the brachytherapy patient within the room, as well as the weight limitations of the room [8]. Empirical radiation survey testing of existing room shielding may also be performed to determine if shielding deficiencies are present before installing remote afterloading equipment [9]. The National Council on Radiation Protection and Measurements (NCRP) Report 49 [10] should be used to guide the determination of the shielding specifications that will achieve the required exposure limits. For

more information on this subject, the reader should refer to Chapter 10. FACILITY DESIGN

Room design details for remote afterloading brachytherapy are summarized in Table 8.1. Electrical power to the device should be provided from a dedicated circuit that is also served by emergency power. If compressed air is required, then the decision whether to use in-house or free-standing compressors must be made. Although it may seem simpler to use the hospital air, a dedicated compressor specifically suited to the device can give greater assurance as long as it can be situated far enough from the patient so that its noise is not disturbing. It is possible to install an air compressor in a small hallway enclosure or in the source preparation laboratory, provided there is adequate space for inspection and servicing. An area radiation monitor with an independent secure power supply should be installed adjacent to the implant patient's bed for maximum sensitivity. A remote

Preparation for a low dose-rate remote afterloading program 115

Table 8.1 Treatment room details for low dose-rate remote afterloading brachytherapy Area radiation monitor (with a dedicated check source and battery pack) and remote display Closed circuit TV (monitor at nurses' station) Compressed air system Electric power on emergency power circuit Emergency container and equipment Remote controls with treatment status displays in the hallway and at the nurses' station

tical, so that one patient can be safely visited without disturbing the treatment in the adjacent room. Door locks should be installed to secure the treatment room when not occupied by a patient, because the remote afterloading device and its source inventory generally remain in the room. 'Radioactive Material' and 'Radiation Area' warning signs must be posted on the room door or at the entrance to the brachytherapy ward. These warnings can conveniently be embossed on a hanging door placard designed also to display treatment forms, nurse instructions, and the room diagram.

Treatment tubing support device Door-mounted board for posted warnings and instructions Door interlock system Door lock Intercom to hallway and nurses'station Rolling bedside shields Permanent shielding in floor and above Wall pass-through for two simultaneous treatments from one device

display for the area monitor is necessary, situated either outside or just inside the doorway to alert anyone entering the room about exposed sources before approaching the implant patient. The area monitor is intended to indicate the safe status of the sources in the entered room only. Therefore, it may be necessary to mount the area monitor against a small lead shield on the wall so that it is not sensitive to radiation from an adjoining brachytherapy room. The remote controls for the afterloaders are usually installed in the corridor, adjacent to the patient's room door. Typically, the treatment room door is closed during treatment and a door interlock switch is installed to automatically retract all sources into the intermediate safe in the event that the treatment interrupt button is not activated prior to entering the room. A window in the door can provide only limited visual contact with the patient. It is recommended to install a closed circuit television camera for remote patient observation from the nurse station. In addition to the normal intercom system from the nurse station to the patient, a two-way hallway intercom to the patient is also practical for limiting the number of treatment interruptions. A remote treatment status display at the nurse station is also recommended, which can indicate whether treatment is progressing, is interrupted, or if an alarm status exists. Display of the remaining treatment time should also be available. If one remote afterloading device is capable of treating two patients simultaneously in adjacent rooms, then a wall pass-through is needed for the source transport tubing. The wall opening should be devoid of sharp edges that could damage the tubing. Each treatment room should have its own independent controls installed, when prac-

AUTHORIZATION FOR REMOTE AFTERLOADING

In some countries, it is necessary to apply for authorization to use an afterloader. Registration of the afterloader may also be necessary depending upon the policies of the agency that regulates its use. The regulatory agency should specify what information must be submitted before authorization and/or registration can be considered. If the agency is not very familiar with afterloading technology, the device manufacturer should be able to suggest which information is required to submit, because the manufacturer will have also gone through a similar submission of specifications and information in order to obtain the approval to market the device. Table 8.2 lists the points that should be addressed when submitting a license amendment proposal to the USNRC. Generally, one should not commit in the application to any procedures that are not required by the licensing agency [8]. However, the licensing agency will be seeking assurance that the proposed treatment program will be safe and has been well thought out. INSTALLATION

The installation of remote afterloaders should be coordinated by a physicist or biomedical engineer. The installation process will proceed smoothly as long as the needs of the manufacturer's installation engineer, in-house engineering, clinicians, nurses, and physicists are understood. The process should begin with a pre-installation meeting, at which time the responsibilities of the manufacturer and the hospital are defined and agreed upon. If existing shielded brachytherapy rooms are to be converted for remote afterloading, temporary relocation of brachytherapy patients may be required during the installation process. Appropriate shielding similar to that in regular use should be provided for these temporary areas. If no supplemental temporary shielding is used, vacating adjacent areas will be necessary unless the exposure rates are within the allowable limits. Therefore, radiation surveys are necessary to verify acceptable exposure levels in the unrestricted areas around the temporary brachytherapy rooms. The manufacturer's engineer initially should review and verify receipt of all equipment. The project coordinator should oversee this process, maintain a file of all

116 Quality assurance in low dose-rate afterloading Table 8.2 Information to submit to the licensing agency when requesting authorization for remote afterloading Remote afterloader model and manufacturer Source description (radionuclide, size, the activity, manufacturer, and physical construction) Certification of federal registration of the device

dures and results should be carefully reviewed by the responsible physicist to determine which tests should be repeated and which additional tests need to be added to the acceptance testing procedure.

83

ACCEPTANCE TESTING

The intended clinical applications The intended users, their training, certification, and experience Radiation-detection instruments to be used Facility floor plan and elevation Calculations that demonstrate acceptable exposure levels in unrestricted areas Describe area security, including access to operating keys, door interlocks, and radiation warning systems Describe patient viewing and communication Describe dosimetry equipment, calibration procedures and frequency, leak test procedures and frequency, and the qualifications of those performing the tests Emergency procedures and frequency of mock emergency drills Personnel-monitoring program Describe the titles and locations of procedure manuals Procedures to prevent multiple treatment devices from operating simultaneously Quality assurance program Training of the source exchangers Training and frequency for operators Disposal of decayed sources Adapted from AAPM eport No. 41 [8].

equipment receipts, and verify that the complete order has been received. The engineer should test the equipment prior to installation, verifying such items as correct battery function, electrical parameters, air pressure sensors, and switches. The installation process includes cable routing between the machine and the remote controls outside the treatment room, wiring the door interlock mechanism, and installation of the radiation monitors. Additional cables are routed to the nurses' station to connect to the remote treatment status display and the closed circuit television monitor. If remotely located air compressors are to be used, a pipefitter will install the appropriate lines to a compressed air outlet near to the treatment machine. The manufacturer's engineer should verify that all cables are properly connected and functioning correctly. If several rooms require installation, it may be possible to schedule the work from one room to the next, with the manufacturer's engineer testing and verifying the installation as it proceeds. This will also allow the physicist to begin the evaluation of the installation, possibly prior to the completion of all the rooms. The device manufacturer's equipment test proce-

8.3.1

Introduction

Acceptance testing for a new remote afterloading device must be performed prior to clinical implementation in order to certify that the device performs in accordance with the manufacturer's specifications. If the treatment facility is also new, then it must also be carefully evaluated. This initial testing also establishes a starting point for machine performance evaluation and provides the basis for the development of an ongoing quality assurance program. There have been several acceptance test approaches reported in the literature [8,11-16]. AAPM Report 41 divides the acceptance testing process into several broad categories, including evaluations of the radioactive sources, the mechanical and electrical operation of the remote afterloading device, the radiation monitors and facility, the applicators, and the treatment planning computer. The following sections of this chapter address many of the issues that comprise a thorough acceptance-testing program. The testing sequence begins with new source evaluations. Once the sources are loaded into the machine, radiation surveys are performed. This is followed by the evaluation of the safety features and interlocks, machine performance and applicator function, and finally the treatment planning system. Some of these tests will yield quantitative results, however much of the testing involves verification of correct function.

83.2

Brachytherapy source testing

Several excellent reviews of brachytherapy source testing can be found in the literature [8,12,17]. The process begins with a careful review of the new source certificates. The isotope, its activity or air kerma strength, the uncertainty of the calibration, the active and physical lengths, and source encapsulation must all be verified to assure that the correct sources have been received. The documentation of acceptable leak tests (l, and for very long exposures G—>0. In this context, 'acute' and 'long' are defined relative to the half-time for repair of sublethal damage (Ti). In general, the G factor in equation 13.2 will depend on the details of the temporal distribution of the dose, as well as on TI. As discussed before, for many simple cases, G can be calculated analytically. For example, for n short, equal fractions, where the separation between fractions is much longer than T|, G«l/n. Formulae for many other standard schemes have also been derived [8,12,13], as has a general formalism for any possible scheme [14]. It is important to note the mechanistic basis of equation 13.2 so that it is not simply an equation which happens to fit cellular survival curves. It has been suggested, for example, that the LQ model can be considered sim-

ply as the first two terms (i.e., dose and dose squared) of a power-series expansion [15]. If LQ were just another empirical model, there would be no good reason for considering the linear dose term to be independent of protraction/fractionation, and the quadratic term in dose to be fractionation dependent. This distinction between the linear and the quadratic terms is at the heart of the LQ model and its application. Based on equation 13.2, we can proceed in two ways. We can either try to equate schemes, i.e., produce a regimen with the same, say, tumor response, as a 'tried and tested' regimen, or we can try to predict absolute responses. Both routes are discussed here, though it is argued elsewhere in the chapter that equating schemes is a far more reliable procedure. Thus, assuming tumor repopulation (described below) is negligible, to match a new fractionation scheme (labeled n) to a given ('old') fractionation scheme (labeled o), we must calculate the dose (DJ in scheme n such that:

Assuming we know how to calculate G, and that we know a suitable value for a/f3, equation 13.3 can clearly be solved to yield Dn. If we wish to proceed to the other route, and actually calculate absolute tumor control probabilities (TCP) or normal-tissue complication probabilities (NTCP), we need models relating cellular survival (S) with TCP or with NTCP. The standard model derives from the suggestion of Munro and Gilbert [16] that TCPs can be calculated from the probability that, after radiation treatment, there are no remaining stem cells capable of initiating tumor regrowth. Let us suppose that a dose, D, delivered in a given fractionation pattern, produces a stem-cell survival probability S. We define K to be the initial number of potential stem cells in the tumor, i.e. the number of cells that have the independent capability to initiate tumor regrowth. Then each initial stem cell will have a probability of not initiating tumor regrowth of (1-S), and thus the TCP is simply:

which, for small values of S, is approximately

The surviving fraction, S, is given by the LQ model as equation 13.2 or 13.7, and so the TCP is:

This same formula may also be used to calculate NTCPs, except that now the parameter K does not refer

192 Radiobiology of HDR, LDR, and PDR brachytherapy

to the number of tumor cells which need to be sterilized, but rather to the number of groups of cells in the normal tissue ('tissue-rescuing units' [17]), whose destruction would result in the late complication. The problem with using formulae such as equation 13.6 to calculate absolute, de novo, values of TCP or NTCP is that the results are exquisitely sensitive to the parameter values, particularly the K parameter, and, in general, the utility of these equations for absolute, de novOy calculations is quite limited. Rather, the main application of the LQ model is for comparisons between regimens equation 13.3, which are much less sensitive to the LQ parameter values.

13*2.2 Our knowledge of LQ parameters Around 1980, Withers and colleagues [18] made the key observation that early-responding and late-responding tissues differed in their responses to fractionation (and, by implication, low dose rate, LDR). Essentially, Withers and colleagues showed that, for a given dose, increasing the fraction size (or, by implication, decreasing the number of fractions or increasing the dose rate) will increase late effects much more than it will increase tumor control. Conversely, decreasing the fraction size (or increasing the number of fractions, or decreasing the dose rate) will decrease late effects much more than it will decrease tumor control. Thus the 'therapeutic ratio' (ratio of tumor control to complications) will increase as the number of fractions increases, or as the dose rate decreases. In terms of the LQ model, these observations can be interpreted in terms of the a/p ratio. In terms of survival curves (see Figure 13.2), the a/b ratio essentially describes the degree of 'curviness' of the acute survival curve. A small value of a/b means that the P (dose squared) term is dominating at radiotherapeutic doses, resulting in a curvy survival curve (bottom curve in Figure 13.2). A large value of a/b means the a (linear in dose) term is dominating, resulting in a straighter survival curve. Now, as a first approximation, the dose-response relation for a fractionated (or LDR) regimen can be thought of as simply the result of multiple repeats of the initial part of the survival curve. Clearly (see Figure 13.2), repeating the early part of a curvy survival curve many times will result in far more sparing than repeating the early part of a straighter survival curve. Thus, late effects, which are very sensitive to changes in fractionation, are characterized by small values of a/b, and early effects (tumor control or early-responding normal sequelae) are characterized by large values of oc/p. As clinical data accumulated during the 1980s and 1990s from which a/P ratios can be derived, the dichotomy between a/b ratios for early and late effects, originally inferred from animal data, has held up remarkably well.

Figure 13.2 The dose-response curve for late-responding tissue is 'curvy', i.e., has a small a/b ratio; for early-responding endpoints such as tumor control, the dose-response curve is straighter, i.e., the a/b ratio is larger. Consequently, dose fractionation spares late-responding tissues more than earlyresponding tissues. (Adapted from reference 63.)

Consequently, when using the LQ model, it is essential to be clear about whether the calculation is designed to refer to early-responding or late-responding tissue. From equation 13.3, it is clear that use of different values of a/P will result in different answers for the isoeffect dose.

1.3.2.3 New extensions to the LQ model REPOPULATION

Equation 13.2, which is the basic LQ equation, addresses only the inactivation of a homogeneous population of cells. There is no doubt, however, that accelerated repopulation of tumor clonogens during radiotherapy is often an important factor in determining tumor control [19,20]. The LQ formalism can also take into account the effects of tumor repopulation, i.e., the effects on tumor control of changes in the overall time. Following the original formulation by Travis and Tucker [21], overall time is taken into account by increasing the surviving fraction by a factor exp(y[T-TD]), where T is the overall treatment time, and TD is the delay after the beginning of the treatment before tumor-cell proliferation begins. Then, the survival is given by:

where

The linear-quadratic model 193

The parameter y determines the speed of the repopulation, and is given by: y=0.693/7;,

(13.8)

where Tp is the effective doubling time of cells in the tumor. If we can ignore spontaneous cell loss, Tp is approximately the same as the measurable in-vitro doubling time of the tumor cells. In summary, then, to match a fractionation scheme (labeled 2) to a given fractionation scheme (labeled 1), we must calculate the dose (DJ in scheme 2 such that:

with the same convention as equation 13.7. It should be noted that, for late-responding tissues, y is effectively zero. In other words, late-responding sequelae do not vary significantly with changes in overall treatment time. REDISTRIBUTION AND REOXYGENATION

The LQ model as used in equation 13.7 incorporates sublethal damage repair and repopulation. These two factors are often referred to as two of the '4Rs' of radiotherapy. Recently, an extension has been proposed to the LQ model, termed LQR, to include also the other two 'Rs': cell cycle redistribution and reoxygenation [22]. In the LQR approach, redistribution (due to progression through the cell cycle) and reoxygenation are both regarded as aspects of a single phenomenon, termed resensitization [23]. Resensitization occurs when a radiation exposure preferentially kills the more radiosensitive cells in a diverse population, producing a decreased average radiosensitivity just after the dose is administered; subsequent biologically driven changes then tend gradually to restore the original population average radiosensitivity. The LQR model represents a generalization of the LQ model. In contrast to some multi-parametric approaches, it uses only two additional adjustable parameters, an overall resensitization time and overall resensitization amplitude. Its essential feature is to replace the LQ cell survival equation (equation 13.7) with the equation:

Here, all the terms except the last are the same as for the LQ survival equation (13.7); they again model lethality, repair, and repopulation. The new term is the last, + {(72 (jD2. This term contains the resensitization magnitude, which is positive and is written }a2. This resensitization magnitude is regarded as an average for the dominant resensitization effects present in a heterogeneous tumor. The influence of fractionation on resensitization is contained in the factor (j of the above equation and depends on a characteristic resensitization time, TS. When simplifying assumptions were introduced

for cell-cycle distribution and reoxygenation [22,23], G turned out to have exactly the same form as the G function for sublethal damage repair, i.e., in the term GfSD2, with the characteristic repair time replaced with the characteristic resensitization time, Ts. However, in contrast to repair, resensitization tends to increase sensitivity as the overall time increases. For example, tumor cells which were in a resistant part of the cell cycle at the time of one fraction and were thus preferentially spared may move to a more sensitive part of the cell cycle. This difference between repair and resensitization is manifest in equation 13.10 by the'+' sign in the resensitization term compared with a'—' sign in the repair term. While mechanistically driven, the model is designed to be sufficiently simple that it can be practically applied to isoeffect calculations in radiotherapy. Its idealizations in the consideration of resensitization parallel those inherent in the standard LQ model relating to repair. The model gives reasonable fits to relevant experimental data in the literature [22]. THE EFFECTS OF TUMOR SHRINKAGE

When there is a significant degree of ongoing shrinkage throughout a course of brachytherapy, and when the radiation sources are centrally situated within the tumor volume, the BED to the tumor may be higher than that calculated with standard equations. Because the physical dose in a brachytherapy treatment varies rapidly with distance from the source(s), radiation oncologists usually select a prescription point (itself an element of a threedimensional isodose surface designed to enclose the assumed tumor volume) at which the reference dose for the treatment is specified. If that reference surface diminishes in size as a result of tumor shrinkage, an increase in physical dose results, because those cells at the dose specification point will move closer to the source(s) during treatment, and will receive a higher dose than that prescribed. The radiobiological consequence of this has been examined in some detail by Dale and Jones [24,25]. By assuming that the linear dimensions of the tumor shrink exponentially with time, the effective BED of a high dose-rate (HDR) brachytherapy treatment consisting of N fractions of dose d (to the dose prescription point) is given by:

where X = 1 +(N/-1)zf

and z is the rate of linear tumor shrinkage (day1), and t is the time between fractions (days). For a continuous low dose-rate (CLDR) treatment delivering a dose rate of 1? Gy h'1 over T hours, the BED is:

where

194 Radiobiology of HDR, LDR, and PDR brachytherapy Y = 1 + zT/24

The similarity of form between equations 13.11 and 13.12 should be noted. For late-responding normal tissues adjacent to the tumor, there will be little or no repopulation during the treatment (i.e., K= 0). If the normal tissues move toward the source(s) as a result of the shrinking of the tumor, then the late-reacting BED will always increase with increasing fraction interval. The interesting point about equations 13.11 and 13.12 is that they indicate that an increase in BED is not an inevitable consequence of tumor shrinkage. In the case of HDR, increasing the time interval (?) between fractions allows for more shrinkage, but this will improve the BED only if the following inequality is satisfied:

Equation 13.13 confirms what is to be intuitively expected, i.e., that such favorable conditions are more likely to exist when the dose equivalent of the repopulation rate (fC) is small, and/or when the shrinkage rate (z) is large. Because equation 13.13 incorporates the ratio K/z, and not merely z, it serves as a reminder that ongoing shrinkage is not, by itself, enough to guarantee that the BED will be favorably increased by the use of larger fraction intervals, i.e., whether or not there is an increase in biological effect with shrinkage is dependent on the ratio of K/z. Dale and Jones [24,25] have examined the possible radiobiological consequences of tumor shrinkage, in terms of the optimal interfraction spacing of HDR brachytherapy. They concluded: 1. When the shrinkage rate (z) is small, then, largely irrespective of the value of K, there will be few benefits associated with the use of a long time gap (?) between fractions. For most values of Kthe BED always reduces with increasing time interval. 2. For higher values of z and moderate or low K values, BED can be usefully increased by increasing the time gaps. 3. Increasing t between fractions is beneficial only when the shrinkage constant and the daily repopulation factor are favorably related. When there is doubt about the radiobiological parameters, or in the absence of predictive assays (of SF2 and Tpot, for example), and if the tumor regression rate cannot be determined during the initial phase of treatment, then relatively close spacing of fractions minimizes the possibility of large variations about the prescribed value of BED. Close fraction spacing is therefore the 'safe' option in such cases. Following from conclusion (3), it is possible to investigate the radiobiological conditions which will allow the BED to increase with increasing fraction interval. In

mathematical terms, this is equivalent to saying that the slope of the curve of BED versus time - given by the differential d(BED)/dt - will be positive for all values of t in this condition. The conditions for which this is true lead to the following conclusion. For critical cases (high K value and/or small shrinkage rate), the ratio K/z will be large, and in such cases the interfraction intervals should be kept as small as possible. This is because the BED finally delivered in such cases will always be less than that intended (primarily because of the dominant effect of the high rate of repopulation), causing the loss of biological effect to increase as the interval between fractions increases, i.e., d(BED)/dt will usually be negative over the range of fraction intervals which are likely to be used in practice. These considerations concerning tumor shrinkage may also impact on the optimal time spacing between external-beam radiotherapy and brachytherapy. The precise time at which tumor shrinkage begins during a course of radiotherapy is an important consideration in judging how teletherapy and brachytherapy should be juxtapositioned. In practice, it is unlikely that dynamic tumor shrinkage will commence immediately after the first radiation delivery and, for this reason, it is likely that equation 13.11 overestimates the increase in BED when the K/z ratio is small. Similarly, there may be underestimation of the decrease in BED associated with a large K/z. The equations in this section may therefore have greater validity when the brachytherapy treatments have been preceded by teletherapy, or other anticancer modalities such as cytotoxic chemotherapy, which also causes tumor volumes to decrease exponentially [26]. It is therefore appropriate to consider separately brachytherapy used alone and brachytherapy used in combination with teletherapy. For radical brachytherapy, relatively large doses will be prescribed, and the conditions of the inequality in equation 13.13 are more likely to be satisfied because the product Nd is large, so that the tumor BED will probably increase with time once tumor shrinkage is initiated. Although difficult to implement in practice, there might be advantages in initially using relatively short interfraction intervals and then increasing them once the tumor regression has attained a steady state. However, even with a small K and/or large z (i.e., small K/z), excessively extended intervals may not be feasible if HDR applicators require to remain in situ throughout the whole course of treatment [27]. It is also possible that overextension of t may allow for accelerated repopulation in squamous cell carcinomas [19,20] or, alternatively, a reduction of the spontaneous cell-loss rate [28], either of these phenomena requiring the delivery of additional dose to restore isoeffectiveness. Brachytherapy is most commonly used in combination with external-beam radiotherapy. For high K/z ratios, the brachytherapy should be included within the overall time required for delivery of the teletherapy

The linear-quadratic model 195

regime. Where a small K/z ratio is known to be obtainable, the application of brachytherapy should be deferred until steady-state tumor shrinkage has been initiated, i.e., brachytherapy will always be more effective if it follows teletherapy in this case. Further improvements can be achieved by optimizing the time gap between the cessation of teletherapy and initiation of brachytherapy, but the overall TCPs remain dependent on tumor size [29,30]. If the tumor shrinkage rate following teletherapy is very small, the brachytherapy BED is unlikely to be significantly enhanced. In such cases, particularly for larger tumors, debulking surgery can be used to reduce clonogen number, followed by brachytherapy to the tumor bed. Alternatively, cytotoxic chemotherapy can be used to reduce tumor repopulation during continued tumor regression, and brachytherapy given at a later stage to the smaller tumor [29,31]. Other considerations may apply for clinical situations in which the tumor center is distanced away from the treatment catheter, as in the case of intraluminal HDR treatments for carcinomas of the bronchus and esophagus. This form of treatment geometry has been considered by Bleasdale and Jones [29], but the overall principles are the same as described in this chapter. With an offset tumor center, any regression will not produce the same degree of physical dose advantage, so that extensions of overall time will not always be advantageous. If the clinical constraints are such that HDR bronchoscopic applications can only be performed every 2 weeks, and the tolerable number of fractions is only three, then brachytherapy should be commenced relatively early within a 6-7-week teletherapy regime [32]. If the three HDR brachytherapy fractions can be delivered over a period of 1 month, when the repopulation factor is likely to be unfavorable, consideration should be given to shortening the external-beam therapy to the same overall treatment time. In all cases it must be remembered that tumor shrinkage may cause adjacent normal tissues to move closer to the treatment source(s). For radical treatments, any decision to increase the tumor BED by prolonging the fraction interval must be tempered by the possibility that the normal tissue tolerance dose may be reached or exceeded. Whether or not this is the case can only be determined by careful measurement or estimation of the movement of the critical normal tissues at the time of delivery of each dose fraction. It is clear that the development of improved brachytherapy treatment requires a greater knowledge of the radiobiological processes which govern treatment outcome, and in this chapter the importance of the opposing effects of tumor shrinkage and repopulation particularly have been highlighted. Predictive assays and serial imaging techniques are already available and are likely to be powerful tools in allowing the mathematical models to be more effectively applied for the benefit of

individual patients. The wider availability and use of such methods would seem to be the obvious next step in the further development of brachytherapy. MOVING ISODOSE SURFACES

Because brachytherapy doses are traditionally prescribed at a specific point, it has become commonplace also to compare radiobiological effects at a defined anatomical point. This has led to the notion that, if therapeutic ratio is not to be seriously compromised, considerable care must be exercised when replacing LDR techniques by fractionated HDR. Many articles have dealt with this aspect of radiobiology, but, as discussed later in this chapter, in certain special situations (of which brachytherapy of the uterine cervix is the most common), it may be demonstrated that HDR brachytherapy in small numbers of fractions may be less detrimental than is sometimes supposed. Dale [33], Brenner and Hall [34], and Orton [35] have shown that, even without relatively favorable radiobiological parameters, a modest extra amount of geometrical spacing of critical normal tissues at HDR allows the use of small numbers of fractions without loss of therapeutic ratio. Improved geometry is easiest to achieve in the case of intracavitary treatments, less so with intraluminal brachytherapy. A refreshing new analysis of the problem has recently been conducted by Deehan and O'Donoghue [36], who considered how the relative positions of isodose surfaces are changed in switching from LDR to HDR. Although the issue is seemingly complex, it may be summarized quite simply. Once a fractionated HDR regime has been designed to match an LDR regime at a particular reference point, the LQ model may be used to calculate the biological effects (BEDs) at other sites closer to, and further away from, the sources. Figure 13.3 illustrates a typical case. It will be noted that, at all points closer to the sources, the HDR treatment delivers a higher BED than the LDR treatment. Conversely, at those sites on the distal side of the matching point, the BEDs with HDR are always lower than in the LDR case. The important point here is that the gradients of the BED versus distance curves differ between HDR and LDR, even though the effects have been matched at the reference point. The separation between these curves, in fact, becomes greater as the fraction number is reduced. The individual elements making up the curves in Figure 13.3 are parts of smooth isoeffect surfaces surrounding the treatment sources. Thus, for sites close to the sources, any particular LDR isoeffect surface moves further out when HDR is used, i.e., the volume of enclosed tissue receiving more than a given biological dose is increased. Similarly, at surfaces beyond the matching point, the isoeffect surfaces move inwards, and the volumes of tissue receiving a given biological dose are reduced. Because the more proximal sites are likely to


volume effects. For intraluminal treatments in particular, consideration of surface movement shows that fractionated HDR may offer benefits over LDR.

133 HIGH DOSE-RATE VERSUS LOW DOSERATF RRAfHYTHFRAPY

13.3.1 From LDR to HDR: general principles

Image Not Available

Basic radiobiological principles tell us that the optimal strategy for any radiotherapeutic regimen requires: 1. Use of large numbers of fractions or LDR to maximize sparing of late-responding normal tissues, and to allow reoxygenation; 2. Use of short overall times to limit tumor repopulation; 3. Use of long overall times to reduce early normaltissue sequelae, especially to the skin and mucosa.

Figure 13.3 Illustration to show how radiobiological equivalence between LDR and HDR is achievable only at the chosen matching point. At sites closer to the sources, the HDR delivers a higher biological dose (BED) than LDR; at sites on the distal side of the matching point, the BED from the HDR is lower than from the LDR. The lateral separation between the two curves increases as the number of HDR fractions is decreased. Because the curves are two-dimensional representations of three-dimensional isoeffect surfaces, the switch from LDR to HDR brings about a (possibly useful) increase in the tissue volume irradiated to more than a given biological dose at sites close to the sources, but a favorable decrease in the volume receiving more than a given biological dose at sites beyond the matching point. (Reproduced from reference 36, with permission.)

be in the vicinity of tumor cells, and the more distal sites are likely to be in the vicinity of normal tissues, this relative shifting of the isodose surfaces will tend to enhance the integral dose (i.e., dose x volume product) for tumor, whilst diminishing that for the normal tissues. Such trends may be ideally expressed in terms of effectvolume histograms. Further extension of Deehan and O'Donoghue's work allows assessment of the linear displacements in the isodose surfaces, and hence of the changes in the included tissue volumes. It thus paves the way to a better understanding of radiobiological differences between HDR and LDR in terms of changes in irradiated volumes, and opens up a new avenue for investigating one of the most elusive aspects of brachytherapy - the modeling of

Because of the physical dose distributions in brachytherapy, the last point is not normally a major concern, and it becomes clear why brachytherapy is often the treatment of choice for those tumors which are reasonably accessible for an implant. It is also clear that moving from LDR to HDR must generally involve a loss in therapeutic advantage. To put it in terms of LQ calculations, if an HDR dose is calculated using, say, equation 13.3, based on producing equal tumor control to an LDR regimen, that HDR dose will not be isoeffective in terms of late effects, but will produce increased late sequelae. Conversely, if an HDR dose is calculated to produce, say, equal late sequelae to an LDR regime, the HDR dose would be expected to produce less tumor control than the corresponding LDR regime. Thus, in general, HDR represents a compromise between therapeutic advantage, which decreases, and some other factor (such as patient convenience, treatment repeatability, etc.), which may increase. 133.2

A special case: cancer of the cervix

It is clear from the previous discussion that many fractions are necessary in order for HDR treatments to be radiobiologically equivalent to LDR, all other things being equal. However, for the treatment of carcinoma of the uterine cervix, it has been well documented that equal, and maybe even superior, results (same local control and survival but with fewer complications) can be obtained with as few as about five fractions [33-35]. This apparent discrepancy between radiobiological theory and clinical evidence is probably because not all other things are equal for cervical cancer radiotherapy. Clearly, one of the major reasons why brachytherapy is so

High dose-rate versus low dose-rate brachytherapy

effective and therefore widely utilized in these treatments is that the radiation sources are placed in and around the tumor and away from the normal tissues most susceptible to late radiation damage, specifically the rectum and bladder. In the previous sections, it was assumed that the doses to tumor and normal tissues were the same, whereas, with cervical cancer brachytherapy, packing and/or retraction, 'optimal' source distributions, and applicator shielding are all strategies that can be applied to keep normal tissue doses below those applied to the tumor. As discussed earlier in this chapter, because cervical cancer brachytherapy dose distributions are so inhomogeneous, it is not really appropriate to consider the dose to just a single point, e.g., Point A, to represent the 'tumor dose' [37]. Doses to single rectal or bladder 'points' similarly do not truly represent 'normal tissue doses' [38]. What are required are the 'effective doses' to tumor and normal tissues derived by analysis of threedimensional dose-volume histograms, where the 'effective dose' is that dose which, if delivered uniformly to the tissue in question, would result in the same probability of effect (TCP or NTCP) as the inhomogeneous dose distribution present in that tissue. Several techniques, though not ideal, have been devised to reduce dosevolume histogram data to a single number, such as 'effective dose' [39]. For brachytherapy treatments for cervical cancer, it has been demonstrated that the vast majority of the cervix tissue receives substantially higher doses than most of the rectal and bladder tissues [38]. This is illustrated for rectal tissues in Figure 13.4. Hence, the 'effective doses' to normal tissues are significantly lower that the 'effective tumor dose.' This needs to be taken into account when applying radiobiological modeling, such as with the LQ theory, for comparison of LDR and HDR. However, such 'protection' of normal tissues is a benefit with both HDR and LDR treatments, so some additional 'protective' attributes of HDR must be contributing to the low complication rates observed. One of these is illustrated in Figure 13.4b, which shows that optimization of the dwell positions of the single HDR stepping source can significantly reduce the effective dose to rectal tissues compared to when 'fixed' LDR sources are used. A similar effect is observed for the bladder [37]. Hence, the almost infinite variety of source distributions obtainable with a stepping source makes it possible to achieve superior dose distributions to those attainable with conventional LDR fixed sources. (Note, however, that pulsed-LDR brachytherapy - PDR, discussed later in this chapter which also uses a single stepping source, will have a similar advantage.) A second potential advantage of HDR over LDR is the ability to make better use of packing or retraction. It has been reported frequently that the short duration of HDR treatments enhances the effectiveness of packing or retraction techniques. For example, gauze packing is known to shrink during long LDR irradiations. Also,

197

Image Not Available

Figure 13.4 Typical differential dose-volume histograms: (a) for cervix, and (b) for rectal tissues obtained using the University of Michigan CT-compatible Fletcher-type applicator for the treatment of carcinoma of the cervix [37]. The prescription called for a minimum dose of 11 Gy to the cervix, which, for a conventional LDR application, would correspond to a Point A dose of about 20 Gy [38]. The solid curves are the dose-volume histograms for non-optimized source loadings typical of those employed in LDR treatments. The dashed curves are the dosevolume histograms obtainable with the HDR stepping-source technology using optimization of dwell positions. (Reproduced with permission of Dr Mary Martel, personal communication.)

extensive retraction during the short HDR treatments can readily be tolerated, especially if the patient is anesthetized or medicated appropriately. Another less obvious potential benefit of HDR relates to differences in rates of repair between tumor and latereacting normal tissue cells. It appears that, on average, tumor cells tend to repair sublethal damage faster than normal cells [40]. This will be an advantage for HDR because almost no repair will be possible during short HDR exposures, whereas, during protracted LDR treatments, tumor cells will be better able to take advantage of the time available for repair, so repair at low dose rates will be enhanced more for tumor than for normal tissue cells.


These qualitative physical and biological potential advantages of HDR can be quantified by the use of the LQ model. LQ MODEL CALCULATIONS FOR CARCINOMA OF THE CERVIX: HDR VERSUS LDR

For radiobiological comparisons of LDR and HDR brachytherapy for cervix cancer, the following terminology will be applied. Let: • /represent the fractional geometrical sparing of normal tissues due to employment of brachytherapy, and therefore obtainable with both HDR and LDR, i.e.,/= effective normal tissue dose/effective tumor dose; • / be the extra fractional geometrical sparing of normal tissues attainable with HDR due to advantages of stepping source technology and better retraction or packing, i.e., j/' is the total geometrical sparing factor for HDR treatments; • |it and |l be the repair-rate constants for tumor and late-reacting normal tissue cells, respectively; • 'therapeutic advantage' (TA) of HDR over LDR be the ratio of the tumor log cell-surviving fractions, HDR versus LDR, for the same late-reacting normaltissue log cell surviving fractions, i.e.,

We can apply the basic LQ formula (equation 13.2) to determine the number of HDR fractions necessary to be equivalent to an LDR regime with effective tumor dose rateO.833 Gyh~'(60 Gyin72 h), assuming the same repair rate constant of 0.46 h~] for tumor and normal tissues (corresponding to repair half-time of 1.5 h) and no conventional brachytherapy geometrical sparing (/=!). This leads to the curves shown in Figure 13.5 for four values of /'. Thisfigureshows that the extra geometrical sparing that can be achieved with HDR, represented by the factor /', plays a very significant role. In this example, which illustrates the least favorable scenario for HDR (no normal geometrical sparing (/= 1) and no difference in repair rates), more than 17 fractions are needed before HDR becomes superior to LDR (TA>1) if /'=!, whereas this number of fractions reduces to 12,8, and 4 as/' decreases to 0.95, 0.90, and 0.85, respectively. With the additional advantages of faster repair of tumor cells and some degree of normal geometrical sparing of normal tissues (/
Each of the four curves in Figure 13.6 represents a different combination of tumor repair rate constant (|n) and LDR dose rate. For combination of / and /' below each curve, HDR is superior to LDR for the parameters assumed; and above, LDR is superior. For example, if |it is assumed to be 1.4 h~', and the LDR tumor dose rate is 0.833 Gy Ir1, HDR will be better than LDR for all combinations of/and/' below the top curve in Figure 13.6,

Low dose-rate versus pulsed dose-rate brachytherapy 199

i.e., for most values of / or /' less than unity, which icc highly likely. At the other extreme, if tumor cell repair rates are assumed to be the same as normal cells (mt = 0.46 h-1), and the LDR dose rate is only 0.417 Gy h'1, there are many combinations of/and/' for which LDR will be the superior treatment, although HDR will always be better if/' 20 Gy/fraction correspond to single acute exposures. The data are plotted in a form [43] such that, if they follow a linearquadratic relationship, the points would fall on a straight line. The ratio of the slope to the intercept of this straight line then provides an estimate of the o/p ratio.

13.4 LOW DOSE-RATE VERSUS PULSED DOSERATE BRACHYTHERAPY

13.4.1 Introduction to PDR Because of its practicality and its logistic similarity to continuous low dose-rate (CLDR) brachytherapy, use of

200

Radiobiology of HDR, LDR, and PDR brachytherapy

pulsed dose-rate (PDR) brachytherapy is increasing [46-48]. In PDR, a CLDR brachytherapy regimen is replaced with one involving a series of high dose-rate pulses, typically (though not always) taking about 10 min h~' and typically (though not always) with the same overall dose and time as the corresponding CLDR regimen. PDR is achieved with a remote afterloader containing a single high-activity source which is stepped through the catheters of an implant, with dwell positions and times adjusted under computer control to achieve the required dose distribution. The advantages of PDR have been discussed elsewhere [41,49,50]. The patient has much more mobility - during the 'off' periods - than in a conventional CLDR regimen, during which nursing and visiting can be safely accomplished. There are two clinical advantages. First, by varying dwell times and locations of the source as it shuttles through the tumor, dose distribution can be optimized for the actual locations of the implanted catheters relative to the tumor and normal tissues. Second, the overall dose rate can be maintained even as the source decays, by increasing the length of individual pulses. Finally, from a practical viewpoint, the use of a single source has both logistic and radiation protection advantages compared with the usual inventory of sources.

13.4,2 'Daytime'PDR The original PDR protocols have been for day and night irradiation. It would clearly be advantageous to design pulsed-brachytherapy (PDR) protocols that are expected to be at least as clinically efficacious (in terms of both tumor control and late sequelae) as CLDR regimens, but that involve irradiation only during extended office hours. The LQ formalism has been used [49] to design PDR schemes in which pulses are delivered during 'extended office hours' (8 a.m. to 8 p.m.), with no irradiation overnight. Generally, the proposed PDR regimes last the same number of treatment days as the corresponding CLDR regimen, but the PDR treatment lasts longer on the final day (i.e., until 8 p.m.). PDR doses were calculated such as to produce a tumor control which is equivalent to standard CLDR protocols, and the corresponding predicted late complication rate was compared with that for CLDR. Ranges of plausible values for the half-times of sublethal damage repair for tumors and for late-responding normal tissues were considered. The efficacy of PDR relative to CLDR depends considerably on the repair rates for sublethal damage repair. The clinical and experimental evidence suggests that average repair half-times for early effects (e.g., tumor control) are less than about 0.5 h, and for late sequelae are more than about 1 h (but see below). If these estimates are correct, daytime PDR regimes can usually be designed which take the same number of days as the corresponding CLDR

regimen, but have comparable or better therapeutic ratios than responding tissues. The suggested protocols allow all of the advantages of a computerized, remotecontrolled afterloader while preserving the benefits of low dose rate. In addition, the protocols could allow the patient to go home overnight, or to stay overnight in an adjacent medical inn or hospital-associated hotel, rather than in a hospital bed - which could have major economic benefits. In such an economic situation, an extra treatment day for the daytime PDR could well be considered, which would virtually guarantee an improved clinical advantage relative to CLDR.

13*43 Equivalent regimens for PDR The key radiobiological question for PDR revolves around the question of equivalence between the results of CLDR and those of a corresponding PDR regimen. Initial calculations [41,50], based on equation 13.3 and LQ parameters from in-vitro systems, suggested that, as long as the time between, say, 10-min pulses was not increased much beyond 1 h, early-responding normal tissues would not show significant differences in response between CLDR and PDR (for the same overall dose and time). An example of the result of such a calculation is shown in Figure 13.9. Subsequent in-vitro experimental results [51,52] have corroborated this conclusion, as have in-vivo studies with an early-responding endpoint [53]. The limited clinical experience with PDR reported to date also suggests that early response is not markedly different from CLDR [45-48]. Several authors, however, have pointed to the need for caution with regard to late effects [41,54-57].

Figure 13.9 Combination of pulse widths and periods between pulses that will yield an equivalent survival to a continuous low dose irradiation of 30 Gy in 60 h. For this particular cell line, any combination of pulse width and period within the marked boundary is predicted to yield equivalent cell killing. The figure shows representative data for one of 38 cell lines analyzed in reference 41. (Redrawn from reference 41.)

Conclusions 201

Essentially, this is because of the fact (discussed above) that late-responding tissues are more sensitive than early-responding tissues to changes in fractionation patterns. These authors pointed out that changes in late effects when moving from CLDR to PDR are essentially determined by the rate of repair of sublethal lateresponding damage - and that these repair rates are simply not well known. Essentially, the trend, schematically illustrated in Figure 13.10, is that rapid repair rates in late-responding tissues would lead to increased late effects in PDR compared with CLDR [58]. On the other hand, slow repair rates would imply that PDR might well produce fewer late effects than the corresponding CLDR regimen. Experimentally, changes in late-responding sequelae are hard to quantify, particularly when these changes may well be relatively small. This is true both in the clinic and in the laboratory. In the clinic, a variety of reports have generally reported no significant difference in late sequelae between PDR and CLDR [45-48]. In a model late-responding system (cataract induction in the rat lens), no significant difference was observed between 15 Gy of X-rays delivered over 24 h and in various PDR regimens with the same overall dose and time [59]. Similar results have been obtained using as an endpoint rectal toxicity in the rat [60,61].

Figure 13.10 Calculated fractional change in cell survival for PDR compared with LDR as a function of the assumed half-time for sublethal damage repair. Both treatments consist of 30 Gy delivered in 60 h, either continuously (LDR) or in 60 10-min 50 cGy pulses delivered every hour (PDR). The calculated quantity is fSPDR - S Ldr) S LDR ; here, the survival (S) is calculated, using the linear-quadratic formalism (3,8), asS = exp(-ccD -GpD2) where D is the total dose, a and P are the linearquadratic formalism parameters, and G is the quantity describing sublethal damage repair (see equation 13.2), which depends on the half-time of sublethal-damage repair, TJ/2. Thus, the quantity calculated is actually exp/-(GPDR - GL JpD2/ -7. In the calculation, it was assumed that (3=0.025 Gy~2, though similarly shaped graphs are obtained for other values of p. (Redrawn from reference 58.)

The equality of late effects from CLDR and PDR in the laboratory must imply that sublethal damage repair is quite slow in this model late-responding system, in agreement with trends observed in the clinic for sublethal damage repair of late sequelae. Such trends would suggest that PDR is unlikely to produce significantly worse late effects than the corresponding CLDR regime, which is in agreement with early clinical data using PDR. Caution, however, is strongly indicated.

13.5 CONCLUSIONS In this chapter we have discussed the principles underlying the use of the LQ model, and some examples in designing equi-effect doses, for either early-responding or late-responding tissues. The main application of the LQ model is likely to be for comparisons of schema, or designing isoeffective schema. Such applications are much less sensitive to the values of LQ parameters than are absolute, de novo, predictions of TCP or NTCP. While it is important to be appropriately critical of the LQ model and its application to radiotherapy, it is equally important to recognize that it is the best model we have. It is a mechanistically based model of cell killing, with parameters that have a clear radiobiological interpretation, and there is a wealth of evidence that cell killing dominates radiotherapeutic response. Of course, the simplest form of the LQ model (equation 13.3) is not necessarily the most appropriate to apply. When repopulation is important, the LQ formalism can be appropriately modified [21]. If redistribution or reoxygenation is important, the LQ formalism can again be appropriately modified [22]. Similarly, if there is evidence that the LQ model is underpredicting survival at high doses, appropriate saturation-related modifications to the LQ formalism have been described [62,63]. A recent study [64] looked at the relationship of the LQ formalism to other commonly used radiobiological models, particularly in terms of their predicted time-dose relationships. It was shown that a broad range of radiobiological models is described by formalisms which result in the standard LQ relationship for dose fractionation/protraction, including the same generalized time factor, G (see equation 13.2). This approximate equivalence holds not only for the formalisms describing binary misrepair models, which are conceptually similar to LQ, but also for formalisms describing models embodying a very different explanation for time-dose effects, namely saturation of repair capacity. In terms of applications to radiotherapy, it was shown that a typical saturable repair formalism predicts practically the same dependencies for protraction effects as does the LQ formalism, at clinically relevant doses per fraction. Overall, use of the LQ formalism to predict dose-time


relationships is a notably robust procedure, depending less than previously thought on knowledge of detailed biophysical mechanisms, because various conceptually different biophysical models lead, in a reasonable approximation, to the LQ relationship including the standard form of the generalized time factor G.

GLOSSARY oc/P ratio The ratio of the parameters a and P in the linear-quadratic model (qv). a is considered to be a measure of the probability that a single radiation event will cause lethal cellular damage; (3 is a measure of the probability that two sublethal events will combine together to create lethal damage. In clinical radiotherapy, the value of a is the principal determinant of overall radiation sensitivity of a tumor or normal issue; the p component governs the fractionation and dose-rate characteristics of a particular cell line. In terms of the underlying cell survival curve, a is the initial slope and P is a measure of the downward 'bendiness' of the curve. Biologically effective dose (BED) A measure of biological effect as calculated by the LQ model. BED values are additive, and are therefore useful in calculating the overall effectiveness of treatments which consist of two or more components. The BED is tissue-specific as its value is dependent on the oc/P ratio and the recovery half-life. BED may be thought of as the dose necessary for a given effect when the treatment consists of an infinite number of infinitely small fractions. Early-responding tissues Those normal tissues in which the radiation damage is normally apparent within weeks or months of exposure; characterized by a relatively large oc/P ratio. High dose rate (HDR) A dose rate such that the time required to deliver a given dose is very short in comparison with the cellular recovery half-lives. Late-responding tissues Those normal tissues in which the radiation damage only becomes apparent months or years after exposure; characterized by a relatively small oc/P ratio. Linear-quadratic (LQ) model Cell-killing model based on the assumption that there are two components to cell killing: a linear component which is directly proportional to the delivered dose, and a quadratic component which is proportional to the square of the delivered dose. In the simplest case of a single instantaneous dose of magnitude dy the cell survival (S) is given by: S = exp(-ad - P^2). The model has been extensively developed to describe many other patterns of radiation delivery. Low dose rate (LDR) A dose rate such that the time required to deliver a given dose is long compared with the cellular recovery half-lives. Medium dose rate (MDR) A dose rate such that the

time required to deliver a given dose is comparable with the cellular recovery half-lives. Potential doubling time (Tpot) The predicted cell doubling time in the absence of cell loss. Pulsed dose rate (PDR) A technique whereby the biological effects associated with continuous LDR irradiation are simulated by the use of 'pulses' of HDR irradiation delivered at approximately 1 -h intervals over a long time period. Radiosensitivity A measure of the radioresponsiveness of a particular cell line. Possible measures of radiosensitivity are the surviving fraction after a single dose of 2 Gy (SF2), and the initial slope of the cell-survival curve (a). Recovery The process whereby the amount of injury to irradiated cells or tissues is able to reduce with time after irradiation. Recovery half-life The half-life which determines the (exponential) rate at which simple sublethal cellular injury may recover. Repopulation effect The concomitant growth of tumor clonogens during a course of radiotherapy. Repopulation factor (K) The daily dose necessary to offset tumor repopulation. In terms of the LQ model, K is defined as: K = 0.693/ccrpot. Sublethal damage That component of cellular injury which is capable of repair. When sublethal damage is accumulated within a given cell, lethal damage may result from an interaction between the sublethal components.

REFERENCES 1. Ellis, F. (1968) Dose, time and fractionation in radiotherapy. In Current Topics in Radiation Research, ed. M. Ebert and A. Howard. Amsterdam, North Holland Publishing Company, 359-97. 2. Barendsen, G.W. (1982) Dose fractionation, dose rate and isoeffect relationships for normal tissue responses. Int.J. Radial Oncol. Biol. Phys., 8,1981-97. 3. Fowler, J.F. (1989) The linear-quadratic formula and progress in fractionated radiotherapy. Br.J. Radiol., 62, 679-94. 4. Anderson, L.L. (1986) A'natural'volume-dose histogram for brachytherapy. Med. Phys., 13,898-903. 5. Saw, C.B. and Suntharalingham, N. (1988) Reference doserates for single-plane and double-plane iridium-192 implants. Med. Phys., 15,391-8. 6. Wu, A., Ulin, K. and Sternick, E.S. (1988) A dose homogeneity index for evaluating 192lr interstitial breast implants. Med. Phys., 15,104-7. 7. Meertens, H., Borger, J., Steggarda, M. and Blom, A. (1994) Evaluation and optimisation of interstitial brachytherapy dose distributions. In Brachytherapy: from Radium to Optimization, ed. R.F. Mould, J.J. Batterman, A.A. Martinez and B.L Speiser. Leersam, The Netherlands, Nucletron International, 300-6.

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14 Predictive assays for radiation oncology JOHN A. COOK AND JAMES B.MITCHELL

14.1

INTRODUCTION

In 1895, Wilhelm Roentgen contributed to the medical profession perhaps one of its most widely used and beneficial diagnostic tests. With the discovery of the X-ray and the rapid development of radiographs, Roentgen's discharge tube enabled physicians non-invasively to visualize anatomical structures quickly and establish sound diagnosis of a variety of medical problems. Diagnostic tests used in medical practice have progressed a long way since the early 1900s, both in type and sophistication. An elaborate array of tests now greatly aids the physician in making a rational diagnosis of a particular medical problem. Expeditious diagnosis is extremely important in the field of oncology and, unquestionably, if certain tumors are detected early enough, successful treatment and eradication of the tumor can be achieved. Unfortunately, not all tumors are detected early and, despite there being a wide variety of treatment options available, including surgery, chemotherapy, and radiation therapy, successful eradication of tumor with acceptable normal-tissue toxicity remains a major challenge to the practicing oncologist. Since the 1980s, radiation oncologists and biologists have recognized the need for additional assays on an individual patient basis that would select the most advantageous treatment approach [1]. We emphasize assays for individual patients for several reasons. First, the cellular radiation sensitivity of the tumor may differ among individuals, even for tumors of the same histological type. If the radiosensitivity of the individual's

tumor were precisely known, perhaps total radiation doses could be adjusted before the end of therapy to maximize tumor response. Alternatively, the option of using radiation sensitizers for 'radioresistant' tumors would have a more rational basis. Second, normal-tissue radiation sensitivity may differ among individuals. This is an important point because the total radiation dose that can be delivered to a patient's tumor is often limited by normal tissue tolerance. Stated differently, frequently radiation oncologists are compelled to treat a patient's tumor with radiation doses that are dictated not by tumor sensitivity but by normal-tissue tolerance, which in many instances results in inadequate dose to the tumor. If one assumes there is a Gaussian distribution of normal-tissue radiosensitivities among humans, then the most sensitive individuals in the population may well dictate radiation tumor doses utilized in the clinic. Because the radiation tumor control dose response curve is quite steep for many tumors, modest increases in the total radiation dose delivered would be expected greatly to enhance tumor control. If it were determined that the patient's normal-tissue radiation response were toward the 'radioresistant' edge of the Gaussian distribution, consideration could be given to administering higher radiation doses. Alternatively, if the patient's normal-tissue radiation response were toward the 'radiosensitive' edge of the Gaussian distribution, the use of radioprotectors could be considered. Unfortunately, selective normal-tissue radioprotectors have yet to be identified. Third, biological, environmental, and physiological factors of tumors may differ among individuals. Factors such as tumor pH, hypoxia, blood flow, and

206 Predictive assays for radiation oncology

growth of the tumor in terms of cell-cycle parameters and potential tumor doubling times (Tpot) can influence the overall radiation responsiveness of the tumor. If these factors were known prior to therapy, the use of hypoxic cell radiosensitizers or, in the case of Tpot values, alteration of fractionation/time schedules could be considered. Numerous predictive assays have been developed over the past two decades to address many of the points cited above and several have been evaluated in a clinical setting. This chapter briefly reviews the current status of several different predictive assays and discusses their advantages and shortcomings. These assays, while evaluated on patients receiving external-beam radiotherapy, are also highly relevant for patients receiving various forms of brachytherapy.

14.2 REQUIREMENTS OF CLINICALLY USEFUL PREDICTIVE ASSAYS A number of diagnostic tests already aid the oncologist in designing the course of treatment. These include: tumor type, histological grade, tumor biochemical markers, size and anatomical location of the tumor (which can be determined by various X-ray procedures), rate of tumor growth, receptor status, ploidy of the tumor cells, and patient performance status and age [2]. A major advantage of these tests is that they can be performed rapidly and are available when options for treatment are considered. The tests have proven to be predictive for both tumor responsiveness to therapy and ultimate survival of the patient. Ideally, predictive assays, particularly those for radiation oncology, should be rapid (ideally within a week) and predictive with low false negativity [3].

type [5]. As an example, cell lines isolated from glioblastoma tumors exhibit a broad range of SF2Gy values (0.2-0.9) [5], yet glioblastoma uniformly respond poorly to radiation. If heterogeneity in cellular radiosensitivity exists in human tumors of the same histological type, the need for an accurate individualized assessment of cellular radiosensitivity becomes extremely important if altered treatment approaches are to be considered in the clinic based on predictive assays. Raaphorst has pointed out that the reproducibility of SF2C}, determinations of an established cell line can be quite variable [6]. Using the radiosensitivity parameter of SF2Gy means that cell killing is usually confined to the first log of survival. Low doses of radiation which result in low levels of cell killing are difficult to resolve statistically due to the summation of statistical errors inherent in conducting survival assays for low radiation doses [7]. Thus, concerns relating to tumor-cell radiosensitivity assessments from a patient's tumors include: (a) whether the radiosensitivity of cells taken from the biopsy sample is representative of the entire tumor; (b) whether the single determination of radiosensitivity is so variable that it would not be useful; and (c) whether radiosensitivity would remain constant during a full course of 25-30 fractions of radiotherapy. While such concerns are reasonable (and perhaps sobering) with regard to tumor-cell biology, it is difficult to second-guess results until experiments are conducted. However, the studies discussed above formed the basis to explore the possibility of determining the inherent cellular radiosensitivity of primary cultures of tumor cells taken directly from the patient. There are several assays available to assess cellular radiosensitivity [8-17], but only those for which most clinical data have been obtained are discussed below.

143*2 Cell adhesive matrix assay 143

SURVIVAL ASSAYS

143*1 Tumor-cell radiosensitivity Intrinsic cellular radiosensitivity of cell lines established from patients' tumors has provided interesting correlations with respect to the radioresponsiveness of specific tumor types in the clinic. Fertil and Malaise, in an analysis of published radiation survival curves, found that cell lines derived from, for example, glioblastoma and melanoma exhibit a high surviving fraction at 2 Gy (SF2Gy) [4]. These tumor types are less responsive to radiotherapy than, for example, tumors such as lymphomas and small lung cancer, which exhibit low SF2Gy values [4]. While there is a semi-qualitative relationship between SF2Gy values of given tumor types and clinical radioresponsiveness, a range of radiosensitivities has been noted in cell lines derived from the same tumor

The cell adhesive matrix (CAM) assay is conducted on tissue culture dishes coated with a substance that facilitates cell attachment and cell growth [18]. Single-cell suspensions of tumor cells are plated onto CAM dishes, incubated for 24 h, and then exposed to varying doses of radiation (1-6 Gy). After a growth period of 10-14 days, the cell monolayer is stained with crystal violet. The density of cell monolayer is assessed by the amount of stain taken up by the surviving cells as recorded by image analysis techniques. By comparing the density of staining of unirradiated cultures to that of irradiated cultures, growth-rate-based cell survival curves can be obtained [18]. Using this assay, Brock et al, determined SF2Gy values of cells derived from biopsies of head/neck tumors prior to radiation therapy [19]. Figure 14.1 shows the cumulative frequency histograms of SF2Cy values for 72 patients evaluated [19]. The range in SF2Gy values in patients achieving local control was from 0.10 to 0.91.

Survival assays 207 Figure 14.1 Cumulative frequency histograms of SFXy values for 72 head and neck cancer patients (patients controlled locally + patients who failed locally) compared to patients with local recurrences. (Redrawn with permission from

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The plot also displays SF2Gy values from 12 patients with local recurrence following radiation treatment. SF2Gy values from this subset of patients ranged from 0.20 to 0.91. Note that patients' tumors with low and high SF2Gy values recurred. The authors concluded that SF2Gy values were not suitable prognostic indicators for this set of patients [ 19]. Preliminary data from Girinsky, et a/., who used the same assay to evaluate head/neck tumor-cell radiosensitivity, reached similar conclusions for SF2Gy values; however, using the calculated a values of the radiation survival curves, a correlation was found between patients with an a value > 0.07 Gy ' and local control [20]. That there was no correlation between tumor sensitivity and clinical response is particularly troublesome, because the assay is both simple and reasonable. A technical difficulty inherent in the CAM assay is the observation that normal host fibroblasts (included in the tumor biopsy) can also grow on the matrix-treated dishes, thus potentially complicating the interpretation of tumor-cell radiosensitivity [20].

1433

Courtenay-Mills soft agar assay

This clonogenic assay is conducted by plating single-cell suspensions from patients' tumors into medium containing soft agar [21]. Standard clonogenic radiation survival curves are conducted from which survival curve parameters such as SF2Gy can be determined. From the time of the initial biopsy to the evaluation of the radiation survival curve is approximately 4 weeks. Using the assay, West et a/., determined SF2Gy values of tumor cells taken from 88 patients with cervical carcinoma [22]. In

reference 19.)

the study, a significant correlation was found between SF2Gy values and both local control and survival, as shown in Figure 14.2. Patients with SF2Gy values > 0.4 had both a lower local control rate and a lower survival when compared to patients with SF2Gy values < 0.4 [23]. 5F2Gy values were independent of disease stage, tumor grade, and patient age [22]; however, there was a loose correlation with tumor volume and diploid status, which suggests that SF2Gy alone may not be a completely independent predictor of local control and survival. As shown for the CAM assay, fibroblasts have also been shown to grow in this soft agar assay [24]. Of all the cell-survival predictive assays presently under evaluation, the data from the Courtenay-Mills assay clearly provide the most encouragement. It will be most interesting to determine if SF2Gy values determined by this assay correlate with local control and survival for different tumors. Likewise, it would be informative to determine if the CAM assay applied to cervical carcinoma would give similar results to the Courtenay-Mills assay. A potential improvement that could be applied to both assays might be to use fractionated radiation (i.e., five 2-Gy fractions) to maximize the importance of repair, which is not apparent for a single 2-Gy dose of radiation [6]. Both assays require several weeks to obtain results. This represents a possible disadvantage, particularly if radiation sensitizers or protectors were to be considered an option as treatment commences. However, both assays can be completed before the end of therapy, thus permitting total tumor dose modification. The finding that host fibroblasts grow in both assays raises concern as to their contribution to the overall radiosensitivity


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Figure 14.2 Local control and survival probability as a function of time after treatment of cervical carcinoma patients. Local control and survival were further separated by examining patients with SF2Gy values greater than or less than 0.4. (a) Local control probability as a function of time after radiation, (b) Survival probability as a function of time after radiation. (Redrawn with permission from reference 23.)

assessment, although such a concern would only be important if tumor-cell and fibroblast radiosensitivities differ.

143*4 Normal-tissue cellular radiosensitivity Is there a correlation between the radiosensitivity of normal tissues and tumor cells from the same animal or patient? The answer to this question is not known for humans. If the answer were yes, then the determination of normal-cell radiosensitivity might be easier to perform and more reliable than tumor-cell radiosensitivity assessments, given that a homogeneous population (with respect to DNA content or chromosome stability) of cells from readily accessible normal tissues could be studied. Data from at least one animal model suggest that normal-tissue and tumor radiosensitivities are indeed similar. Budach et al. showed that tumors arising in severe combined immunodeficient (SCID) mice exhibited the same radiosensitivity as their normal skin fibroblasts [25]. The study, however, represents an extreme example, in that SCID mice are approximately threefold more radiosensitive than normal mice. In recent human studies, however, Stausbol-Gron et al. examined the SF2Gy of both fibroblasts and tumor cells from 71 head and neck patients and found no statistical correlation between the fibroblast and tumor SF2Gy [26]. The question as to whether there is a similarity of radiosensitivities between tumor and normal tissues in 'normal' mice and humans remains unanswered.

Another question that warrants consideration is whether normal-cell radiosensitivity (fibroblasts, lymphocytes, etc.) correlates with radiation-induced normal-tissue complications. Several studies have attempted to address this question [27-33]. Geara et al. evaluated the radiosensitivity of fibroblasts taken from 21 patients with head/neck tumors who subsequently received radiation therapy [34]. Fibroblast SF2Gy values were compared to the acute and late effects of skin and oral mucosa during and after radiation treatment, as shown in Figure 14.3 [34]. SF2Gy values correlated well with late normal-tissue reactions (Figure 14.3a). That is, patients whose fibroblast radiosensitivity was characterized by high SF2Gy values exhibited fewer late reactions. Likewise, low SF2Gy values correlated with more severe late effects. No correlation was found between SF2Gy values and acute reactions (Figure 14.3b). Russel et al. studied the sensitivity of dermal fibroblast from 79 breast cancer patients and attempted to correlate the SF2Gy with the degree of breast fibrosis [33]. Although there was significant variation in intrinsic radiation sensitivity, there was only a weak correlation between the SF2Gy and breast fibrosis. Other studies have suggested that acute effects may correlate with fibroblast radiosensitivity, but these studies are preliminary and require further verification [35]. Despite differences, collectively the studies suggest that radiation-induced,'late' normal-tissue reactions correlate to some extent with fibroblast radiosensitivity [32]. It is hoped that study of larger populations of patients will confirm and extend the preliminary findings to other tissues and organs at risk for radiation damage. Recently, the gene for ataxia telangiectasia (AT) has

Oxygen measurements and tumor response 209

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Figure 14.3 SF2Gy values as a function of the grade of either late or acute normal-tissue reactions, (a) Late reactions scored after the radiation treatments, (b) Acute reactions of the skin and mucosa scored weekly during the radiation treatments. (Redrawn with permission from reference 34.)

been cloned [36]. Fibroblast cultures derived from homozygous AT patients have long been known to exhibit extreme radiosensitivity [37]. Likewise, ataxia telangiectasia patients also exhibit severe normal-tissue reactions if given a standard course of radiotherapy [38]. Dunst et al. examined chromosome breaks in lymphocytes from cancer patients undergoing radiotherapy. This study included three individuals who had proven ataxia telangiectasia (AT homozygotes) [31]. It found a higher number of chromosomal breaks in the lymphocytes from patients who had extreme normal-tissue reactions to the radiation, while the ataxia patients had the highest break frequency of all. There is also evidence that ATheterozygotes exhibit slightly increased radiosensitivity [39] compared to fibroblasts from normal individuals. What makes the observation clinically important is that approximately 18% of patients with breast cancer may be heterozygous for the AT gene [40]. Application of molecular techniques may allow for the rapid identification of AT heterozygotes, thus allowing for a more precise attempt to correlate radiosensitivity and normaltissue damage. In the future, as more insight into human genetics and radiation responsiveness is gained, it maybe feasible to screen quickly for selective markers.

14.4 OXYGEN MEASUREMENTS AND TUMOR RESPONSE Inherent cellular radiosensitivity may not necessarily correlate with clinical radioresponsiveness because the tumor microenvironment may influence radiation response. A major modifier of the radiation response is

molecular oxygen [41]. Cells exposed to X-rays at low oxygen levels are more resistant than fully oxygenated cells by a factor of about three. Should hypoxic cells exist in tumors, they might pose a potential obstacle to successful tumor eradication. The ability to determine if hypoxic cells are present in human tumors has been facilitated by the use of sensitive oxygen electrodes. These tiny glass electrodes are inserted directly into the tumor and many oxygen measurements are made as the electrode is mechanically moved along a track of tissue (2-40 mm). The procedure can be done several times through different parts of the tumor, does not cause pain or discomfort to the patient, and can be completed in approximately 1 h. Oxygen levels in normal tissue can also be determined for comparison. Disadvantages of the technique include the invasive nature of the procedure and the inaccessibility of some tumors. Several studies using the oxygen-sensitive electrode to measure PO2 levels in head and neck carcinomas, cervical carcinomas, breast carcinomas, soft tissue sarcomas, and in squamous cell carcinoma metastases have been reported [42-46]. In squamous cell carcinoma metastases prior to radiation treatment, Gatenby et al. showed a relationship between tumor response and tumor PO2 levels [43]. Patients who achieved a complete response to radiation therapy had higher PO2 levels (< 26% of the tumor volume measuring < 8 mm PO2) in their tumors than did patients who did not respond (> 26% of the tumor volume measuring < 8 mm PO2). More recent clinical experience with oxygen electrodes has confirmed and extended the observations by Gatenby. Vaupel and Hockel published a series of studies in which PO2 levels were measured in patients with breast and cervix cancer and related to survival and/or recurrence-free survival


[44,45]. Examples from their studies are shown in Figures 14.4 and 14.5. Figures 14.4a and b showPO2 distributions for normal breast tissue (N = 16) and breast tumors (N = 15, Stage T1-T4), respectively [45]. The median PO2 level in normal breast was 65 mmHg compared to 30 mmHg for breast tumors. Notice that for breast tumors there was a significant number of values < 10 mmHg, whereas normal breast tissue had no measurements < 10 mmHg. A level of oxygen < 10 mmHg is within the range in which the oxygen enhancement ratio (OER) changes from a value of 1 (aerobic) to a maximum of 3 (hypoxic). Thus, values < 10 nimHg might be considered 'hypoxic.' The PO2 profiles shown in Figures 14.4a and b are mean values for a group of patients. Interestingly, PO2 profiles of individual breast cancer patients appear to have normal PO2 readings (Figure 14.5a) and yet other profiles that contain significant hypoxic readings < 10 mmHg (Figure 14.5b) [44]. Adams et al. examined the PO2 profiles of 37 head and neck cancer patients and also found a significant degree of hypoxia in these tumors as compared to subcutaneous PO2 readings [42]. Dunst et al. examined 49 cervical carcinoma patients both before and during radiotherapy

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0

100

Figure 14.5 P02 profiles from two individual breast cancer patients. In both panels, n = number of oxygen measurements made. (Redrawn with permission from reference 45.)

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Figure 14.4 P02 profiles from breast tumors and normal breast tissue. (A) P02 profiles of normal breast tissue (N = 16). (B) P02 profiles of breast tumors (M = 15). In both panels, n = number of oxygen measurements made. (Redrawn with permission from reference 45.)

[47]. They found PO2 changes occurred during radiotherapy, with a majority of those patients with either a pretreatment median PO2 > 10 mmHg or a median PO2 > 10 mmHg at 19.8 Gy having complete response to the radiation treatments. The example serves to reinforce the importance of individualized assessment of hypoxia in human tumors, particularly in the context of evaluating or considering the use of hypoxia-cell radiosensitizers. Figure 14.6 shows survival curves of patients with cervical carcinoma whose median PO2 profiles were either greater than or less than 10 mmHg. These preliminary data clearly show that survival is enhanced for those patients whose tumors had median PO2 profiles > 10 mmHg prior to treatment. This was true for patients receiving radiotherapy alone as well as for those who received surgery, chemotherapy, or combined therapies. The data, while of interest to radiation oncologists, are also of interest to tumor biologists, in that patients with tumors with PO2 profiles < 10 mmHg did not respond well to any therapy. The reason for the response profile is not clear, but it indicates that hypoxia is a marker of aggressive, poorly responsive tumors [48]. Likewise, the presence of hypoxia in soft tissue sarcomas may be predictive for metastatic potential [46]. Several other techniques to measure tissue PO2 levels

Cell-cycle analysis and tumor response 211

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Figure 14.6 Survival probability of cervical carcinoma patients as a function of time after treatment (either radiation, surgery, or chemotherapy alone, or a combination of these treatments). Survival was separated based on whether the median ?02 was

Figure 14.7 Actuarial survival of head and neck patients as a function of time after treatment (either accelerated fractionation or conventional fractionation). Survival was

either less than or greater than 10 mmHg. (Redrawn with

(slow). (Redrawn with permission from reference 60.)

separated based upon a Jpot < 4 days (fast) or a T^, > 4 days

permission from reference 44.)

are currently under development [49]. Oxygen electrode measurements do not yield the complete PO2 profile of the entire tumor. Ideally, it would be advantageous to have a technique that could provide non-invasive assessment of PO2 levels for the entire tumor. The use of nitroimidazoles, which bind to macromolecules under hypoxic conditions [50,51 ], is one approach toward noninvasive imaging of hypoxic tissue. The nitroimidazole can be labeled with radioactive iodine-123 and evaluated by single photon emission computed tomography (SPECT) [52], labeled with an isotope of fluorine (fluorine-18) and evaluated by positron emission tomography (PET) [53] or detected histochemically [54]. Other techniques include the use of electron paramagnetic resonance (EPR) coupled with free radical probes [55,56] or India ink [57] and fluorine (fluorine-19) magnetic resonance spectroscopy [58]. These techniques hold great promise, but are still in the early stages of development.

14.5 CELL-CYCLE ANALYSIS AND TUMOR RESPONSE Because tumors are known to grow at different rates, it might be beneficial to have an assay to access the potential doubling time (Tpot) of the tumor. Such an assay has the potential to identify those patients with rapidly growing tumors who might benefit from accelerated or hyperfractionated radiation treatment. Technology has rapidly advanced over the past few years, making estimation of the rpot of a patient's tumors relatively simple and straightforward. The assay involves bolus injection of a halogenated pyrimidine (bromodeoxyuridine or iodo-

deoxyuridine). Over the next 2-4 h the halogenated pyrimidine is incorporated into the tumor-cell DNA. The tumor is biopsied and a single-cell suspension is prepared. The cells are then treated with a fluorescentlabeled antibody that recognizes the specific halogenated pyrimidine incorporated in the DNA. Following this treatment, the cells are analyzed by flow cytometry. From the DNA flow cytometry histogram, an estimate can be made of the rpot of the tumor [59]. Recent clinical studies have shown that local tumor control (using conventional fractionation) in patients with tumors with Tpot values < 4 days was significantly worse than that for tumors with Tpot values > 4 days, as shown in Figure 14.7 [60]. However, patients whose Tpot values were < 4 days and received accelerated fractionation achieved local control comparable to that of patients with Tpot values > 4 days who received either conventional or accelerated fractionation. Similar findings have been reported by other investigators [61]. In contrast, a recent study with 74 patients with head and neck tumors failed to show a correlation between Tpot values and local regional control using conventional radiotherapy [62]. These studies serve to demonstrate how important Tpot determinations might be in identifying candidates for altered fractionation schedules and perhaps high or low dose-rate brachytherapy. A cautionary note must be sounded because the number of patients analyzed in this fashion has been small, and verification with larger patient populations and different tumor types is needed. In addition, relying on a single biopsy for determination of Tpot values may be misleading. A recent study showed that when five biopsies were taken from individual esophageal tumors and rpot values determined, heterogeneity in T values were obtained [63].


14.6 CONCLUSIONS

clonogenic assay with chromosome aberrations scored using premature chromosome condensation with

Predictive assays are far from being incorporated into the routine radiation treatment decision-making process. Yet progress has been made and indeed much can be learned about tumor and normal-tissue biology and physiology through the development of such assays. Perhaps what will evolve from the cited initial studies is a battery of predictive assays that, when used together, will aid the radiation oncologist better to individualize treatment. There is no doubt that molecular techniques will aid ultimately in identifying new markers that will facilitate accurate and individualized predictive assays. There are indications that predictive assays have the potential to revolutionize the way in which the radiation oncologist will approach patient treatment. What is needed now is continued support by the radiation community of research and development that will lead to effective and practical assays.

fluorescence in situ hybridization. Int.J. Radiat. Oncol. Biol. Phys., 30,1127-32. 10. Olive, PL and Durand, R.E. (1992) Detection of hypoxic cells in a murine tumor with the use of the comet assay. J. Natl Cancer Inst., 84,707-11. 11. Fairbairn, D.W., Olive, PL and O'Neil, K.L (1991) The comet assay: a comprehensive review. Mutat. Res., 339,37-59. 12. Olive, PL, BanathJ.P.and MacPhail, H.S. (1994) Lack of a correlation between radiosensitivity and DNA doublestrand break induction or rejoining in six human tumor cell lines. Cancer Res., 54,3939^6. 13. Jones, L.A., Clegg, S., Bush, C., McMillan, T.J. and Peacock, J.H. (1994) Relationship between chromosome aberrations, micronuclei, and cell kill in two human tumour cell lines of widely differing radiosensitivity. Int. J. Radiat. Oncol. Biol. Phys., 66,639^2. 14. Bakker, P.J., Tukker, LJ., Stap, J., Veenhof, C.H. and Aten, J.A. (1993) Micronuclei expression in tumors as a test for radiation sensitivity. Radiother. Oncol., 26,69-72.

REFERENCES

15. Bush, C. and McMillan, T.J. (1993) Micronudeus formation in human tumour cells: lack of correlation with

1. Chapman, J.D., Peters, LJ. and Withers, H.R.(1989) Prediction of Tumor Treatment Responses, New York,

radiosensitivity. Br.J. Cancer, 67,102-6. 16. Wuttke, K., Streffer, C. and Muller, W.U. (1993) Radiation induced micronuclei in subpopulationsof human

Pergamon Press. 2. DeVita, V.T., Hellman, S. and Rosenberg, S.A. (1993)

lymphocytes. Mutat. Res., 286,181-8. 17. Wasserman, T.H. and Twentyman, P. (1988) Use of a

Cancer, Principles and Practice of Oncology, Philadelphia, J.B. LippincottCo. 3. Suit, H.D. and Walker, A.M. (1985) Predictors of radiation response in use today: criteria for new assays and methods of verification. In Prediction of Tumor Treatment Response, ed. J.D. Chapman, LJ. Peters and H.R. Withers. New York, Pergamon Press, 3-19. 4. Fertil, B. and Malaise, E.P. (1985) Intrinsic radiosensitivity of human cells lines is correlated with radioresponsiveness of human tumors: analysis of 101 published survival curves. Int.J. Radiat. Oncol. Biol. Phys., 11,1699-707. 5. Allalunis-Turner, M.J., Barron, G.M., Day, R.S., Fulton, D.S. and Urtasun, R.C. (1992) Radiosensitivity testing of human primary brain tumor specimens. Int.J. Radiat. Oncol. Biol. Phys., 23,339-43. 6. Raaphorst, G.P. (1993) Prediction of radiotherapy response using SF2: is it methodology or mythology? Radiother. Oncol., 28,187-8. 7. Al per, T. (1975) Cell Survival after Low Doses of Radiation: Theoretical and Clinical Implications. London, John Wiley and Sons. 8. Brown, J.M., Evans, J. and Kovacs, M.S. (1992) The prediction of human tumor radiosensitivity in situ: an approach using chromosome aberrations detected by fluorescence in situ hybridization. Int.J. Radiat. Oncol. Biol. Phys., 24,279-86. 9. Sasai, K., Evans, J.W., Kovacs, M.S. and Brown, J.M. (1994) Prediction of human cell radiosensitivity: comparison of

colormetric microtiter (MTT) assay in determining the radiosensitivity of cells from murine solid tumors. Int. J. Radiat. Oncol. Biol. Phys., 15,699-702. 18. Baker, F.L., Spitzer, G., Ajani, J.A. etal. (1986) Drug and radiation sensitivity measurements of successful primary monolayer culturing of human tumor cells using celladhesive matrix and supplemented medium. Cancer Res., 46,1263-74. 19. Brock, W.A., Baker, F.L, Wike, J.L, Sivon, S.L and Peters, L.J. (1990) Cellular radiosensitivity of primary head and neck squamous cell carcinomas and local tumor control. Int.}. Radiat Oncol. Biol. Phys., 18,1283-6. 20. Girinsky.T., Lubin, R. and PignonJ.P. (1992) Predictive value of in vitro radiosensitivity parameters in head and neck cancers and cervical carcinomas: preliminary correlations with local control and overall survival. Int.J. Radiat. Oncol. Biol. Phys., 25,3-7. 21. Courtenay, V.D. and Mills, J. (1978) An in-vitro colony assay for human tumours grown in immune-suppressed mice and treated in vivo with cytotoxic agents. Br.J. Cancer, 68, 819-23. 22. West, C.M.L, Davidson, S.E., Burt, PA. and Hunter, R.D. (1995) The intrinsic radiosensitivity of cervical carcinoma: correlations with clinical data. Int.J. Radiat. Oncol. Biol. Phys .,31,841-6. 23. West, C.M.L, Davidson, S.E., Roberts, S.A. and Hunter, R.D. (1993) Intrinsic radiosensitivity and prediction of patient response to radiotherapy for carcinoma of the cervix. Br.J. Cancer, 68,819-23.

References 213 24. Lawton, PA, Hodgkiss, R.J., Eyden, B.P. and Joiner, M.C. (1994) Growth of fibroblasts as a potential confounding factor in soft agar clonogenic assays for tumour cell radiosensitivity. Radiother. Oncol., 32,218-25. 25. Budach, W., Hartford, A., Gioioso, D., Freeman, J., Taghian, A. and Suit, H.D. (1992) Tumors arising in SCID mice share enhanced radiation sensitivity of SCID normal tissues. Cancer Res., 52,6292-6. 26. Stausbol-Gron, B., Bentzen, S.M., Jorgensen, K.E., Nielsen, O.S., Bundgaard, T. and Overgaard, J. (1999) In vitro radiosensitivity of tumour cells and fibroblasts derived from head and neck carcinomas: mutual relationship and correlation with clinical data. Brit.J. Cancer, 79,1074-84. 27. Loeffler, J.S., Harris, J.R., Dahlberg, W.K. and Little, J.B. (1990) In vitro radiosensitivity of human diploid fibroblasts derived from women with unusually sensitive clinical responses to definitive radiation therapy for breast cancer. Radial Res,, 121,227-31. 28. Geara, F.B., Peters, L.J., Ang, K.K., Wike, J.L and Brock, W.A. (1992) Radiosensitivity measurement of keratinocytes and fibroblasts from radiotherapy patients. Int.}. Radial Oncol. Biol. Phys., 24,287-93. 29. West, C.M.L, Elyan, S.A.G., Berry, P., Cowan, R. and Scott, D. (1995) A comparision of the radiosensitivity of lymphocytes from normal donors, cancer patients, individuals with ataxia-telangiectasia (A-T) and A-T heterozygotes. InlJ. Radial Oncol. Biol. Phys., 32, 1371-9. 30. Brock, W.A., Tucker, S.L., Geara, F.B. etal. (1995) Fibroblast radiosensitivity versus acute and late normal skin responses in patients treated for breast cancer. InlJ. Radial Oncol. Biol. Phys., 27,1173-9. 31. Dunst, J., Neubauer, S., Becker, A. and Gebhart, E. (1998) Chromosomal in-vitro radiosensitivity of lymphocytes in radiotherapy patients and AT-homozygotes. Sfra/7/On/ro/., 174,510-16. 32. Budach, W., Claben, J., Belka, C. and Bamberg, M. (1998) Clinical impact of predictive assays for acute and late radiation morbidity. Strahl. Onkol., 174,20^. 33. Russel, N.S., Grummels, A., Hart, A.M. et al. (1998) Low predictive value of intrinsic fibroblast radiosensitivity for fibrosis development following radiotherapy for breast cancer. InlJ. Radial Oncol. Biol. Phys., 73, 661-70. 34. Geara, F.B., Peters, L.J., Ang, K.K., Wike, J.L. and Brock, W.A. (1993) Prospective comparison of in vitro normal cell radiosensitivity and normal tissue reactions in radiotherapy patients. InlJ. Radial Oncol. Biol. Phys., 27, 1173-9. 35. Burnet, N.G., Nyman, J., Turesson, I., Wurm, R., Yarnold, J.R. and Peacock, J.H. (1994) The relationship between cellular radiosensitivity and tissue response may provide the basis for individualising radiotherapy schedules. Radiother. Oncol., 33,228-38. 36. Savitsky, K., Bar-Shira, A., Gilad, S. etal. (1995) A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science, 268,1749-53. 37. Taylor, A.M.R., Harnden, D.G., Arlett,C.F.20.0

0

1

2 3 4

16.7

Table 16.5 Obstruction score

Trachea Main stem Lobar bronchi

10 6 2

5 3 1

2 1 -

Atelectasis/pneumonia received additional 2 points per lobe.

Table 16.6 Symptom index scoring system

Dyspnea 0 None 1 Dyspnea on moderate exertion 2 Dyspnea with normal activity, walking on level ground 3 Dyspnea at rest 4 Requires supplemental oxygen Cough 0 1 2 3 4

iridium-192 for more rapid delivery of dose. In some of the low dose-rate protocols, delivery of radiation took as long as 60 h. The increase of iridium-192 activity allowed the treatment time to be decreased to 1.5-4 h. This range was based on (1) shorter times when the sources were new versus longer times after the sources decayed, and (2) the use, for the first time, of multiple catheters to deliver treatment. All treatments were performed in the outpatient setting and followed a protocol that is outlined in the next section.

None Intermittent, no medication necessary Intermittent, non-narcotic medication Constant or requiring narcotic medication Constant, requiring narcotic medication but without relief

Hemoptysis 0 None 1 Lessthan2/week 2 Less than daily but greater than 2/week 3 Daily, bright red blood or clots 4 Decrease of hemoglobin and/or hemotocrit > 10%; greater than 150 cm, requiring hospitalization or transfusion Pneumonia/elevated temperature 0 Normal temperature, no infiltrates, white blood count less than 10 000 1 Temperature greater than 38.5 °C and infiltrate, white blood count less than 10000 2 Temperature greater than 38.5 °C and infiltrate and/or white blood count greater than 10000 3 Lobar consolidation on radiograph 4 Pneumonia or elevated temperature requiring hospitalization

PROTOCOL

The protocol alluded to earlier in the chapter was initiated in 1986 when EBBT was transformed from low dose-rate manual afterloading to medium dose-rate remote afterloading procedures. This was a transitory step of short duration, lasting for 9 months. The HDR remote afterloader was, in fact, a Nucletron Selectron low dose-rate remote afterloader that was modified to accept a longer source train and a higher level of radioactivity. The activity was typically maintained at greater than 740 MBq, or 20 mCi cm"1. Dose rates initially were calculated at a 5 mm depth perpendicular to the source train, and were in the range of 5-10 cGy min-1.

16.7.1

Eligibility

Eligibility for the protocol included the following. 1. Disease must involve the trachea, main stem, or lobar bronchi. Involvement of the segmental bronchi without involvement more proximal was not considered sufficient for entry into the protocol. 2. The central airway disease must be intraluminal, visualized and biopsied via bronchoscopy. Patients requiring transbronchial biopsy were ineligible for the protocol. 3. Patients must have significant symptomatology within the four symptom groups consisting of cough, dyspnea, signs and symptoms of obstructive pneumonia, and/or hemoptysis. Evaluation of the patients meeting eligibility criteria for the EBBT protocol schedule was reviewed within the context of all patients diagnosed with lung cancer in the referral area from 1986 through 1996. This involved the greater Phoenix/Maricopa County area and, based on the Tumor Registry, an incidence of approximately 9000 cases of lung cancer during the 10-year period was calculated. Of these, only 19% received radiation and 16% of that group, or 3% of all patients, were treated on protocol, while an additional 11% of patients receiving radiation (or 2% of all patients) were treated with brachytherapy off protocol. Thus, 27% of all patients receiving radiation, or 5% of all diagnosed lung cancer

234 Endobronchial brachytherapy in the treatment of lung cancer

patients, received brachytherapy. For patients on the curative protocol, these figures were 3% and 0.5%, respectively.

16.7.2 Indications Indications for treatment are outlined in Table 16.7.

16.7.3

Protocol 1.0 curative intent

To be eligible for this protocol, patients must not have had prior radiation within the thoracic area, which would preclude the adequate delivery of a full dose of external radiation. Patients must be inoperable and have a primary lung carcinoma with non-small cell histology. Stages accepted were Tl,2,3, Nl,2, MO. These correspond to stage groupings I, II, and Ilia. Performance status using the East Coast Oncology Group (ECOG) fourtiered system must be 0, 1, or 2 and weight loss using a four-tiered weight loss system, likewise, must be 0, 1, or 2 and correspond to weight losses of 0, less than 5% or less than 10%, respectively, of the patient's weight in the 6 months prior to diagnosis. The rational for selection of this level of weight loss is described in 'Oncologic assessment using the four-tiered scoring system' [38].Patients were treated within groups 1-4, with dose modifications as described in Table 16.8.

16.7.4

Protocol 2.0 palliative intent

PROTOCOL 2.1 Eligibility for these patients includes: primary lung cancer with non-small cell histology, and stage T4, N3 and/or Ml disease. These corresponded to stage groupings Illb and IV. In addition, the patients ineligible for protocol 1.0 because of performance scores of 3 or 4 or a weight loss of 3 or 4 (>10% >20%) were reallocated to this protocol. Patients were treated within groups, characterized by dose, as described in Table 16.8. PROTOCOL 2.2

Primary lung cancer consisting of small cell histology, both limited and extensive; primary lung cancer with contralateral metastatic disease involving the endobronchial mucosa; and non-lung primaries with metastases primarily to the mucosa were treated within this category. Patients were treated within the group characterized by dose as described in Table 16.8.

16.7.5

Protocol 3.0 recurrent patients

All patients who had received prior radiation for a curative intent for carcinoma of the lung were included within this category. Patients were treated within the

Table 16.7 Indications for treatment with endobronchial brachytherapy

Tumors must be seen and biopsied by bronchoscopy (intraluminal)

Tumors presenting with extrinsic compression of the airway as seen by bronchoscopy and the biopsy must be performed transbronchially (extraluminal)

Intraluminal brachytherapy delivers a very high dose to tumor close to the source axis; extraluminal disease due to its much greater distance from the axis, would lead to unacceptable doses to the bronchial mucosa and surrounding structures

Tumors must be in the central airways which are defined as the trachea, main stem, and lobar bronchi

Tumors in peripheral airways which are defined as segmental bronchi or beyond

Significant symptomatology is most often caused by disease in central airways; treatment of small peripheral airways leads to stenosis of those airways

Tumors in central airways causing significant symptomatology

Patients with significant pre-existing dyspnea unrelated to carcinoma; patients with dyspnea secondary to effusion, or large extrinsic masses

Patients with symptoms second to disease other than central airway disease are not expected to improve with intraluminal brachytherapy

In-situ carcinoma for inoperable patients

Patients entered into national protocols using other modes of treatment, i.e., photodynamic

Preserves lung and pulmonary function; excellent treatment for multifocal disease

Pre-op. for submucosal spread from a peripheral/central lesion

Patients should be good candidates for lobectomy or pneumonectomy

Treatment provides a clear margin for surgery

Protocol 235 Table 16.8 Modification of doses by year for the curative, palliative and recurrent protocols

Curative protocol 1 2 3 4 Palliative protocol 1

1986-1988 1988-1990 1990-1992 1992-1994

6000 6000 6000 6400

30 30 30 32

1000 1000 750 500

5 10 10 10

3 3 3 3

MDR HDR HDR HDR

1986-1988

3750

15

2

1988-1990

3750

15

3

1990-1992

3750

15

4

1992-1994

3750

15

1000 1000 1000 1000 750 750 500 500 750

5 5 10 10 10 10 10 10 10

3 3 3 3 3 3 3 4 3

MDR MDR HDR HDR HDR HDR HDR HDR HDR

Recurrent protocol 1 2 3 4

1986-1988 1988-1990 1990-1992 1992-1994

1000 1000 750 500

5 10 10 10

3 3 3 4

MDR HDR HDR HDR

group characterized by dose, as described in Table 16.8. Group I patients were treated with medium dose rate. In the palliative protocol, the brachytherapy was constant and the use of external radiation was optional, at the discretion of the treating oncologist. Its use was restricted to patients with extrinsic disease that caused a significant contribution to the level of obstruction and/or symptomatology.

16.7.6

Results

The following results incorporate 600 patients treated in the curative, palliative, and recurrent protocols outlined previously. In each of the successive periods of the operation of the protocol, the eligibility factors for the curative, palliative, and recurrent protocols have remained constant. All patients treated in curative protocols with external radiation received 2 Gy per fraction and, in palliative protocols, 2.5 Gy per fraction. If patients received concurrent brachytherapy and external radiation, the two treatments were not given on the same day. For the curative protocol, brachytherapy was delivered during weeks one, three and five. For palliative or recurrent protocols, brachytherapy was delivered weekly for three or four fractions, depending on the protocol. The distribution of patients into the protocol groups was as follows: curative 19%, palliative 48%, and recurrent 33%. The age distribution of the patients had a median of 68 years and a mean of 67.1 years. Most of the

patients fell within the range of 60-80 years old. The gender distribution was 62% male and 38% female. The percentage of female patients increased from 28% in Group 1 to 41% in Groups 3 and 4. The breakdown for male/female patients was similar to that of all patients presenting with carcinoma of the lung within the geographical treatment area. Squamous cell carcinoma is by far the most common cell type, overall, in the study (49%), and even to a greater extent for those treated in the curative protocol (70%). This percentage is considerably higher than is currently being seen in newly diagnosed outpatients with lung cancer (27%). This fits with prior observations that squamous cell carcinomas tend to be more central and adenocarcinomas more peripheral. The use of laser photoresection predated the wide use of HDR brachytherapy for airway carcinoma. In this study there was a gradual decrease in photoresection from an initial 32% to 16% in the latter part of the study. It is currently estimated that less than 5% of patients with central airway disease require laser photoresection. The protocol required that patients must have one or more of the four primary symptom complexes in order to be included in this study. The incidence of the symptoms in the study were: cough, 99%; dyspnea, 97%; hemoptysis, 64%; and the signs and symptoms of obstructive pneumonia, 49%. Using the Four-tiered symptom index as outlined in Table 16.6, the severity of the symptoms was weighted and the total weighted scores was subsequently normalized to 100%. Response for each symptom score is related to each brachytherapy


procedure and the first follow-up bronchoscopy (Figure 16.2). Hemoptysis had the most dramatic and rapid of the responses with improvements of 70%, 90%, and >99% at each intervention point. Pneumonia improvement was only slightly less dramatic, with responses of 57%, 85%, and >99%. Improvement in dyspnea occurred in 36%, 54%, and 86% respectively. The fourth symptom, cough, showed improvements of 32%, 52%, and 85%, respectively. The improvements in hemoptysis and pneumonia were commonly seen within the first 24 h following the first brachytherapy procedure. Patients, who were admitted to the hospital with obstructive pneumonia and/or sepsis, or with severe bleeding requiring transfusion, generally had a prompt response. In the palliative protocol, the use of concurrent external radiation with brachytherapy was optional. When the weighted responses were measured for brachytherapy only, versus brachytherapy and external radiation, the results in terms of improvement at follow-up were as follows: hemoptysis, 94% and 97%; pneumonia, 86% and 82%; dyspnea, 54% and 48%; and cough, 51% and 57%. There was no statistical difference in response for each symptom group for each of these two therapies. The use of brachytherapy only was sufficient to provide palliation, without the need to add supplemental external radiation.

Airway obstruction scores (as seen in Figure 16.3), were analyzed in a different fashion. All of the scores were converted into median scores, which were normalized to 100%. These were obtained for each brachytherapy procedure and at the first follow-up bronchoscopy. The median score was normalized to 100% and the residual level of obstruction expressed as a percentage. Any tissue including inflammatory tissue was included as part of the obstruction score. The curative patients and the palliative groups fared better than the recurrent group, with scores of 12%, 12.5%, and 19% respectively (Figure 16.3). This is not unexpected, considering that patients with recurrent carcinoma have had previous external radiation, which may select for a slightly more radioresistant carcinoma. It is interesting that neither the use of concurrent external radiation nor the use of laser photoresection led to improved clearing of obstruction. Thus, as in the symptom index results, the addition of external radiation or laser resection did not add to clearing endobronchial disease. The survival of patients by protocol group was, for the curative patients, 10%, and for palliative-recurrent, 5% at 5 years. The cause of death shows a significant local failure rate in all categories. These rates were 31% and 30%, respectively, for the curative and palliativerecurrent protocols. As has been seen in numerous other studies, despite gradual increasing doses of radiation Figure 16.2 Response in the symptom index as measured by the decrease of the symptom index scores comparing the initial score at the first brachytherapy (normalized to 100%) and the scores at subsequent encounters as the percent residual.

Figure 16.3 Response in the obstruction score with the mean initial score normalized to 100% at the first brachytherapy and the percent residual at the first bronchoscopicfolloW-up (F/U).

Protocol 237

over the last several decades, local disease continues to be a significant problem. Survival curves for curative versus the palliativerecurrent patient illustrated in Figure 16.4 are calculated from the date of diagnosis and date of the first brachytherapy procedure. There was no statistically different result between these two groups when analyzed

from the date of diagnosis (p = 0.1). However, from the date of the first brachytherapy treatment, thep-value was 15 Gy, prior laser therapy, second brachytherapy treatment, and concurrent external-beam radiation therapy. Twenty of the 25 patients whose deaths were assessable and related to hemoptysis had recurrent and/or residual tumor suspected at the hemoptysis site. The chronology of the massive hemoptysis leading to death occurred between 9 and 12 months after completion of the HDR procedure. This was in stark contrast to deaths from all other causes, which usually occurred 3-6 months after completion of the HDR procedures [40].

Pros and cons 239

Brachytherapy-related bronchitis and stenosis are managed depending on the level of severity of the reaction and/or stenosis. This can include observation for mild treatment-related bronchitis for the least symptomatic presentation, versus active treatment for its more debilitating form, with oral and/or aerosol administration of steroids, aerosol-administered bronchodilators, codeine-based or narcotic-based cough suppressants, and antifungal or antibiotic therapies as indicated. More aggressive interventional management for debilitating and/or life-threatening levels of bronchitis and/or stenosis may be managed with balloon and/or bougie dilatation, laser photoresection, bronchoscopic debridement, and/or placement of intraluminal stents. Although lung brachytherapy has been advocated by radiation oncologists for the past 20 years, recent technological developments in the area of HDR brachytherapy, such as the design of small, high-activity iridium-192 sources and remote afterloading machines, have prompted renewed interest in HDR endobronchial brachytherapy. The specific role of lung EBBT is not clearly defined within the standard and/or uniform community practice. There is an ongoing evolution for the selection criteria to identify those patients most likely to benefit from EBBT as part of definitive therapy. The American Brachytherapy Society (ABS) HDR Consensus Guidelines [41] currently state that, although endobronchial brachytherapy has demonstrated efficacy for the symptomatic relief of bronchial obstructions and hemoptysis, either alone or in combination with externalbeam radiation therapy, the curative benefit of brachytherapy in addition to conventional externalbeam radiation therapy and/or chemotherapy has not been proven. The ABS recommends that brachytherapy for the definitive treatment of lung cancer is done within the context of controlled clinical trials. Outside of clinical trials, the ABS suggests that brachytherapy be reserved for palliative treatments alone. Although the guidelines do not clearly state the indications for additional externalbeam radiation in newly diagnosed lung cancer patients, EBBT alone is recommended for recurrences after fulldose external-beam radiation therapy treatments have been administered. No single-dose fractionation scheme has been identified which provides a superior therapeutic ratio. Dose specifications to be prescribed have been recommended to a depth of 1 cm from the source center for uniform prescription dosimetry comparisons. A study by the Radiation Therapy Oncology Group (RTOG) evaluated the palliation provided by externalbeam radiation to patients with newly diagnosed nonmetastatic, non-small cell lung cancers [42].This study, by Simpson et al, demonstrated that a short course of external-beam radiation therapy delivering 30 Gy in ten fractions provided relief of hemoptysis in 74% of patients, of cough in 55% of patients, and of dyspnea in 43% of patients. Median survival was around 6 months. Compared to this RTOG study, brachytherapy alone

appears to provide palliation equivalent to or better than external-beam radiation, with a similar survival outcome. Given this fact, brachytherapy may give more prompt symptomatic relief of obstructive symptoms, in a more cost-effective manner. In a small group of 19 patients treated with HDR to a total dose of 15 Gy [43], a detailed assessment with rigorous testing was performed both before and after administration of the HDR brachytherapy. This enlisted chest X-rays, computerized tomography scan of the thorax, direct bronchoscopic evaluation, objective obstruction index scoring, 5-min walking stress tests, isotope ventilation and profusion lung scanning, and formal pulmonary function tests with maximum inspiratory and expiratory full volume measurements. Symptomatic relief was reported in 17 of the 19 patients. Atelectasis of a collapsed lobe or lung reported in 13 patients was demonstrated to have reinstituted ventilation in nine cases by radiographic imaging. Bronchoscopic evaluation of luminal patency demonstrated improvement in 18 of the 19 patients. Isotope lung scans showed significant increase in the percentage of total lung ventilation and perfusion in the abnormal lung. This rigorous study demonstrated the high correlation between objective and subjective improvement of the presenting symptomatology in these patients. In addition, it confirmed the palliative benefit of brachytherapy, which has been described in larger groups of patients. Further prospective studies of brachytherapy and external-beam radiation therapy are clearly needed to rigorously document treatment efficacy and toxicity, as well as cost-benefit and quality of life analyses in this setting.

16.10

CONCLUSIONS

Endobronchial brachytherapy is an excellent method of palliative treatment for patients who are symptomatic from endobronchial disease as part of definitive therapy for curative intent patients; however, a survival advantage is not shown. This group of patients should be randomized to external-beam radiation therapy versus external-beam plus intraluminal radiation to evaluate prospectively any survival advantage. Further studies will also be necessary to determine the optimal dose and number of fractions that will provide the greatest patient benefit, the lowest morbidity, and the lowest cost of treatment.

16/11

PROS AND CONS

Pro Endobronchial brachytherapy is ideal for delivering very high doses of radiation to neoplastic tissue in or within a 1 cm radius of the main airway.

240 Endobronchial brachytherapy in the treatment of lung cancer Con Because brachytherapy doses depend on the inverse square law (that is, the dose decreases by the square of the distance), neoplastic tissue >1 cm from the airway is not effectively treated. Pro Endobronchial brachytherapy provides relief of airway obstruction to a greater extent and significantly faster than external radiation. Con Obstruction of airways by extrinsic compression is best treated by external radiation. Pro Endobronchial brachytherapy can be used in the trachea main stem, lobar and segmented bronchi to an extent greater than feasible with the YAG laser. Con YAG laser works immediately (endobronchial brachytherapy takes 4-24 h for a partial response) and is sometimes necessary for very bulky exophytic tumors. Pro For palliation of airway signs and symptoms due to intrinsic disease, endobronchial brachytherapy provides excellent relief with minimal morbidity. Con Extrinsic compression such as nodal or parenchymal masses or pleural effusion can nullify benefits of brachytherapy, unless these other factors are adequately dealt with. Pro Endobronchial brachytherapy can cure occult cancer of the lung. Con Occult cancer has a high rate of synchronous lesions that must also be identified and treated.

9.

10. 11.

12.

13.

14.

15.

16. 17.

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38. Speiser, B. (1995) Oncological assessment using the fourtiered scoring system. Curr. Oncol., 2(2), 54-9. 39. Gollins, S., Burt, P., Barber, P. etal. (1994) High dose rate intraluminal radiotherapy for carcinoma of the bronchus: outcome of treatment of 406 patients. Radiotherapy, 33,31^0. 40. Gollins, S.W., Ryder, W.J., Burt, P.A. etal. (1996) Massive haemoptysis death and other morbidity associated with high dose rate intraluminal radiotherapy for carcinoma of the bronchus. Radiat. Oncol., 39,105-16. 41. Nag, S., Abitbol, A.A., Anderson, LL etal. (1993) Consensus guidelines for high dose rate remote brachytherapy in cervical, endometrial, and

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REFERENCES PORTABLE 16.2 A1

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A13

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radiation for malignant airway occlusion. Int.}. Radial Oncol. Biol. Phys., 23,133-9. Sutedja, G.( Baris, G., Schaake-Koning, C. et al. (1992) High dose rate brachytherapy in patients with local recurrences after radiotherapy of non-small cell lung cancer. Int. J. Radial Oncol. Biol. Phys., 24, 551-3. Speiser, B. and Sprattling, L (1993) High dose rate brachytherapy for the local control of endobronchial carcinoma. Int. J. Radial Oncol. Biol. Phys., 25, 579-88. Zajac, A.J., Kohn, M.L, Heiser, D. et al. (1993) High-dose rate intraluminal brachytherapy in the treatment of endobronchial malignancy. Radiology, 187, 571-5. Tredaniel, J., Hennequin, C., Zalcman, G. et al. (1994) Prolonged survival after high-dose rate endobronchial radiation for malignant airway obstruction. Chest, 105, 767-72. Chang, LF.L, Horvath, J., Peyton, W. et al. (1994) High dose rate afterloading brachytherapy in malignant airway obstruction of lung cancer. Int. J. Radial Oncol. Biol. Phys., 28, 589-96. Collins, S., Burt, P., Barber, P. et al. (1994) High dose rate intraluminal radiotherapy for carcinoma of the bronchus: outcome of treatment of 406 patients. Radiotherapy, 33, 31-40. Cotter, G.W., Larisey, C., Ellingwood, K.E. et al. (1993) Inoperable endobronchial obstructing lung cancer treated with combined endobronchial and external beam irradiation: a dosimetric analysis. Int. J. Radial Oncol. Biol. Phys., 27, 531-5. Goldman, J., Bulman, A., Rathmell, A. et al. (1993) Physiological effect of endobronchial radiotherapy in patients with major airway obstruction. Thorax, 48, 110-14. Marsh, B.R., Colvin, D.P., Zinreich, E.S. et al. (1993) Clinical experience with an endobronchial implant. Radiology, 189,147-50. Nori, D., Allison, R., Kaplan, B. et al. (1993) High dose rate intraluminal irradiation in bronchogenic carcinoma. Chest, 104,1006-11. Pisch, J., Villamena, P., Harvey, J. et al. (1993) High dose-rate endobronchial irradiation in malignant airway obstruction. Chest, 104, 3721-5. Madia, H.N., Wahlers, B., Reichle, C. et al. (1995) Endobronchial radiation therapy for obstructing malignancies: ten years' experience with iridium-192 high-dose radiation brachytherapy afterloading technique in 365 patients. Lung, 173, 271-80.

A25

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Huber, R., Fischer, R., Hautmann, H. et al. (1995) Palliative endobronchial brachytherapy for central lung tumors. Chest, 107(2), 463-70. Gustafson, G., Vincini, F., Freedman, L et al. (1995) High dose rate endobronchial brachytherapy in the management of primary and recurrent bronchogenic malignancies. Cancer, 75(9), 2345-50. Sur, R., Mahomed, G., Pacella, J. et al. (1995) Initial report on the effectiveness of high dose rate brachytherapy in the treatment of hemoptysis in lung cancer. Endocuriether. Hypertherm. Oncol., 11,101-6. Speiser, B. (1995) The role of endobronchial brachytherapy in patients with lung cancer. Clin. Pulmonary Med. 2(6), 344-52. Saito, M., Yokoyama, A., Kurita, Y. et al. (1996) Treatment of roentgenographically occult endobronchial carcinoma with external beam radiotherapy and intraluminal lowdose rate brachytherapy. Int. J. Radial Oncol. Biol. Phys., 34,1029-35. Delclos, M.E., Komaki, R., Morice, R.C. et al. (1996) Endobronchial brachytherapy with high-dose rate remote afterloading for recurrent endobronchial lesions. Radiology, 201(1), 279-82. Huber, R.M., Fischer, R., Hautmann, H. et al. (1997) Does additional brachytherapy improve the effect of external irradiation? A prospective, randomized study in central lung tumors. IntJ. Radial Oncol. Biol. Phys., 38(3), 533^0. Corsa, P., Parisi, S.S., Raguso, A. et al. (1997) High-dose brachytherapy in endobronchial neoplastic stenoses. Radiol. Med. (Torino), 94(1-2), 94-9. Perol, M., Caliandro, R., Pommier, P. et al. (1997) Curative irradiation of limited endobronchial carcinomas with high-dose rate brachytherapy. Results of a pilot study. Chest, 111(5), 1417-23. Ornadel, D., Duchesne, G., Wall, P. et al. (1997) Defining the roles of high dose rate endobronchial brachytherapy and laser resection for recurrent bronchial malignancy. Lung Cancer, 16(2-3), 203-13. Ofiara, L, Roman, T., Schwartzman, K. et al. (1997) Local determinants of response to endobronchial highdose rate brachytherapy in bronchogenic carcinoma. Chest, 112(4), 946-53. Hennequin, C., Tredaniel, J., Chevret, S. et al. (1998) Predictive factors for late toxicity after endobronchial brachytherapy: a multivariate analysis. Int. J. Radial Oncol. Biol. Phys., 42(1), 21-7.

17 Brachytherapy in cancer of the esophagus A.D. FLORES

17.1

INTRODUCTION

It is estimated that, in the year 2001,13200 new cases will be diagnosed with carcinoma of the esophagus in North America and, of these, 12 500 will die as a result of the disease during the same year. This number corresponds to only 1 % of all cancer cases seen in this particular year [ 1 ]. Whereas the incidence of cancer of the stomach in the last 40 years has been declining, the incidence of adenocarcinomas arising in the esophagus has substantially increased, and now comprises 20-40% of all esophageal malignancies seen in North America and Western Europe [2-5]. Similarly, there has been a significant increment in the incidence of cardioesophageal lesions in relation to carcinomas developing in the distal portion of the stomach [2-5]. Higher incidence rates (40-50 per 100000 population) have been reported in certain regions of Iran, South Africa, China, and the former Soviet Union. Although etiological factors are still unknown, many environmental factors (alcohol, smoking, dietary, etc.) have been associated with the disease [6]. The clinical presentation, behavior, and prognosis of cancers arising in the esophagus and/or the cardioesophageal junction are similar. Unfortunately, conventional treatments have not altered the poor prognosis these patients have and survival rates of 5-7% have remained unchanged in the last four decades [7-9]. Most patients have advanced disease when first diagnosed and only palliative treatment is available to them.

Only 20% of all new patients seen could be eligible for treatment with an intention of cure. However, the treatment for these patients presenting with early disease is controversial. Although, historically, surgical treatments have produced a poor overall survival similar to that of radiation treatments [7-9] trials designed to compare these two treatments have been difficult, not enough patients could be recruited and they therefore had to be abandoned [10]. Results of investigations using preoperative or postoperative conventional radiotherapy have been mixed [11-15]. Cooperative efforts employing multimodality conventional treatments have also been disappointing. Chemotherapy regimens have not affected metastasis or stopped the development of metastasis in recent studies. Similarly, encouraging preliminary results using chemotherapy as an adjuvant treatment to surgery or radiation have been associated with increased toxicity and have resulted in neither significant improved survival nor better quality of life [16-28]. Clearly, new innovative treatment protocols will be required to enhance the cure rate for cancers arising in the esophagus and cardioesophageal junction.

17.2

NATURAL HISTORY OF THE DISEASE

The majority of patients with carcinoma of the esophagus are diagnosed with dysphagia, which is a manifestation of

244 Brachytherapy in cancer of the esophagus

extensive local disease causing malignant obstruction. In the western world, 80% of patients are diagnosed when the tumor is larger than 5 cm or extended beyond the esophageal wall (T2-T3). Even in early operable cases, lymphatic spread is recognized in 70% of the resected esophageal specimens 9 Anatomically, the esophagus does not have a serosal layer and the neoplasm could easily reach the adjacent peri-esophageal tissues and spread through the rich submucosal lymphatics to the most proximal esophageal wall and to the mediastinal, perigastric, and cervical lymph nodes. The study of patterns of failure in several institutions confirms that the overwhelming majority of patients (more than 80%) with esophageal cancer fail and die with persistent local or loco-regional disease and metastasis [26,27,32-36]. From these facts, it is reasonable to assume that if local control of the disease could be enhanced by innovative treatments, better quality of life and possibly even longer survival will result. It is, therefore, imperative that new protocols be designed with the specific aim of enhancing the local therapeutic ratio of external irradiation. 173 HISTORY AND TREATMENT RATIONALE FOR INTRALUMINAL BRACHYTHERAPY The potential therapeutic value of intraluminal brachytherapy for esophageal cancer was already recognized at the beginning of the twentieth century. As early as 1909, some investigators had reported useful palliation of dysphagia by directly placing radium beads in the esophagus housed in a nasogastric plastic tube [37,38]. It was, however, not until 1969 that successful intraluminal brachytherapy was reported in a selected group of eight patients by Rider and coworkers in Toronto [39]. Although these investigators stressed the usefulness of brachytherapy for esophageal malignancies, this type of procedure was unfortunately not actively pursued. The lack of interest was due to many factors, among them: the introduction of megavoltage units and deviation of interest towards external irradiation, technical difficulties of the brachytherapy procedure, and, most importantly, the poor tolerance of patients due to longer treatment times. The Second World War and legitimate concerns regarding radiation exposure also delayed the development of new radioactive isotopes for medical use until 1948, when cobalt-60 was introduced. In 1953, Henschke developed the idea of afterloading and designed plastic tube devices in an attempt to reduce the radiation exposure of the medical personnel [39a]. In more recent years, the production of safer and higher specific activity radioactive sources (Table 17.1) facilitated the fabrication of miniaturized sources, significantly decreased treatment times, introduced automatic remote control radiation delivery, and completely eliminated the problem of radiation exposure. This improved

Table 17.1 Linear activities of radioactive sources

Cesium-137 tubes Cesium-137 pellets lridium-192(10Ci/4 mm)

21 mCi cm-1 or 770 MBq cnr1 1 126 mCi cm or 4660 MBq crrr1 20 Ci cm-1 or 74000 MBq cm-1

technology made brachytherapy in general a more acceptable treatment modality for esophageal cancer and malignancies at other sites. The basic rationale for choosing brachytherapy in esophageal cancer is that while the amount of irradiation that can be given by external irradiation is limited by the tolerance of the normal tissues in the chest (lung, spinal cord, mediastinal structures, etc.), intraluminal brachytherapy places the highest concentration of irradiation directly into the intraluminal disease but delivers significantly lower doses to the adjacent normal tissues (due to the rapid dose fall-off). In view of this physical advantage, therefore, it is possible to increase the dose to the cancer with the use of brachytherapy without affecting the adjacent normal tissues, thus enhancing the therapeutic ratio.

17.4 CLINICAL STAGING AND PRETREATMENT INVESTIGATIONS The TNM classification for esophageal malignancies has changed. Tumor size and degree of circumferential involvement are no longer criteria to define the extent of the primary tumor. The new staging classification is based on the histopathological assessment of the depth of tumor penetration in the esophageal wall (Table 17.2). Because it is not always possible to obtain a representative sample of the full thickness of the esophagus by

Table 17.2 TNM classification: esophagus Primary tumor (T)

TX TO Tis T1 T2 T3 T4

Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ Tumor invades the lamina propria or submucosa Tumor invades the muscularis propria Tumor invades adventitia Tumor invades adjacent structures

Lymph node (N) NX Regional lymph nodes cannot be assessed NO No regional lymph node metastasis N1 Regional lymph node metastasis Distant metastasis (M) MX Presence of distant metastasis cannot be assessed MO No distant metastasis M1 Distant metastasis

Therapy decision process 245

endoscopic biopsy, pretreatment clinical staging of this cancer has been difficult. Recently, endoscopic ultrasonography, a new diagnostic procedure, has produced satisfactory imaging of the different layers of the esophageal wall and regional lymphatics. Several investigators have demonstrated good clinico-pathological correlation, with ultrasonography suggesting superiority over computerized tomography (CT) or magnetic resonance imaging (MRI) scans in the clinical staging of esophageal cancer [40]. The routine use of endoscopic ultrasonography to assess the extent of esophageal malignancies has been endorsed by the International Society of Gastroenterology [41]. If the diagnosis of cancer of the esophagus is suspected, the initial evaluation should include routine blood tests and full physical examination, including an evaluation of the lymph node regional bearing areas. Then, adequate radiological studies of the upper gastrointestinal tract and endoscopic examination for direct biopsy of a suspicious area should follow. If the lesion is located above the tracheal bifurcation, a bronchoscopic examination at the same setting is advisable. This will permit a better evaluation of the tumor extension and exclude invasion to the membranous portion of the adjacent bronchus or trachea. Once the diagnosis of a malignancy has been confirmed, CT scan of the chest and upper abdomen is performed to assess the extent of the primary disease and exclude metastasis. As discussed earlier, endoscopic ultrasound is desirable to determine with certainty the extent of the local and regional disease and for clinical staging prior to definitive treatment. Only 20% of the patients diagnosed with cancer of the esophagus have their disease confined to the esophageal wall (T1NO, T2NO) and could be suitable for treatment with curative intent. In most patients, the esophageal disease has already extended beyond the wall and cannot be resected adequately (T3, T4). The presence of regional lymph node metastasis (Nl, N2) is also a sign of poor prognosis, even if the esophagus is resected, as only 15% or fewer patients with positive nodes will survive [7,8,30,31]. Because, overall, 5-year survival rates with conventional treatments are extremely poor, a careful and adequate assessment of the clinical staging prior to treatment is essential. This information is extremely useful when selecting the most suitable treatment according to prognosis and to avoid unnecessary complications associated with radical treatments [42,43]. The addition of intraluminal brachytherapy to external irradiation is a good treatment strategy, as it is simple, well tolerated, and can enhance the local control and quality of life of most of these patients. 17.5

TREATMENT STRATEGIES

Attempts to improve local control by increasing the amount of external irradiation have failed due to poor

tolerance of the normal tissues adjacent to the esophagus. Newer schedules of fractionated radiotherapy (accelerated, superfractionation, etc.), concurrent chemotherapy, chemical modifiers, or sensitizers aiming to enhance the effect of external irradiation are also likely to fail for the same reasons. Because the local failure is high, it is sensible to assume that better control can be obtained by combining radiotherapy and surgery. Results of studies using postoperative irradiation have been negative and those of preoperative irradiation trials have been mixed. Two European phase III studies [11,12], comparing esophagectomy alone and preoperative conventional external irradiation showed no advantage for either group. In these trials, the radiotherapy schedule was unusual (4000 cGy in ten fractions) and a high rate of complications resulted. Three other studies [13-15], comparing esophagectomy alone with a more conventional preoperative external irradiation, reported significant benefits in the preoperative irradiation arm. Due to concerns regarding perioperative complications, current trials have not considered a preoperative irradiation treatment arm. Instead, newer programs involve studying the value of neoadjuvant or concurrent chemotherapy added to either surgery or external irradiation. However, the impact of these new programs should be expected to be minimal and a larger number of patients will be required to show differences between the treatment arms. The esophagus above the tracheal bifurcation lies contiguous and posterior to the membranous portion of the trachea and the proximal aspect of the left main bronchus. These anatomical characteristics show the obvious weakness of esophagectomy alone as a rational treatment for cancers of the esophagus. Furthermore, the morbidity and mortality associated with esophagectomy are higher for upper esophageal lesions. The lower end of the esophagus is relatively free and more accessible for adequate removal. Conventional external irradiation produces similar results to surgery in early cases and may be better for palliation in more advanced tumors. The morbidity associated with external irradiation compared to surgery is mild and similar for all levels of the esophagus, and no additional toxicity should be expected with intraluminal brachytherapy [44].

17.6

THERAPY DECISION PROCESS

Patients with cancer of the esophagus could be candidates for either palliative or curative treatment, depending on the extent of their disease, performance status, associated illnesses, and age. Patients with distant metastasis have an average lifespan of only 3-6 months, and the palliative treatment should be short, simple, and specifically designed to improve their quality of life in terms of swallowing and pain. The same philosophy


should be applied to elderly patients with locally advanced disease and poor condition. Because dysphagia and nutrition are the main concerns at presentation, most patients require dilatations and/or parenteral feeding prior to their treatment for palliation or curative intent. In palliative conditions, a single intraluminal treatment alone or combined with a short course of external irradiation (1800 cGy in three fractions given by parallel and opposed fields) may be sufficient to restore and maintain swallowing and improve the quality of life of these patients. Patients with only loco-regional disease (as per CT scan and endoscopic sonogram findings) and in good overall condition are suitable for a form of radical treatment designed to control the disease. They could be eligible for trials of investigation using radiotherapy or esophagectomy and adjuvant treatments. Patients with esophageal malignancies located above the tracheal bifurcation may be best treated with radiotherapy programs alone or in combination with chemotherapy in prospective trials. Lower esophageal lesions can be treated also by radiotherapy regimens, reserving esophagectomy for persistent or recurrent disease. Primary esophagectomy should only be considered in prospective clinical trials and opposed to radiotherapy programs. Radiotherapy with curative intent requires adequate planning and several weeks of external irradiation using multiple portals. Intraluminal brachytherapy can be given before, during, or after the course of external irradiation. Treatment planning should be tailored to each patient needs and to whether concurrent chemotherapy is used. It would be preferable to give part of the external treatment by parallel AP/PA opposed portals to prevent lung toxicity when chemotherapy is given concurrently. Tumor doses given by external irradiation are usually 4000 cGy in 15 fractions, or 5000 cGy in 20 fractions in 4 weeks to an 8 x 8 x 16 cm treatment volume. The intraluminal brachytherapy dose is estimated at 1 cm of the axis of an 8-12 cm linear source and consists of 3000 cGy in 48 h with low dose-rate sources (radium, cesium), or a single 1500 cGy with intermediate and high dose-rate sources (in 1.5h or a few minutes respectively). The radiobiological reasons for these doses are discussed below. General guidelines for esophageal brachytherapy have been published recently [45].

tube. Catheters of 8 mm or less external diameter can be easily placed through the nose and are, in general, better tolerated. Larger diameter catheters require the oral route and adequate sedation (xylocaine spray and valium 3-5 mg intravenously is usually sufficient). With either route, the suctioning of oral secretions and/or salivation is essential to maintain patient comfort and avoid aspiration. The following is a step-by-step plan and outline of the procedure. 1. The precise anatomical location and extension of the cancer are determined by reviewing the barium swallow X-rays, endoscopic and CT scan findings. 2. Localization and planning of the treatment area are performed in the simulator unit using a limited barium swallow study, at least 24 h prior to the procedure. The treatment centers and fields for external irradiation and intraluminal brachytherapy are chosen, and points of reference (bony landmarks, skin tattoos, etc.) identified (Figure 17.1).

17.7 INTRALUMINAL BRACHYTHERAPY TECHNIQUE The placement of the endoesophageal catheter for intraluminal brachytherapy is a very simple outpatient procedure and it is usually performed under local anesthesia and mild sedation. The catheter can be placed via the oral or nasal route, depending on the diameter of the

Figure 17.1 Simulator film showing treatment center and fields for external and intraluminal brachytherapy. Note bony landmarks and skin tattoo.

Intraluminal brachytherapy technique 247

3. In a fluoroscopy room, the patient is sedated and his or her nose and throat are adequately anesthetized in the sitting or supine position. It is important to have a suction unit available to assist the patient during the procedure. 4. A thin, cut-end (French 8 or 10) nasogastric tube containing a fine, soft, atraumatic Teflon-coated guide wire is passed or swallowed into the stomach, under fluoroscopy. If the obstruction is significant, the nasogastric tube is passed only to the level of stricture, and then, under fluoroscopy, the guide wire alone is maneuvered through the stenosis to the stomach and its position anchored in the body of this organ (Figures 17.2, 17.3 and 17.4). 5. The esophageal stricture is dilated, either by a balloon or a Savory dilator, through the guide wire if required before the placement of the applicator tube for brachytherapy (Figure 17.5). 6. The exact positioning of the intraluminal treatment is verified using dummy sources according to plan, and the applicator position is secured to the mouth guard or taped to the nose. X-ray films are then obtained for planning and dosimetry (Figures 17.6 and 17.7). 7. The patient is treated, preferably using a remote afterloading medium dose-rate (MDR; i.e., 1000 cGy h-1) or a high dose-rate (HDR; i.e., 50000-20000 cGy h-1) unit (Figures 17.8 and 17.9).

Figure 17.2 An 8-mm nasogastric tube containing a guide wire at the level of strictured esophagus.

Figure 17.3 The guide wire is negotiated through the stenotic esophagus.

Figure 17.4 The position of the guide wire in the stomach is verified.


Figure 17.5 Balloon dilatation.

Figure 17.6 Passage of the intraluminal applicator through the esophagus, using the guide wire. Note the dummy cesium (MDR) pellets in the applicator, used as reference for the intraluminal treatment position.

17.8 RADIOBIOLOGICAL AND CLINICAL CONSIDERATIONS

Prior to 1980, intraluminal brachytherapy for esophageal malignancies was only sporadically used, and mainly to treat patients with recurrent disease. In the 1980s, the Vancouver Clinic utilized radium and later cesium tubes (four tubes, each with 2 cm active length and 10 mg radium equivalent). These elements were placed in tandem within an esophageal plastic tube with the aim of delivering a dose of 3000 cGy at 1 cm from the axis in 48 h, and a low dose rate (LDR) of 75 cGy Ir1 (Figure 17.10). This treatment was used only in selected patients who had not responded to conventional external radiotherapy. Although this treatment required hospitalization, it was well tolerated and an adequate temporary palliation of the dysphagia was achieved. An esophageal applicator [46] became available in February 1985 that

could be connected to a remote afterloading unit (Selectron). This unit operated radioactive cesium pellets, each of 2.5 mm in diameter and 40 mCi of radium equivalent; 40 pellets placed in tandem generated a linear source of 10 cm in length with a dose rate of 1000 cGy h'1 at 1 cm from the axis (MDR). Similar applicators are now available for HDR iridium-192, which uses a stepping but smaller radioactive source of only 1.1 mm in diameter, which produces a higher dose rate (50000-20000 cGy h-1) (see Figures 17.7 and 17.9). Because higher biological effects should be expected with higher dose rates, a linear quadratic model [47] was used to estimate equivalent doses to standard LDR brachytherapy. Assuming a recovery time to sublethal effects of irradiation of 2 h and an a/p ratio of 4 for late effects and 10 for acute effects, this model showed that 3000 cGy given with LDR radioactive materials were equivalent to 1500 cGy given by HDR sources (Figure 17.11). It can also be seen that, according to this formula,

Radiobiological and clinical considerations 249

Figure 17.7

Verification of position of the intraluminal

applicator using dummy sources for an iridium (HDR) stepping source, in a similar patient to Figure 17.6.

tissue effects do not change for dose rates higher than lOOOcGylr 1 . The isodose distribution of intraluminal brachytherapy and rapid dose fall-off in depth can be appreciated from Figure 17.12. The outer diameter of the applicator is also important when considering intraluminal brachytherapy. It determines the dose to the surface of the tumor or normal mucosa in contact with the applicator. The dose is usually prescribed at 1 cm from the axis of the source. The actual dose to the mucosa lying adjacent to the surface of an applicator with smaller outer diameter (i.e., 6 mm) will be significantly higher than when a larger outer diameter applicator is used (i.e., 10 mm). Higher morbidity, mucositis, ulceration, and fibrosis should be expected with smaller outer diameter applicators if the patient survives. Therefore, the use of larger outer diameter applicators and confining the brachytherapy boost only to the area affected by the disease could minimize complications. Intraluminal brachytherapy for esophagus can be used alone for palliation of dysphagia in advanced or metastatic cases. It can also be used as a complement to external irradiation in earlier cases with the intention of cure. In these situations, brachytherapy can be given before, during, or after external irradiation. If the obstruction is significant, it may be advantageous to start with brachytherapy as dysphagia could be improved and tolerance to external treatment thus enhanced. On the other hand, intraluminal brachytherapy may be more effective after external irradiation, as the bulk of the disease will be reduced and the depth dose given to the base of the tumor by brachytherapy is significantly better. In a study conducted in Vancouver there was, however, no

Figure 17.8 A patient undergoing treatment with an oral-esophageal applicator. Note the head support and mouth route. MDR cesium pellets.

250 Brachytherapy in cancer of the esophagus Figure 17.9 A patient undergoing treatment with a naso-esophageal applicator. Note the patient comfort and suction unit. HDR iridium source.

Figure 17.11 Dose equivalencies for different dose rates according to the linear quadratic equation, (i - recovery time to sublethal effects of irradiation.)

Figure 17.10 X-ray film showing an endoesophageal tube containing four radium tubes in tandem. LDR treatment and 8 cm active length.

repeated discomfort and the probability of more complications due to trauma and inconvenience for a patient whose quality of life has already been significantly affected by the disease.

17.9 TREATMENT RESULTS significant difference in outcome when brachytherapy was used either before or after external irradiation. A single brachytherapy boost of 1500 cGy (MDR or HDR) had been preferred at the Canadian Vancouver Cancer Clinic, and proved to be an effective, well-tolerated treatment in more than 700 patients. Brachytherapy has been given in three or more fractions in other centers, but multiple applications need to be balanced against

In China, where the incidence of esophageal carcinoma is high, a mass screening program was conducted in the rural areas of Linxian in 1970-1974. This program detected a large number of patients with esophageal malignancy, not all of whom could be treated conventionally with external irradiation due to the scarcity of machines [48]. Thus, 203 patients were treated only with

Treatment results 251 Figure 17.12 Isodose distribution for a linear radioactive source.

intraluminal brachytherapy using cobalt-60 wires with two to four applications and variable doses. Seventeen out of 203 patients survived 5 years or more and were apparently cured [49]. A randomized study of 200 patients, performed at the Shanxi cancer hospital between 1982 and 1986 [50], comparing external radiotherapy alone versus external plus intraluminal brachytherapy, showed significant difference in favor of the treatment arm with brachytherapy (17% versus 10% 5-year survivals, respectively). Hishikawa, from Japan, also using a cobalt linear source and external radiotherapy, reported an 18% 5-year survival rate in a group of 66 patients with disease limited to the esophagus [51]. In Vancouver, a phase I-II study was conducted between 1985 and 1987 to evaluate the toxicity and efficacy of a combined treatment consisting of 4000 cGy in 15 fractions given by external irradiation plus 1500 cGy at 1 cm given by intraluminal brachytherapy. All patients (171) seen during that period, except for those with impending tracheal or bronchial fistula, were treated in that manner. This was a feasibility study and to assess the toxicity and response of additional intraluminal brachytherapy to external irradiation. It was concluded that this combined treatment was feasible, well tolerated, and could be done as an outpatient procedure. Morbidity was only related to temporary mucositis, and there was no associated treatment-related mortality. A quality-of-life assessment after treatment in relation to patients' performance status, ability to swallow, weight, and pain demonstrated improvement in all of these parameters [29]. A subsequent phase III study, with a similar group of patients, but designed to compare the value of brachytherapy before and after external irradiation in 219 patients, showed no significant difference

between these two treatment arms. From 1985 to 1993, over 700 patients with cancer of the esophagus and cardia were treated with intraluminal brachytherapy at the Cancer Agency in Vancouver. The first 150 patients were treated with a linear source made of radioactive cesium pellets that generated a dose rate of 1000 cGy tr1 (MDR) at 1 cm. All subsequent patients were treated using a stepping radioactive source of iridium (HDR), producing a dose rate between 50 000 and 20 000 cGy Ir1 (depending on the activity/age of the source) at 1 cm. The treatment dose chosen for both radioactive sources was the same or 1500 cGy at 1 cm from the axis, as estimated by the linear quadratic model [46]; however, the treatment time was significantly shorter with the HDR unit. The clinical evaluation of the acute and late effects of patients treated by LDR (radium or cesium), MDR (cesium pellets), or HDR (iridium) showed similarity of effects, suggesting good correlation with the predicted values by the linear quadratic equation for the different dose rates. Two hundred and ninety-seven patients with cancers of the esophagus and cardia treated in Vancouver with external and intraluminal irradiation were eligible for an analysis and a minimum follow-up to 5 years. Ninetythree patients (31%) had an upper esophageal cancer above the carina, and 204 had esophageal tumors below the tracheal bifurcation. Forty upper esophageal cancers had only palliative treatment (five of them had distant metastasis and 35 had advanced disease and were in poor condition). Only two of the 93 patients with upper esophageal cancers survived 5 years. Of the 204 (69%) patients who had lower esophageal cancers, 114 (56%) had an inoperable disease (29 had distant metastasis and 85 locally advanced disease). Eight out of 85 (9.4%)


patients with local advanced disease survived 5 years, whereas none of the patients with distant metastasis survived. Ninety patients were explored, but only 66 (73%) were resected. Of the 24 patients who were considered inoperable at the time of exploration, none survived. Only three patients had palliative resection (all had liver metastasis), none survived more than 4 months. Of the 63 patients who had curative esophagectomy after external and intraluminal irradiation, 31 (49%) had survived the disease for 5 years or more after treatment. A summary of the clinical presentation, treatment, and results for all patients is shown in Table 17.3. The study of the 63 pathological specimens after external and intraluminal radiotherapy permitted an evaluation of the changes induced by brachytherapy in the esophageal tissues. The macroscopic effect in the specimen was obvious, and the localized changes seen in the mucosa reflected the effect of the intraluminal treatment. The historical examination revealed marked pyknotic changes, with no evidence of viable tumor at different levels of the wall of the esophagus (Figure 17.13). The radiation effects and the depth of tumor penetration were determined separately for each specimen and subsequently correlated with local control and survival. The depth was expressed according to the four layers of the esophagus: level 1 when penetration was no deeper than the muscularis mucosa; level 2 when there was more penetration but no deeper than the submucosa; level 3 when it was deeper than the muscularis propria; and level 4 when it involved the peri-esophageal tissues [52]. A ratio of 1 (radiation effect/tumor penetration) was present in 43 cases and this correlated with local tumor control in 95% of them. The survival was superior when there was complete sterilization of malignancy in the surgical specimens, as can be seen in Table 17.4. The histopathological findings of radiation effects in regional lymph nodes were surprising. Periesophageal nodes considered to have been involved by the cancer were pathologically sterilized in 11 cases by the treatment combination and this was also reflected in survival, as can be seen in Figure 17.14. The combined treatment of external and intraluminal radiotherapy was well tolerated, morbidity was low, and

Figure 17.13

Pathological specimen of esophagus showing

esophageal layers and radiation effect of intraluminal brachytherapy.

there was no associated mortality in over 700 patients. A summary of treatment complications is shown in Table 17.5. Acute radiation mucositis, although common, was usually transient. Persistent mucositis was due to extensive disease or associated factors (candidiasis, etc.) and dysphagia was related to persistent disease. Bleeding as a complication following brachytherapy is extremely rare in our experience; however, it should be expected if the tumor is advanced or significant trauma occurred during the insertion of the applicator. Fibrosis and stenosis

Table 17.3 Cancer of the esophagus: treatment results in 297patients

Above carina Advanced Below carina Advanced Below carina Resected3 Number of patients with distant metastasis Number of patients explored and found inoperable Palliative resection (liver metastasis)3 All cases (overall) 3

88 85 63 34 24 3 297

Total esophagectomy after external + intraluminal brachyth< rapy. External + intraluminal brachytherapy, Vancouver (1985-198!J).

2 8 32 0 0 0 42

2 9.4 49

14

Conclusions 253

are common in long-term survivors, and occurred in 42% of our patients with advanced cancers surviving more than 5 years. Dilatations at regular intervals were required in most of these cases. From the results obtained, it can be seen that intraluminal brachytherapy enhances the therapeutic ratio when added to external irradiation for this disease. A comparison of results with other recent combined treatment modalities showed superiority of external and intraluminal radiotherapy over esophagectomy plus chemotherapy or external irradiation combined with adjuvant chemotherapy (Table 17.6).

17.10

CONCLUSIONS

Because the prognosis and survival of patients with esophageal cancer are poor, an adequate evaluation of these patients prior to any treatment is essential. The emphasis of treatment in advanced cases should be palliation and improving the quality of life of these patients. A short course of external irradiation alone or combined with a single intraluminal brachytherapy may be sufficient for most patients. A recent prospective, randomized trial has shown no

Table 17.4 Cancer of the esophagus: radiation pathology

Sterilized (no recognizable disease) Ratio 1 (radiation damage to all levels) Ratio < 1 (radiation damage to superficial layer only)

16 24 23

3 7 16

1 3 2

12 14 5

75 58 21

Totals

63

26

6

31

49

NED = no evidence of disease. Table 17.5 Cancer of the esophagus: complications of external irradiation + brachytherapy

Radiation esophagitis Radiation pneumonitis Broncho-esophageal fistula

Mild

Moderate!

Severe

358

72 (14%)

60 (12%) 1a 30 (6%)b

a

Unrelated to intraluminal brachytherapy. Related to disease; occurred 6 months or more after treatment. Mild: transient, requires symptomatic medication only. Moderate: transient but may require supplementary care. Severe: requires hospitalization or intervention. b

Table 17.6 Cancer of the esophagus: summary of treatment results

Non-surgical (a 11 cases) XRT + chemotherapy XRT +brachytherapy Extensive disease Limited disease XRT + brachytherapy Extensive disease Surgical combined (early cases or limited) Preoperative chemotherapy Preoperative chemotherapy + XRT Preoperative XRT + brachytherapy ? Data are not available. [*] Vancouver series. XRT = irradiation.

[18]

61

2

30

?

82 66

0 0

7 37

0 18

138

0

33

48 43 63

11 8 0

25 50 65

[51]

[*]

[23] [20]

7.2

18 34 49


retrospective study of esophageal cancer presenting to an endoscopy unit. Gut, 32, A555. 6. Parkin, D., Pisani, P. and Ferlay, J. (1999) Global cancer statistics. CA Cancer J. Clin., 49(1), 33-64. 7. Earlam, R. and Cunnha-Melo, J.R. (1980) Esophageal squamous carcinoma: a critical review of radiotherapy. Br. J.Surg., 67,457-61. 8. Earlam, R. and Cunnha-Melo, J.R. (1980) Esophageal squamous carcinoma: a critical review of surgery. Br.}. SHrg.,67,381-90. 9. Matthews, H.R. and Waterhouse, J.A. (1987) Cancer of the Esophagus. Clinical Monograph, Volume 1. Basingstoke, Macmillan Press. 10. Earlam, R. (1991) An MRC prospective randomized trial of radiotherapy versus surgery for operable squamous carcinoma of the esophagus. Ann. R. Coll. Surg. Engl., 73, 8-12. 11. Launois, B., Delarue, D., Campion, J. and Kerbaol, M. (1981) Preoperative radiotherapy for carcinoma of the Figure 17.14

Survival versus peri-esophageal lymph node

status.

benefit from chemotherapy prior to esophagectomy in early operable cases [28]. The combination of external and intraluminal radiotherapy has obvious advantages over other treatments in esophageal cancer: it is simple, cost effective (hospitalization is not required), and has lower morbidity than adjuvant chemotherapy and/or esophagectomy. As it does not increase the operative morbidity associated with esophagectomy, it should be the treatment of choice in early cases, radical surgical treatment being reserved only for persistent or recurrent disease. Future prospective trials must consider combined external and intraluminal brachytherapy as the main treatment arm in early operable esophageal cancer cases to determine the best local therapy. These future trials must also evaluate morbidity and the quality of life of survivors.

REFERENCES

esophagus. Surg. Gynecol. Obstet, 2,690-2. 12. Gignoux, M., Russell,A., Paillot, B.etal. (1987) The value of preoperative radiotherapy in esophageal cancer. Results of the EORTC World J. Surg., 11,426-32. 13. Huang, G., Gu, X., Wang, L etal. (1988) Combined preoperative irradiation and surgery for esophageal carcinoma. In International Trends in General Thoracic Surgery: Esophageal Carcinoma, ed. E.W. Wilkins and J. Wong. Philadelphia, Saunders, 315-18. 14. Wang, M., Gu, X.Z., Yin, W.B., Huang, G.J., Wang, LJ. and Zhang, D.W. (1988) Randomized clinical trial on the combination of preoperative irradiation and surgery in the treatment of esophageal carcinoma; report on 206 patients. Int.J. Radial. Oncol. Biol. Phys., 16,325-7. 15. Nygaard, K., Hagen,S., Hansen, H.S.etal. (1992) Preoperative radiotherapy prolongs survival in operable esophageal carcinoma. A randomized, multicenter study of preoperative radiotherapy and chemotherapy. The second Scandinavian trial in esophageal cancer. World J. Surg., 16,1104-9. 16. Schlag, P., Herrman, R., Raeth, V.etal. (1988) Preoperative chemotherapy in esophageal cancer. A Phase II study.4cta Oncol., 27,811-14. 17. Roth.JA, Pass, H.I., Flanagan, MM. etal. (1988) Randomized clinical trial of preoperative and postoperative adjuvant chemotherapy with cisplatin, vindesine, and bleomycin for carcinoma of the

1. Greenlee, R.T., Hill-Harmon, M.B., Murray, T. and Thun, M. (2001) Cancer statistics 2000. CA CancerJ. Clin., 51,15-36. 2. Blot,W.J., Devesa,S.S., Kneller, R.etal. (1991) Rising incidence of carcinoma of the esophagus and cardia. JAMA, 265,1287-9. 3. Powell, J. and McConkey, C.C. (1990) Increasing incidence of adenocarcinoma of the gastric, cardia and adjacent sites. Br. J. Cancer, 62,440-3. 4. Reed, P.I. (1991) Changing patterns in esophageal cancer. Lancet, 338,178. 5. Johnson, B.J., Hill, M.J. and Reed, P.I. (1991) Fifteen years

esophagus./ Thorac. Cardiovasc. Surg., 96,242-8. 18. Herskovic,A., Martz, K., Al-Sarraf, M.etal. (1993) Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N. Engl.J. Med., 326,1593-7. 19. John, M.J., Flam, M.S., Monry, P.A. etal. (1989) Radiotherapy alone and chemoradiation for non metastatic esophageal carcinoma. A critical review of chemoradiation. Cancer, 64,2397-03. 20. Forastiere, A.A., Orringer, M.B., Perez-Tamayo, C., Urba, S.G. and Zahurak, M. (1993) Preoperative chemoradiation

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Urba, S.G., Orringer, M.B., Perez-Tamayo, C., Bromberg, J. and Forastiere, A. (1992) Concurrent preoperative chemotherapy and radiation therapy in localized

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36. Ruol, F., Segalin, A., Castoro, C. etal. (1987) Patterns of neoplastic recurrence after radical and palliative resection of the esophagus. In Diseases of the Esophagus, ed.J.R. Siewert. Berlin, Springer-Verlag714-16. 37. Guisez, J. (1909) Essais de traitement de quelques cas d'epithelioma de I'esophage par les applications locales directes de radium. Bull. Soc. Med. Hop. Paris, 27, 717-22. 38. Harriman, F.R. (1927) Malignancy of the larynx and the esophagus treated by radium emanation. Laryngoscope,

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27. BossetJ.F., Gignoux, M.,Triboulet,J.P. etal. (1997) Chemotherapy followed by surgery compared with

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44.

2499-505. Flores, A.D., Nelems, B., Evans, K.G., Stoller, J. and Hay, J. (1987) Combined primary treatment of cancer of the

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Pichmair, H. (1990) Surgical therapy of esophageal carcinoma. Br.J. Surg., 77,845-57. 31. Desai, P.B., Vyas, J.J., Sharma, S., Deshpande, R.K. and

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Badwe, R.A. (1989) Current status of surgical treatment of cancer of esophagus. Semin. Surg. Oncol., 5,359-64. 32. Kavanagh, B., Anscher, M., Leopold, K.etal. (1992) Patterns of failure following combined modality therapy for esophageal cancer, 1984-1990. Int.J. Radiat. Oncol. Biol. Phys., 24, 633-42. 33. Mantravadi, R.V.P., Lad, T., Briele, H. and Liebuer, E.J. (1982) Carcinoma of the esophagus. Sites of failure. Int.J. Radiat. Oncol. Biol. Phys., 8,1897-901. 34. Isono, K., Onoda, S., Ishikawa, T., Sato, H. and Nakayama, K. (1982) Studies on the causes of death from esophageal carcinoma. Cancer, 49,2173-9. 35. Mandard, A.M., Chasle, J., Marnay, J. etal. (1981) Autopsy findings in 111 cases of esophageal cancer. Cancer, 48, 329-35.

Berlin, Springer-Verlag, 741-9. 45. Gaspar, L.E., Nag, S., Herskovic, A., Mantravadi, R. and Speiser, B. (1997) American Brachytherapy Society (ABS) consensus guidelines for brachytherapy of esophageal cancer. Clinical Research Committee, American Brachytherapy Society, Philadelphia, PA. Int.J. Radiat. Oncol. Biol. Phys., 38(1), 127-32. 46. Rowland, C.G. and Pagliero, K.M. (1985) Intracavitary irradiation in palliation of carcinoma of the esophagus and cardia. Lancet, 2,981 -3. 47. Dale, R.G. (1985) The application of the linear quadratic dose-effect equation to fractionated and protracted radiotherapy. Br.J. Radiol., 58, 515-28. 48. Wei-bo, Y. (1990) Personal communication. 49. Wei-bo, Y. (1989) Brachytherapy of carcinoma of the esophagus in China. In Brachytherapy 2 Proceedings of the 5th International Working Conference, ed. R.F. Mould,

256 Brachytherapy in cancer of the esophagus Leersum, The Netherlands, Nucleotron Corporation, 139-41. 50. Yan-jun, M.,Xian-zhi,G., Wei-bo \.etal. (1982) Intracavitary irradiation in the treatment of esophageal cancer. Chin.J. Oncol., 4,45-7. 51. Hishikawa, Y., Kurisu, K., Taniguchi, M., Kamitonya, N. and Miura, T. (1991) High dose rate intraluminal

brachytherapy for esophageal cancer: 10 years experience in Hyogo College of Medicine. Radiother. Oflco/.,21,107-14. 52. Berry, B., Miller, R.R., Luoma, A., Nelems, B., Hay, J.H. and Flores, A.D. (1989) Pathological findings in total esophagectomy specimens, after intracavitary and external beam radiotherapy. Cancer, 64,1833-7.

18 High dose-rate afterloadingbrachytherapy for prostate cancer P.J. HOSKIN

18.1

INTRODUCTION

Brachytherapy as a treatment modality for prostate cancer has been used with varying degrees of enthusiasm for many years. Early techniques used direct open implantation with live source permanent implants, typically gold grains or iodine seeds [ 1 ]. The relatively poor results of this treatment from the 1960s led to disenchantment with this approach, but in the last decade developments in both imaging techniques and brachytherapy equipment have led to this form of high dose radiation therapy becoming an important integral part of the management of localized prostate cancer. Manual afterloading using iridium wire to deliver a medium dose-rate (MDR) implant has been employed in prostate cancer. The largest published series from Long Beach, California, reports 450 patients treated with 30-36 Gy external-beam radiotherapy in 3.5-4 weeks followed by an iridium interstitial implant boost delivering 30-40 Gy in 40-60 h. A local control rate of 92% with a 76% 10-year disease-free survival and 6% moderate to severe morbidity rate was obtained [2]. High dose-rate (HDR) afterloading enables small diameter catheters of around 2 mm external diameter to

be used for interstitial implantation, with the great flexibility of dose delivery inherent in the stepping source system. Catheter placement exploiting the advantages of transrectal ultrasound and computed tomography (CT) imaging to provide accurate positioning and reconstruction of the implant can ensure high-quality implants and precise dosimetry related to anatomical structures. The advantages of high dose localization inherent in brachytherapy can therefore be fully exploited and, in a situation in which a dose response has been demonstrated for radiation therapy [3], an improvement in local rates of control without additional normal tissue morbidity is a realistic expectation. Delivery of radiation at high dose rate, however, carries biological implications which demand careful attention to dose fractionation and dose distribution. The challenge with HDR brachytherapy in prostate cancer is to deliver a safe, effective dose using a technique which will enable several fractions of treatment to be given over several days whilst retaining the high quality of the implant throughout. Unlike low dose-rate (LDR) brachytherapy for prostate cancer, a biological advantage cannot be claimed for HDR over external-beam treatment. The better geographical localization of dose with brachytherapy is

258 High dose-rate afterloading brachytherapy for prostate cancer

a major advantage, but its clinical implementation is probably optimized by using it in conjunction with external-beam treatment. The natural history of prostate cancer includes early invasion of the prostatic capsule and seminal vesicles. A high proportion of patients presenting with apparently localized disease will already have microscopic disease within the immediate vicinity of the prostate gland. Predictors for this include a prostate-specific antigen (PSA) level greater than 10, a Gleason score greater than 7, and a clinical stage of T2b or higher, all of which would carry a greater than 30% chance of regional microscopic disease [4]. In this scenario, external-beam treatment is undoubtedly superior in covering the wider field necessary to incorporate these patterns of spread. In a manner analogous to many other sites where brachytherapy is shown to be a vital component of successful radical treatment, HDR afterloading brachytherapy can then be used as a high dose localized boost treatment to the primary bulk of tumor.

3. The skin is prepared and full sterile theater precautions should be used throughout for the implant to avoid the introduction of infection. 4. The prostate gland is subject to considerable movement, in particular rotation about its axis, if steps are not taken to avoid this. Fixation needles are inserted as the first step in most implant procedures. Positions in the template away from those likely to be immediately implanted are chosen. Two needles, one in each lateral lobe, are usually adequate, although some advocate a third needle anteriorly. 5. A blunt needle to define the length of implantation and position of the bladder neck has also been advocated. The advantage of this is that it gives an additional gauge against which the applicator position can be checked, particularly if imaging quality is variable, as can happen where there is interference from adjacent planes on the ultrasound as the implant builds up.

18.2

18.4 FLUOROSCOPIC IMPLANTATION PROCEDURE

IMPLANT TECHNIQUES

Open procedures are no longer used for prostate implantation. The common route is transperineal, although transrectal approaches are also described. Transperineal implants typically use a template on the skin to define catheter position of entry. A common approach in current use is to combine this with transrectal ultrasound to provide direct real-time imaging as the implant is inserted. Two types of applicator are in common use: rigid needles or flexible plastic catheters. The rigid needles may have the advantage of easier positioning, being less readily deflected by the tissues after skin entry, but they may be more traumatic to the tissues and less well tolerated when an implant remains in place for several days. Fixation of the needles on the perineal skin is also a challenge. 183 PROCEDURE: GENERAL CONSIDERATIONS 1. All patients will require general or spinal anesthesia. The patient is placed in the lithotomy position with the pelvis tilted anteriorly as far as possible. This aids the passage of the applicators below the pubic arch into the more anterior portion of the prostate gland. However, for patients who are elderly, perhaps with degenerative hip disease, care must be taken in positioning the patient while anesthetized to avoid damage to the pelvis and hips. 2. An indwelling urethral catheter will be required and will be retained until removal of the catheters at the end of the last fraction of treatment. This is both to facilitate urinary drainage and also to provide a marker for urethral position, which is an important consideration in catheter placement and dosimetry.

1. The C-arm of the imaging intensifier requires careful positioning to enable imaging of the prostate implant to be seen together with the bladder base. As it is difficult during the procedure to move the C-arm, an antero-posterior or lateral view will be chosen. In general, the lateral view provides better information, particularly for multiplane implants, although some prefer an oblique or direct anteroposterior view. 2. The urinary catheter balloon will be filled with hypaque or a similar contrast-enhancing medium so that it can be readily visualized on the fluoroscope screen. This then defines the bladder base. Ideally, previous CT images will have been obtained in a diagnostic setting to define the position of the prostate in relation to the bladder base. Often, the prostate will be seen to impinge above a catheter balloon in the bladder and it is important this is known so that coverage of the apex of the gland is adequate. 3. Applicators will then be inserted transperineally through a template, if used, and their cranial position, defined by their relation to the bladder base, marked by the catheter balloon. Fluoroscopy will help enable the catheters to be inserted in parallel, although this may become more difficult to judge as sequential planes are built up. 18.5 TRANSRECTAL ULTRASOUND IMPLANTATION TECHNIQUE 1. Transrectal ultrasound (TRUS) is now the standard means of guiding applicators accurately into the

Catheter insertion and fixation 259

prostate gland. For implantation, a probe mounted on a frame with a stepping platform enables reproducible positioning of the catheters. Onto the frame is fixed a template, the image of which can be superimposed on the ultrasound images to relate a catheter position to the anatomy seen, as shown in Figure 18.1. A further feature is to have a dual crystal probe which can produce both transverse and longitudinal images. This then enables catheter placement to be followed in both planes. 2. The role of a pre-implant ultrasound study to define the treatment volume and design an ideal implant prior to the procedure is not mandatory with this technique. Whilst necessary for LDR iodine seed implants, for which the seeds have to be ordered and loaded in a fixed array, the flexibility of HDR afterloading dosimetry means that, provided catheters are inserted in a fixed format - that is, in parallel rows as defined by the template - covering the prostate volume, post-implant dosimetry is adequate to define the dwell positions for coverage of the volume. Pre-implant imaging and dosimetry are not necessary for HDR afterloading, although diagnostic CT or MR images are of value both to give information on the size of the prostate gland and also to predict pelvic arch interference, notwithstanding their role in providing accurate staging information. 3. Setting up of the TRUS prior to implantation is very important and, if not done carefully and accurately, will greatly detract from the final quality of the implant. Important criteria to observe are that the inferior border of the gland is as flat as possible, and considerable variation in gland contour can be achieved simply by altering the angle of the probe, as shown in Figure 18.2. A flat inferior border with the most inferior row of applicators parallel and just inside the gland is required. 4. The urethra should be identified and positioned between vertical rows of applicators around the center

Figure 18.1 Transrectal ultrasound probe and stepping frame set up as used for HDR prostate implant showing template, stabilizing needles, and HDR applicators.

Figure 18.2 Transrectal ultrasound images of the prostate gland showing how shape may change with angle of probe at the same position in the gland.

of the implant and followed throughout its course into the bladder neck to ensure that the prostate is lying straight in its axial plane along the probe.

18.6

CATHETER INSERTION AND FIXATION

Typically, the stepping TRUS technique is used with a 1 cm grid template developing parallel rows of catheters in a square multiplane array. A second template maybe used in addition to the one attached to the ultrasound frame to guide skin entry. Manipulation of the catheters after skin entry may be achieved manually, using the ultrasound images to guide direction. Parallel multiplane implants are generally required; typically, three or four planes will be necessary to cover the depth of the gland. The pubic arch and pelvic side walls may present physical obstacles in placing the most peripheral catheters. Whereas the template technique generally improves geometry, a rigid template against the perineal skin reduces the ability to move the catheter slightly out of plane to avoid the pubic arch or other bony interference. The advantage of flexible catheters is that they may be seen to bend around the pubic arch and then regain


their plane in the more anterior aspects of the prostate gland. Extreme pubic arch interference should be predicted prior to the implant from CT images or a preplanned ultrasound, and in some circumstances this may be a contraindication to proceeding with the implant if a satisfactory source distribution cannot be anticipated. Once in position, fixation of the catheters to ensure reproducible positioning on sequential fractions is one of the more difficult aspects of this technique. A rigid applicator may be sutured to the skin and rigid needles fixed into this using a locking device within the template. Rigid needles may be individually sutured to the skin, but where a typical implant may comprise 12 to 20 needles, this becomes somewhat tiresome and difficult. 18.7 MOUNT VERNON APPLICATOR AND TEMPLATE TECHNIQUE At Mount Vernon Hospital we have developed an HDR implant technique using a flexible template and flexible HDR applicators. A standard TRUS system with stepping unit is used for imaging, with the template attached to the ultrasound frame, as shown in Figure 18.1. The template has been modified by increasing the diameter of the guiding holes to enable the flexible catheters to pass through them so that the applicator maybe removed over the proximal ends of the catheters at completion of the implant. Once the ultrasound is placed in position and set up as defined above, a flexible latex template is placed against the perineal skin. This is aligned to be exactly matching the ultrasound template. The flexible template has rubber 'O' rings incorporated in it in a 1 cm grid identical to that of the ultrasound template. It is fastened to the skin using adhesive, the skin having previously been shaved to make removal less painful. The implant procedure then continues with placement of the applicators guided by the ultrasound template passing through the corresponding 'O' ring of the flexible template against the perineal skin. An added advantage of this approach is to give clearance between the two templates which enables digital guidance of the applicators where necessary, the flexible template allowing movement at skin entry. At completion of the implant the ultrasound probe is removed and the ultrasound template is removed over the proximal ends of the flexible applicators. These are then held in position, gripped by the 'O' rings of the flexible template. Retaining sutures in each corner of the flexible template are used to prevent it buckling when the legs are brought together, and this can be trimmed to improve comfort around its edges. The flexible catheters are kept capped to avoid contamination of the HDR channel, their length from the 'O' ring to their distal connecting end is carefully measured, and each catheter is labeled with its grid position. This length is carefully documented and is vital in maintaining quality assur-

ance for the implant as it is measured on each occasion treatment is given to identify any catheter movement. A completed implant in situ is shown in Figure 18.3.

18.8

IMPLANT RECONSTRUCTION

Following recovery from the anesthetic, reconstruction of the implant is required. Although this may be done using the TRUS images obtained during the procedure, we have found that post-implant CT imaging provides better reconstruction of the implant, allowing volume definition on the basis of the anatomical information on the CT scan. It also readily interfaces with the planning system to provide accurate volume and catheter position transfer. Transrectal ultrasound images in general will require manual digitization to import the volumes into the planning system. There are changes following implantation and, in particular, prostate volume increases are recognized when comparing post-implant CT images to TRUS taken during the implant, which may need to be taken into account, and CT gives accurate positioning of the rectum which may be very different once the TRUS probe has been removed. Conventional orthogonal film reconstruction of the implant is, of course, possible and will give adequate information regarding the catheter positions, but none

Figure 18.3 HDR implant of prostate.

Dose prescription 261

in relation to the prostate gland and rectum. Although adequate, therefore, in terms of implant reconstruction, it does not provide the information required for optimization of the implant in relation to the soft tissue. Once the implant has been reconstructed and the catheter positions defined, the dose distribution can begin to be calculated. All the modern HDR systems have associated planning programs with them to facilitate this process. The principles of dosimetry are to deliver a homogeneous dose within the denned volume, with rapid fall-off particularly posteriorly towards the anterior rectal wall, and with a relative cold spot around the urethra. Catheter placement usually takes into account these requirements, with peripheral grid positions being filled, but leaving one or two central positions empty around the urethra. Dwell positions will be defined along the catheters, initially using one of two conventions, either Paris dosimetry or Manchester dosimetry. From this baseline, individual optimization may then be required [5]. Paris dosimetry has the advantage of simplicity in that uniform linear activity, achieved by equal times in each dwell position, is the requirement. Inevitably, however, because an ideal Paris implant requires catheters longer than the volume to be treated, it will, unless the distal end of the implant has been taken well beyond the apex of the prostate, be cold around the apex. In contrast, Manchesterbased dosimetry, with weighting of the dwell positions at the ends and periphery of the implant volume typically aiming for a 2:1 weighting, reproducing the Manchester rule requiring two-thirds of the dose to be delivered to the periphery, will give a more homogeneous dose to the limits of the catheters. Current planning systems have more complex optimization techniques which can then be introduced, although they may not give superior results to conventional individualized planning and often result in marked ranges of dwell time along the catheter. Once satisfactory dose distribution has been obtained, this will be transferred into the HDR control program as a series of dwell times for each catheter. A typical distribution with corresponding dwell times is shown in Figure 18.4. The treatment delivery is relatively simple, although careful and meticulous attention to identify any catheter movement and having a rigorous protocol to ensure that the correct channels are attached to the appropriate catheter are vital. Typical treatment times are very short, most catheters having a total dwell time of only a few seconds, and total treatment times for the implant being of the order of 5 min, depending upon the total number of catheters.

18.9 COMPUTED TOMOGRAPHY-BASED THREE-DIMENSIONAL PLANNING A novel technique has been described from the group in Offenbach [6], relying on three-dimensional reconstruc-

tion of an implant inserted under ultrasound control using four rigid steel needles placed transrectally. Two crossing needles are placed in the upper and lower left and two in the upper and lower right peripheral regions of the gland. An optimized distribution is then defined using three-dimensional reconstructed CT images for HDR afterloading. Because only four needles are used to cover the entire volume, extensive high dose regions are introduced, with up to 50% of the volume receiving 200% of the reference prescription dose. Early clinical results have not revealed significant additional morbidity. 18.10

DOSE PRESCRIPTION

HDR afterloading implants for prostate cancer are rarely, if ever, used as sole treatment. Their use is generally designed to be part of a treatment program in which external beam accounts for two-thirds of the total dose, equivalent to a dose sufficient to eliminate microscopic disease, followed by the remaining one-third of the radical dose delivered by the implant. However, a review of the actual doses prescribed in the various centers using this technique reveals considerable variation, particularly in relation to the implant dose. There appears to be general agreement that a dose of 40-45 Gy in 4-5 weeks or its equivalent is an appropriate external-beam schedule, no doubt reflecting experience from other sites where this approach to radical treatment is successful, for example the head and neck, and cervix. As can be seen in Table 18.1, however, the implant doses typically given in two to three fractions vary enormously [7-12]. This may, in part, be explained by the lack of conformity in dose definition for interstitial implantation and, perhaps more critical in assessing the dosimetry, is the actual dose distribution and relative dose to normal structures compared to the high dose volume. A better comparison of the different dose fractionation schedules may be achieved using the biological equivalent dose (BED) formula, acknowledging the limTable 18.1 Prostate HDR brachytherapy doses

Michigan [7] Oakland,CA [8]

18

Seattle [9]

3

16.5

3

Goteborg[12]

20

2

Kiel [10]

30

2

Berlin [11]

18

2

Offenbach [6]

28

4

Melbourne"

20

4

MVH

17

2

" Personal communication, Professor G. Duchesne. NB: where centers have quoted a range of doses, the most recent schedules have been stated here.


Figure 18.4 Dose distribution (a) and catheter dwell times in nominal seconds (b) for completed implant.

Dwell position 1 2 3 4 5 6 7 8 9 10 II 12 13 14 15

1

2

3

4

5

6

0 5 3 3 3 3 3 3 3 2 1 2 3

5 4 3 3 3 3 3 3 3 3 3 4 2

5 3 4 3 3 3 3 3 3 3 3 4 4 2

5 4 1 0 2 2 . 1 1 0 1 1 4 4

4 4 0 1 0 1 0 1 0 0 0 0

0 5 4 3 3 3 3 3 4 3 4 3 2

Channel c.hanrtel 7 8

9

10

II

12

1

5 3 1 0 1 0 0 0

5 3 1 0 1 0 0 0 0 0 0

0 0 3 2 2 2 0 0 0 1 2 2 3 3

5 2 3 2 2 1 1 1 1 1 1 2 2 3

0 0 0 4 3 2 2 1 2

0

5 3 3 3 3 3 3 3 3 4 3 4 I 3

2 3 4 3 3 3 3 3 3 3 3 4 3

1 1

0 4

1

1

3

itations of this when applied to a two-fraction or threefraction implant using large doses per fraction. This is shown in Table 18.2, together with equivalent 2 Gy fraction doses, which are perhaps a more familiar format to consider the dose equivalence of the different schedules. The rectal tolerance in this setting is also uncertain. The nearest analogy would be to gynecological brachytherapy, in which rectal dose is also one of the major limiting normal tissue effects. Indeed, the externalbeam and HDR combination doses used in the prostate cancer schedules are very similar to those for cervical cancer, where the limit for rectal dose would be a 2 Gy equivalent of 64-66 Gy. This, of course, does not take into account the volume effect, whereby a much higher dose may be tolerated to a small volume provided there is ade-

2 2 2 2 3

quate recovery in surrounding areas. This may be more apparent in prostate implantation where 5 mm CT slices or TRUS images are being used to define the dose distribution. The general rule of thumb, however, is to keep the rectal dose within 60% of the tumor dose. This is reflected in the Mount Vernon schedule, in which, from a tumor dose of 8.5 Gy using the HDR implant, the target rectal dose is 5 Gy or less. Equivalent rectal doses from the published schedules are shown in Table 18.3. Similarly, urethral tolerance is poorly denned. It would appear that the urethra is able to tolerate far higher doses than the rectum, but experience from LDR iodine-125 implants confirms that urethral problems can arise if steps are not taken to reduce the central dose of the implant [13].

Complications and toxicity 263

Table 18.2 HDR brachytherapy doses: biological equivalent doses (BED) and 2 Gy equivalents for different oc/P ratios

Michigan [7] Oakland,CA[8]

90.0

38.6

48.0

28.8

28.8

24.0

77.0

33.0

46.7

28.0

25.6

21.3

Goteborg[12]

153.3

65.7

86.7

52.0

40.0

33.3

Kiel [10]

330

141.4

Berlin [11]

126

54.0

72.0

Offenbach [6]

158.7

68.0

86.7

37.2

113.3

48.6

Seattle [9]

Melbourne3 Mount Vernon Hospital b

75.0

62.5

43.2

34.2

28.5

93.3

56.0

47.6

39.7

53.3

32.0

30.0

25.0

65.2

39.1

31.5

26.3

180

108

Personal communication, Professor G. Duchesne.

Table 18.3 Rectal dose from HDR schedules (assuming 60% of tumor dose and o/p = 3)

Michigan [7] Oakland, CA [8]

28.8

17.3

103.3

62.0

Seattle [9]

28.0

16.8

103.0

61.8

52.0

31.2

135.3

81.2

64.8

191.3

114.7

43.2

25.9

115.2

69.1

Offenbach" [6]

56.0

33.6

131.0

78.6

Melbourne*

32.0

19.2

108.7

65.2

Mount Vernon Hospital

39.1

23.5

107.5

64.5

Goteborg[12] Kiel [10]

108

Berlin [11]

"Quoted mean rectal dose is 3 Gy, i.e., 42.8% of prescription dose. ''Personal communication, Professor G. Duchesne.

The disparity and uncertainty regarding dose prescription for this technique make it imperative for all centers undertaking this work to carefully document and report normal tissue toxicity in addition to tumor control rates.

18,11

TREATMENT RESULTS

Reporting of results from this technique is still at an early stage, with most data being relatively immature, particularly in a tumor which has a natural history spanning 10 or 15 years untreated. A summary of the published data is shown in Table 18.4. The only conclusions that can be drawn are that this is an effective form of treatment, that high control rates from locally advanced disease as well as early prostate cancer can be achieved, and that, to date, morbidity is within acceptable limits for a high dose radical radiotherapy schedule, although later normal tissue effects require clarification.

While single center reports are of value, the ultimate question that will arise is how this technique relates in its outcome to LDR iodine-125 seed implantation and optimized external-beam treatment alone using conformal and possibly intensity modulated radiotherapy techniques. Currently, only one randomized trial is underway at Mount Vernon Hospital, comparing a standard external-beam technique of 55 Gy in 20 daily fractions with the HDR schedule shown above.

18.12

COMPLICATIONS AND TOXICITY

In general, this technique appears well tolerated, with no additional complications other than those which would be anticipated from high dose pelvic radiotherapy. The implant procedure itself appears straightforward, notwithstanding the inevitable risks of anesthesia in a patient population which is predominantly elderly. This is, of course, amplified with techniques and programs


Table 18.4 Clinical results

Michigan

33 [7]

T2:26 T3: 7

91

Bowel:

86

59 [14]

5

7

Oakland, CA [8]

110

85

Rectal: Urinary:

1 4

Seattle [9]

104

84

Bowel: Urethra I:

0 7

72:110 T3: 59

T2:89 T3: 85

Bowel: Bladder:

3 7

82

T2:21 T3:61

All: 53

Bowel:

3.6

59

Not reported

Goteborg[12]

171

Kiel [10] Berlin [11] Offenbach [6] Melbourne

Not reported

3

Mount Vernon Hospital

None

Not reported Not reported

° Personal communication, Professor G.Duchesne.

which deliver successive fractions with a new implant on each occasion. During the implant itself, there may be minor discomfort, but this is usually controlled with simple or moderate analgesia. Indeed, after the first hour or so of recovering from the anesthetic, most patients require no additional anesthesia. Hematuria is common, but rarely of great consequence. Rectal symptoms are few. Some disturbance of bowel function often follows, our own schedule incorporating an enema preoperatively to empty the bowel followed by a constipating regime for 24 h to prevent bowel motions whilst the implant is in situ. Many men then find it takes a week or two for bowel motions to return to a normal pattern and may require a gentle laxative for a few days. Urinary symptoms once the catheter is removed may persist for a week or two, with mild dysuria and hematuria. Occasionally, patients who have had significant outflow obstruction with symptoms prior to the implant may require catheterization for a period of a week or two after the implant whilst the initial edema settles. Long-term catheterization, however, has not been encountered in our experience. Urinary incontinence as a complication is not reported. Experience from LDR implants suggests that transurethral resection is a risk factor for urinary symptoms and incontinence after implantation [13] and we regard this as a contraindication at present, although data on HDR implants after transurethral resection (TURP) are not currently forthcoming. The incidence of expected late complications such as rectal fibrosis and stenosis, bladder telangiectasia, and urethral stricture is unknown on examination of the literature. The most mature data to report this from Kiel [10] and Berlin [11] suggest the incidence will be of the order of 3% for severe bowel complications, with per-

haps a similar or slightly higher incidence of severe urinary symptoms.

18.13

CONCLUSION

HDR afterloading implants to the prostate gland can be achieved with a high level of technical accuracy and enable the delivery of a concentrated high dose radiation treatment to a defined volume encompassing the prostate gland. Doses to the rectum can be limited to remain within normal tissue tolerance and adjustment of catheter placement and dwell positioning can also minimize the dose to the urethra. In combination with external-beam treatment, this approach offers a treatment program which combines a moderate radiation dose sufficient to control microscopic disease along patterns of regional spread with a central high dose treatment to known sites of macroscopic tumor. As such, it is both conformal and intensity modulated, and early results suggest it is highly effective in the management of localized prostate cancer.

REFERENCES 1. Khan, K.( Crawford, D.E. and Johnson, E.L (1983) Transperineal percutaneous iridium-192 implant of the prostate. Int.J. Radial Oncol. Biol. Phys., 9,1391-5. 2. Puthawala, A., NisarSyed, A.M., Austin, PA.etal. (1996) Combined interstitial iridium-192 implant and external beam irradiation in the treatment of carcinoma of the prostate. Radiother. Oncol., 39 Suppl. 1, S1. 3. Hanks, G.E., Kerring, D.F. and Kramer, S. (1985) Patterns of

References 265

4.

5.

6.

7.

8.

9.

care studies: dose-response observations for local control of adenocarcinoma of the prostate. Int.J. Radiat. Oncol. Biol.Phys., 51,153-7. Partin, A.W., Subong, E.N.P., Walsh, P.C. etal. (1997) Clinical stage and Gleason score to predict pathological stage of localized prostate cancer. JAMA, 277,1445-51. Hoskin, P.J. and Rembowska, A. (1998) Dosimetry rules for brachytherapy using high dose rate remote afterloading implants. Clin Oncol., 10,226-30. Martin, T., Kolotas, C, Dannenberg, T. etal. (1999) New interstitial HDR brachytherapy technique for prostate cancer: CT based 3D planning after transrectal implantation. Radiother. Oncol., 52,257-60. Stromberg, J., Martinez, A., Gonzalez, J. et al. (1995) Ultrasound-guided high dose rate conformal brachytherapy boost in prostate cancer: treatment description and preliminary results of a Phase l/ll clinical trial. Int.J. Radiat. Oncol. Biol. Phys., 33,161-71. Rodrigues, R. and Demanes, D.J. (1997) HDR brachytherapy: ultimate in conformal radiotherapy for the treatment of prostate cancer. In New Developments in Interstitial Remote Controlled Brachytherapy, ed. N. Zamboglou. Munich, WZuckschwerd undVerlag, 119-25. Mate, T., Gottesman, J., Hatton, J. et al. (1998) High dose rate afterloading iridium-192 prostate brachytherapy:

10.

11.

12.

13.

14.

feasibility report. Int.J. Radiat. Oncol. Biol. Phys., 41, 525-33. Kovacs, G., Wirth, B., Bertermann, H. etal. (1996) Prostate preservation by combined external beam and HDR brachytherapy at nodal negative prostate cancer patients - an intermediate analysis after ten years experience. Int. J. Radiat. Oncol. Biol. Phys., 36 (Suppl.) S80,198. Dinges, S., Deger, S., Koswig, S. etal. (1998) High-dose rate interstitial with external beam irradiation for localized prostate cancer - results of a prospective trial. Radiother. Oncol., 48,197-202. Borghede, G., Hedelin, H., Holmang, S. etal. (1997) Irradiation of localized prostatic carcinoma with a combination of high dose rate iridium-192 brachytherapy and external beam radiotherapy with three target definitions and dose levels inside the prostate gland. Radiother. Oncol., 44,245-50. D'Amico, A.V. and Coleman, C.N. (1996) Role of interstitial radiotherapy in the management of clinically organconfined prostate cancer: The jury is still out. J. Clin. 0ncol.,14,304-15. Rodriguez, R.R., Demanes, D.J. and Altieri, G.A. (1999) High dose rate brachytherapy in the treatment of prostate cancer. Hematol. Oncol. Clin. North Am., 13, 503-23.

19 Low dose-rate brachytherapy for breast cancer JULIA R. WHITE AND J. FRANKWILSON

19.1

INTRODUCTION

Low dose-rate (LDR) brachytherapy has had a long history of use for the treatment of breast cancer. Its primary use has been as a boost following whole breast radiation therapy (WBRT) as part of breast conserving treatment (BCT) for early-stage disease. Additionally, it has had some broader application for the treatment of locally advanced as well as locally recurrent breast cancer. As a result of both technical and philosophical changes in the radiation treatment of breast cancer, the use of LDR brachytherapy has declined significantly. Despite this, there remains a role for LDR brachytherapy in breast cancer treatment.

19.2

HISTORICAL PERSPECTIVE

LDR brachytherapy played an important part in the dramatic practice shift over the past three decades toward BCT as the preferred local therapy for eligible breast cancer patients [1]. While most of the transition to BCT happened over the last two decades, it was actually just shortly after the turn of the twentieth century that visionary investigators began the insertion of radium needles into primary and recurrent breast cancer as an alternative to surgical resection [2]. As early as 1910, Dr Henry Janeway, a surgeon at Memorial Hospital in New York, gained experience treating primary and metastatic breast cancer with the insertion of capillary glass seeds containing radon [3]. In 1924, a British surgeon, Sir

Geoffrey Keynes, began systematically treating primary breast cancer with radium needle insertion instead of radical mastectomy. He routinely included the breast, as well as the supraclavicular, infraclavicular, axillary, and internal mammary regional nodal areas in his treatment volume (Figure 19.1) [4]. In 1929, reporting his results of treating 90 women with definitive interstitial irradiation, he proclaimed, 'at the present time we regard treatment by buried needles as preferable to operation,' for operable breast cancer. Subsequently, in 1937 Keynes modified his technique to include tylectomy of the primary breast mass prior to radium needle insertion [5]. Similarly, in 1932, Dr George Phaler, a Philadelphia radiologist, reported his experience using radium 'for intensive local effect by interstitial implantation' in combination with roentgen rays for primary treatment of 127 breast cancer patients [6]. He reported an 81% control rate at 'well over 5 years' for 40 patients with resectable breast cancer treated with radiation alone because they had either refused surgery or were medically inoperable. This early work with interstitial LDR implants became the foundation of experience upon which BCT would be built, and preceded the first published reports of external-beam therapy with or without tylectomy by at least 10 years [7,8]. The development of better X-ray generators and greater understanding of radiobiologic principles, combined with frustration with the stagnant results and physical deformity from radical mastectomy, led to the emergence of more reports utilizing external radiation for BCT [9-11]. Shortly after the Guy's London Trial [12] comparing tylectomy and breast radiation to radical mastectomy was initiated in 1955, Pierquin et al. began

Early-stage breast cancer 267

Figure 19.1 Distribution of radium needles used by Sir Geoffrey Keynesfor the definitive treatment of operable breast cancer between 1924 and 1929 [4].

routinely treating operable breast cancer with radical radiation therapy alone, consisting of whole breast external-beam irradiation (WBRT) and an LDR interstitial implant into the tumor-bearing quadrant [13]. Similar work combining WBRT and brachytherapy after tumor excision for BCT began in the USA as well [14]. These single institution experiences, by consistently demonstrating comparable survival and good local control in comparison to treatment with radical mastectomy, helped further the acceptance of BCT for treatment of early-stage breast cancer. Their work ultimately led to the prospective randomized trials [15-20] which established BCT as the preferred alternative to mastectomy in eligible patients. LDR brachytherapy remains a part of the radiation management of breast cancer some 80 years after its inception.

193

EARLY-STAGE BREAST CANCER

193.1 Low dose-rate brachytherapy as boost treatment The predominant use of LDR brachytherapy has been in the setting of BCT to deliver a 'boost' or supplemental dose of radiation to the tumor-bearing quadrant of the

breast after WBRT. This was an ideal application for an interstitial implant, given that the anatomy of the breast is readily accessible to an implant and the resulting dose distribution allows a localized area of high dose, while sparing much of the remaining breast, underlying chest wall, and lung. Until linear accelerators capable of generating high-energy electron beams became generally available, an interstitial LDR implant was the method of choice for delivering the boost dose for patients treated with BCT. The wide acceptance of LDR brachytherapy as a boost technique is evidenced by the fact that in two of the randomized trials comparing BCT to mastectomy for early-stage breast cancer, an LDR interstitial implant was part of protocol radiation [18,19]. There has been considerable variation in terms of the surgery, radiation, and implant techniques utilized among different institutions (Table 19.1). However, in general, 10-30 Gy was delivered by LDR irradiation over 1-3 days, either before or after WBRT of 45-50 Gy had been given over a 4-5week time period. This yielded local breast recurrence rates varying from 3.7% to 16%, after 5-15 years of follow-up (Table 19.2). Over the past decade, many institutions have abandoned using an LDR implant for the boost dose. Results from the 1983 Radiation Oncology Patterns of Care Study in the USA for definitive breast irradiation demonstrated 29.8% of boost doses were delivered with an LDR implant [32]. In comparison, the 1989 US Patterns of Care Survey included 449 cases from academic (30%), hospital-based (38%), and free-standing (32%) radiation oncology practices. Ten percent, 2%, and 13% of these respective practices used an LDR interstitial implant for the boost technique [33]. This change in practice pattern probably reflects a combination of the availability and convenience of high-energy electron technical capabilities and the controversy associated with routinely boosting the lumpectomy bed after WBRT. The rationale for boosting the tumor-bearing quadrant is supported by the work of Holland et a/., who performed histologic examination of 282 mastectomy specimens from breast cancer patients with solitary tumors less than 5 cm in size who would otherwise have been good candidates for treatment with BCT. The amount and distribution of microscopic tumor foci outside the index mass in the adjacent normal breast tissue were mapped. This demonstrated that in 177 (63%) of cases, tumor foci were found outside of the index lesion, with 20% of these being within a distance of 2 cm, and 43% at distances greater than 2cm [34]. In view of the high risk of residual microscopic tumor burden in the 2-4 cm of tissue surrounding the index mass, and the cosmetic deformity of such a large excision margin in most cases, boosting the affected area with higher localized doses of radiation seemed a logical solution. Multiple prospective and retrospective series utilizing more limited surgery in combination with WBRT and a boost have demonstrated breast recurrence rates of

Table 19.1 Techniques from various institutions using LDR brachytherapy as a boostfollowing whole breast treatment for breast conserving therapy

Netherlands Cancer Institute [21 -24]

WLE

Positive Close Negative Unknown

9 15 46 30

Positive Negative Unknown

15 56 2.9

50/2

15-25

Paris3

2

15

2.5

45/1.8

15-20

0.30-0.5

2

17.5

N/A

Thomas Jefferson University/ University of Kansas [25]

WLE

Hopital Henri Mondor, Institut Gustave-Roussy [26]

Tumorectomybfor T size 3 cm or after excision (n = 15) for tumors < 3 cm in size [73]. A total dose of 30 Gy was delivered by a single LDR implant after excision. For treatment with brachytherapy alone, two separate insertions were done, delivering cumulative total doses of 60-70 Gy. For the entire group, the second local recurrence rate was 21% after a mean follow-up of 40 months. With a mean follow-up of 48 months, 4/15 (27%) of the excision and brachytherapy group had a second local recurrence, in comparison to 4/23 (17%) in the brachytherapy-alone group after a mean follow-up of 36 months. The 5-year overall and disease-free survivals were 61% and 31% respectively, for the entire population. Local control in the group treated with brachytherapy after excision might have been better had a higher dose than 30 Gy been used. Toxicity included necrosis in one patient and chronic breast pain in another, both requiring mastectomy. In comparison, Kurtz et al. reported a 32% second local recurrence rate after a median follow-up of 51 months for 50 patients with breast failure after BCT treated with local excision alone [74]. While mastectomy remains the recommended treatment for recurrence after BCT, brachytherapy after local excision represents a potential alternative in selected cases.

19.4

LOCALLY ADVANCED BREAST CANCER

In an attempt to expand the benefits of BCT to patients with locally advanced breast cancer, LDR interstitial implants have been used as a boost after induction chemotherapy and WBRT alone or in combination with lumpectomy (Tables 19.4 and 19.5). The total implant dose delivered tended to be slightly higher in this setting, ranging from 25 Gy to 40 Gy (Table 19.4). Local control rates from these series range from 74% to 91%, with the majority of patients treated with exclusive radiation. Breast preservation rates were 78-94% of attempted cases. This held true even when larger tumors and more

274 Low dose-rate brachytherapy for breast cancer Table 19.4 Techniques from various institutions using LDR brachytherapy as a boost following whole breast treatment for more locally advanced breast cancer

Hopital Tenon, Hopital Pitie Salpetriere [75]

Induction:3 4 cycles Adjuvant:1312 cycles

None 33 WLE 27 MRM 37

45/1.96

25-30

Centre Hospitaller et Universitaire[76]

Induction:0 3 cycles Adjuvant:" 6 cycles

None 32 WLE 45 MRM 81

45/2.25

15-35

Neckar Hospital [77]

Induction:6 4-6 cycles Adjuvant:'5-12 cycles

None

23/5.0-6.3

20-30

Hopital Pitie Salpetriere [78]

Induction only

None

45/1.8 23/1.5-6.5

25-30

Memorial Medical Center of Long Beach [79]

None

Incisional biopsy

50/2.0

Breast 30-40 Axil la 20-30

a

5-Fluorouracil, adriamycin, cyclophosphamide. Cyclophosphamide, methotrexate, 5-fluorouracil. c Mitoxantrone, vincristine, cyclophosphamide, 5-fluorouracil. "As above, with epirubicin. 'Vinblastine, thiotepa, methotrexate, 5-fluorouracil, prednisone with adriamycin. WLE, wide local excision; MRM, modified radical mastectomy. b

advanced stages were treated. Survival was comparable to those series with similar chemotherapy regimens which routinely employed mastectomy [80]. As reviewed earlier, the Institute Curie has demonstrated improved local control from an LDR interstitial implant versus an electron boost in a prospective randomized trial [61] when treating primary breast cancers 3-7 cm in size with radiation therapy alone without definitive surgery. Therefore, in this setting, an LDR interstitial implant is the recommended and preferred boost method.

19.5

TECHNIQUE

Iridium-192 is the most commonly used isotope for LDR breast implants (see Table 19.1). Alternatively, a few institutions have used iodine-125 and reported clinical advantages in comparison to iridium-192 in terms of easier shielding and dose optimization [53]. However, iodine-125 requires significant physics time and expertise for the assembly and dismantling of custom ribbons. In most cases, a minimum of two planes is necessary for appropriate coverage by the implant of the lumpectomy site. A double-plane implant can generally be used to treat volumes with thicknesses up to 2.5-3 cm. For treatment volumes with thicknesses > 3-3.5 cm, a three-plane implant is generally warranted to improve dose homogeneity [81]. Single-plane implants are reserved for treatment volumes with a thickness of 1 cm

or less, which may occur in very small breasts or in the periphery of the breast, particularly the upper inner quadrant. Spacing between planes and the individual ribbons within a plane typically varies between 1 and 2 cm. The planes can be arranged so that the needles in opposing planes are parallel, creating a square configuration between needles in different planes. For breast implants, the needles in adjacent planes are commonly staggered. This means that the needles in one plane are situated at half the in-plane separation of the opposing plane, so that there is a triangular configuration between needles in different planes (Figure 19.2a). This latter arrangement has been used extensively in the Paris System for interstitial radiation therapy, for which the recommended spacing between individual needles in the same plane is 15, 18, or 20 mm and the interplanar separations are 13, 16, and 18 mm, respectively, or nearly equidistant [82]. There is substantial clinical experience supporting the efficacy of the Paris-type arrangement for LDR interstitial implants in the breast (see Table 19.2). In using the Paris System the operator should be aware that, as the distance between needles and planes increases to cover larger target volumes, so does the relatively higher dose region in the center of the implant [83]. For this reason, others have recommended varying needle and plane separations to improve dose homogeneity [84,85]. As an example, Zwicker et al. use a Quimby-like system which maintains a constant needle spacing of 1 cm within the plane as the interplanar spacing varies with target thickness in

Table 19.5 Outcomes from various institutions using LDR brachytherapy as a boost following whole breast treatment for more locally advanced breast cancer.

97

IIIA-IV

6.6

86

78

78

16/60 (17)

80

69

Centre Hospitalier et Universitaire [76]

158

T2-T3

5.6

38

48.7

N/A

6/77

73.2a

-

Necker Hospital [77]

137 94

IIA-B IIIA-B"

3-15

62

94

85

337196 (17)

IIA KB IMA 1MB

95 80 60 58

-

Hopital Pitie-Salpetriere [78]

135

T3-T4b

8.5

96

90

72

26d/135 (19)d

All T3 T4

64 66 56

50 52 47

7V85

47

Hopital Tenon, Hopital F'itie-Salpetriere[75]

(8)

Memorial Medical Center of Long Beach [79]

78

III

N/A

48-84

90

65

(8) 'Disease-free survival. "Including inflammatory limited to part of the breast. C 27 isolated with metastasis, 23 breast, 4 axillary. d 11 with DCIS. e 5 breast failures, 2 axillary. BCT, breast conserving treatment. N/A Not available.

276 Low dose-rate brachytherapy for breast cancer

Figure 19.2 Isodose distributions in (a) transverse, (b) coronal, and (c) sagittal planes for a rigid implant demonstrating staggered interplane needle arrangement.

order to reduce the high-dose region at the center of the implant [85]. Interstitial breast implants are generally placed with the patient under general anesthesia. In some cases, conscious sedation combined with local infiltration is adequate. The patient is positioned to match what was utilized for her preplanning, or otherwise is generally positioned so that the ipsilateral arm is abducted to approximately 90°. The entire breast, with a generous margin, should be sterilely prepped and draped. In general, 15-20 cm hollow, stainless-steel needles are used. The deep plane is generally placed first. The orientation of the needles depends on the location of the tumor bed within the breast. Care is taken that the superficial plane is sufficiently deep to the skin (0.5-1 cm) to avoid exces-

sive skin dose. Once all the needles are in position, they can be replaced with flexible plastic catheters. Flexible catheters have the benefit of improving patient comfort. The major disadvantage is the potential for change in the implant geometry and dosimetry with patient movement [86]. To maintain ideal geometry, some have advocated that the needles or catheters be fixed in position by either endplates [82] or a bridge [87] (Figure 19.2). Once the implant is completed, a small amount of antibiotic ointment can be placed around the needle puncture sites and the implant covered with loose-fitting gauze until loading. After the patient has recuperated sufficiently from her anesthesia, post-implant treatment planning proceeds. In general, prophylactic antibiotics are not required unless the patient has a comorbidity such as

Treatment planning 277

cardiac valve disease. Usually, the patient can be comfortably maintained with mild analgesics throughout her treatment. Patients are allowed bathroom privileges, but activity should be restricted so that the implant geometry is maintained. It has been shown that the implant dosimetry can change with the patient position [86]. Once the radiation is completed, removal of the implant is done at the bedside, using a sterile technique.

19.6

TREATMENT PLANNING

Typically, an LDR interstitial implant boost can be performed 1-2 weeks before or after initiation of WBRT. Significant time delays between WBRT and the implant should be avoided, as this was correlated with a greater risk of local breast recurrence by Dubray et al. in the Creteil experience. In that analysis, the mean time delay between the WBRT and the LDR implant was prolonged at 5.9 ± 1.7 weeks [88]. Because most patients in this series were treated by exclusive radiation without breast surgery, it is not clear whether this finding is applicable to WBRT plus implant following excision as well. For patients receiving an LDR implant as the sole radiation modality following lumpectomy, implants should probably be performed within 4-6 weeks of the final breast surgery. Performing the implant at the time of excision or reexcision has the important advantage of allowing direct visualization of the surgical bed, ensuring that it is covered by the needle geometry. Furthermore, implants done at the time of the re-excision or the axillary node dissection have the added benefit of avoiding a separate surgical procedure and anesthesia. The disadvantage of implanting at the time of the breast surgery is that the presence of any adverse pathologic feature and status of the final resection margins are unknown. For this reason, delayed loading of the implant for 48 h after periexcision placement is recommended, to allow for wound healing and availability of the pathologic review and margin assessment [89]. Others have loaded the implant within 6 h after peri-excision placement and reported no greater occurrence of wound complications and have adjusted total dose for any adverse pathologic features found at the time of pathology review [56,90]. Another disadvantage of performing the implant at the time of the excision or re-excision is that it is limited to those patients who are treated at centers with both surgical and radiation oncology capabilities on site. At many large referral centers, this would preclude an interstitial implant for the numerous patients who have had their breast surgery performed elsewhere. Patients who do not have the interstitial implant performed at the time of breast surgery require careful localization of the excision cavity. This includes all implants done at the time of the axillary node dissection

before WBRT, as well as those performed after WBRT. De Biose et al. found that clinical examination (physical examination, operative report, and mammograms) underestimated the full extent of the lumpectomy cavity 87% of the time in comparison to preoperative and intraoperative ultrasound definition [91]. Sedlmayer et al. demonstrated a potential error rate of 51% from estimating the location of the tumor bed based upon the clinical criteria of preoperative mammography, surgical reports, and palpation of postoperative indurative changes in comparison to radiographs of surgical clips outlining the excision cavity [92]. This potential error rate rose to 78.5% for large pliable breasts. As a result, this group advocates that the excision cavity be marked with surgical clips. Demarcating the lumpectomy site with surgical clips has also been shown to be equally important when planning WBRT and electron boost volumes to ensure adequate coverage [93,94]. For this reason, it is our belief that the lumpectomy cavity should always be marked with surgical clips to avoid geographic misses by any radiation modality, not just in the setting of an implant. When the lumpectomy cavity has not been demarcated with surgical clips, localization with either computerized tomography (CT) scan and/or ultrasound is necessary. Both of these modalities are dependent on the presence of a seroma and/or hematoma to outline the cavity. Therefore, it is necessary to perform these studies for localization purposes as close to the breast surgery as possible, as postoperative changes can resolve within a few weeks. Prior to going to the operating room, the treatment volume to be implanted should be determined and mapped on the skin of the breast. Also, the depth of the deepest plane necessary to adequately cover the excision cavity should be planned preoperatively as this is frequently also underestimated by clinical examination [91]. One proposed method to ensure accurate tumor localization and intraoperative reproduction of a preplanned implant is to make a mould of the breast that will provide fixed geometry for the implant. Teo and Chung first reported using a cobex cast of the breast to aid in the planning of LDR implants that were a component of radical radiation for locally advanced breast cancer [95]. Once the cobex cast of the breast was made, a CT scan was performed for tumor localization with the cast in place. A geometrically ideal implant for tumor coverage was planned from the CT scan, and the entry and exit points for the needle placement drilled into the cast preoperatively. Intraoperatively, the cast was refitted to the patient's breast and the implant constructed via needle placement through the predrilled holes. This technique was modified by Perera et al. for use together with surgical clips marking the lumpectomy cavity. The surgical clips were added because of difficulty separating the tumor bed from normal dense breast tissue with the use of CT alone [96]. Their technique used the simulator first


to localize the tumor bed based on the position of the clips within the breast. This area was then mapped out on a breast mould and marked by radio-opaque catheters attached to the mould. Similarly, after CT localization, the optimal implant for coverage of the treatment volume was planned and the exit and entry points for the implant needles placed on the mould in relation to the radioopaque markers. Reconstruction of the implant was then done intraoperatively after the mould had been refitted to the patient's breast. Vicini et al. have used a similar technique to preplan implants using ultrasound to initially map the lumpectomy cavity prior to a CT done with radio-opaque markers placed directly on the breast instead of a mould or cast. The positions of the radioopaque markers were subsequently drawn directly on the breast. Using a three-dimensional treatment planning system, they were able to create a volumetric model of their fixed template system and virtually plan the ideal position of the implant on the CT. Digitally reconstructed radiographs of the skin surface were generated demonstrating the needle exit and entry points relative to the radio-opaque markers to guide intraoperative placement [97]. Sedlmayer reported a technique for preplanning implants based solely on simulator localization of the clips marking the excision cavity to determine the depth and trajectory of the implant planes [92]. This information is then mapped directly on the affected breast with the patient in the same position to be used at the time of surgical placement. At The Medical College of Wisconsin, we have adopted a similar technique, preoperatively mapping the position of clips onto the skin of the breast and estimating the depth of the planes in the simulator with the patient in a position that will mimic what will be used intraoperatively. In addition, we routinely use a C-arm fluoroscopic unit intraoperatively to confirm inclusion of the clips marking the excision cavity within the needle geometry after the first few needles have been placed prior to completing the entire implant. Multiple dosimetry systems for preplanning interstitial implants have been formulated. These are meant to guide seed activity and spacing, as well as intraplanar and interplanar needle spacing, so as to deliver a certain dose rate over a given volume. These include a nomogram [84], which specifies ribbon spacing based upon the linear activity of the sources and target volume, and planning tables [85], which determine the seed activity and interplanar separation needed to achieve a desired dose rate at the boundaries of the treatment volume of dimensions specified in the table. These preplanning tables and monographs have been particularly useful for implants performed at the time of lumpectomy. They should not replace post-implant treatment planning as the actual geometry of the implant performed at the time of surgery can vary significantly from what was preplanned. Post-implant treatment planning should consist of a minimum of two variable angle films, typically 60-90°

apart. Ribbons containing radio-opaque dummy seeds are loaded into all the implanted needles or catheters and, by their different appearances, allow identification of the separate needles. The positions of the dummy seeds and the surgical clips demarcating the cavity on the orthogonal films are digitized into the planning system, allowing reconstruction of the implant. The radiation oncologist should specify the volume to be covered by the reference dose rate on the treatment planning films. Evaluation of isodose curves in the sagittal and coronal as well as in the transaxial planes gives a better understanding of the volume irradiated and the dose heterogeneity (Figure 19.2a-c). Ideally, isodose curves should be generated in more than just the central plane. It is particularly important to evaluate other planes if a nonrigid implant was performed, as central plane dosimetry will not reliably represent any convergence or divergence of the needles that may have occurred. CT scan-based dosimetry is very useful for planning and documenting tumor volume coverage of multiplane implants [98]. It reduces the time necessary for reconstruction from the orthogonal radiographs, reliably demonstrates areas of uneven spacing, and can evaluate the isodose coverage of the lumpectomy site. Dose prescription includes selection of the dose rate and total dose to be delivered to a specified volume. Doses for boost therapy after lumpectomy and WBRT range from 10 Gy to 25 Gy, with dose rates typically varying from 0.4 Gy to 0.8 Gy h~' (see Table 19.1). Doses for boost therapy after WBRT in cases of exclusive radiation therapy for locally advanced disease tend to range from 20 Gy to 40 Gy given over similar dose rates (see Table 19.4). For the Paris System, the reference dose rate is 85% of the basal dose, or the average minimum dose between the sources [31]. A dose-rate effect for local control was reported by Mazeron et al. in a review of 398 T1-T3 adenocarcinomas of the breast treated by exclusive radiation therapy without surgery. An LDR interstitial implant of 37 Gy was done after WBRT of 45 Gy. Significantly higher rates of breast relapse were noted when the implant dose-rate was < 0.6 Gy rr1 [99]. Deore et al. demonstrated a similar effect for LDR implant boosts after lumpectomy and WBRT [55]. In this series of 273 patients, an increased rate of local recurrence was seen in a small number of cases in which the dose rate of the implant boost was 0.2-0.29 Gy (4/17, 24%) versus >0.3 Gy h-1 (16/253, 6.3%). However, little information is available in this report regarding the presence of other adverse prognostic features in this group of 17 patients. Overall, dose rates > 0.4 Gy h"1 have yielded very high local control rates after lumpectomy (see Table 19.2). Special attention should be paid to the skin dose during the implant treatment planning. Excessively high skin doses may result in telangiectasis and skin retraction as a late outcome. For this reason, the most superficial sources should be at least 5-10 mm beneath the skin surface. Implants with large interplane separations

References 279

may need up to 10 mm to avoid excessive skin dosage. Van Limbergen studied the location of the dermal vascular structures of 30 healthy skin samples from ten mastectomy specimens and found that the dermal vascular structures responsible for telangiectasia are located in the first 5mm under the skin surface [100]. Thermoluminescence dosimetry (TLD) measurements made over several points on the skin surface of the breast during the implant and WBRT suggested that doses > 50 Gy to the skin are associated with a higher probability of late telangiectasia [86]. At The Medical College of Wisconsin, two to three BBs are placed over the skin at the time of post-treatment planning in the simulator. These are then digitized into the planning system along with the dummy seeds and the surgical clips. This provides us with an estimate of skin dose. While it is necessary that the desired dose accurately covers the treatment volume to secure local control, it should be kept in mind that the parameters of total dose and treatment volume can influence the cosmetic and toxicity outcomes. The irradiated boost volume and total dose significantly influence the formation of late fibrosis. A very carefully executed study evaluating breast fibrosis was performed in 404 patients with early-stage breast cancer who underwent BCT [23]. This study demonstrated that the odds of developing moderate to severe fibrosis were dependent on overall dose, particularly for doses > 70 Gy. Furthermore, for any given dose, there was a proportional increase in late fibrosis with increasing irradiated volumes, (see Figure 19.3). Specifically, for each 107 cm3 added to the irradiated volume, the risk of fibrosis increased by a factor of 4. Similarly, McRae et al. correlated soft-tissue complications with the implant volume in 56 breast implants [ 101 ]. In contradiction to these findings, others have not found a correlation between implant volume and cosmetic or toxicity outcome [59].

Implicit in the prescription of dose with LDR interstitial implants are those volumes of tissue that will receive markedly higher doses due to dose heterogeneity. Several investigators have proposed methods for quantifying dose uniformity. These include the dose homogeneity index (DHI), dose non-uniformity ratio (DNR), and double dose volume ratio (DDVR) [81,102,103]. The DHI represents the percentage of the target volume receiving dose rates between 100% and 150% of the reference dose rate [81]. The DNR is defined as the ratio of the high-dose volume relative to the reference volume [ 102]. Lastly, the DDVR is the ratio of the volume of tissue receiving twice the prescribed dose divided by the volume of tissue receiving the prescribed dose [103]. Acceptably homogeneous implants are recommended to have a DHI of > 0.8, a DDVR of < 0.1, and the minimum DNR. The value of these indices is that they allow comparison of implants in terms of dose actually delivered versus prescribed dose. Ideally, the 150% isodose line should be broken up and visible around individual ribbons only. The importance of the interaction between total treatment volume and dose heterogeneity for determining cosmetic and toxicity outcomes further demonstrates the need for careful treatment planning.

19,7 CONCLUSION Low dose-rate brachytherapy for the treatment of breast cancer has a well-established track record for providing high levels of local control and good cosmetic outcomes. Careful quality control with special attention to target localization and dose specification has proved crucial in the success of LDR implants. While its role as a boost after WBRT is diminishing in cases of BCT, newer applications are emerging. In particular, brachytherapy as the sole radiation modality following lumpectomy appears promising. Even as HDR brachytherapy becomes more prevalent for the treatment of breast cancer, the wealth of LDR experience and data provides an important benchmark for success in terms of local control and late outcomes.

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lumpectomy cavity for interstitial brachytherapy of the breast. Int.J. Radial Oncol. Biol. Phys., 38(4), 755-9. Sedlmayer, F., Rahim, H., Kogelnik, D. etal. (1996) Quality assurance in breast cancer brachytherapy: geographic miss in the interstitial boost treatment of the tumor bed. Int.]. Radial. Oncol. Biol. Phys., 34(5), 1133-9. BedwinekJ. (1993) Breast conserving surgery and irradiation: the importance of demarcating the excision cavity with surgical clips. Int.J. Radial Oncol. Biol. Phys., 26,675-9. Solin, L, Danoff, B.etal. (1985) A practical technique for the localizing of the tumor volume in definitive irradiation of the breast. Int.J. Radial Oncol. Biol. Phys., 11,1215-20. Teo, P. and Chung, D. (1987) An accurate method of 192 Ir write implantation for locally advanced carcinoma of the breast. Acta Oncol, 26,273-6. Perera, F., Chisela, F., Engel, J. etal. (1995) Method of localization and implantation of the lumpectomy site for high dose rate brachytherapy after conservative surgery forT1 and T2 breast cancer. Int.J. Radial Oncol. Biol. Phys ,31(4),959-65. Vicini, F., Jaffray, D., Horwitz, E. etal. (1998) Implementation of 3D-virtual brachytherapy in the management of breast cancer: a description of a new

98.

99.

100.

101.

102.

103.

method of interstitial brachytherapy. Int.J. Radial Oncol. Biol. Phys., 40(3), 629-35. Regional Medical Physics Department (1986) The use of simulator-based computed tomography in iridium-192 dosimetry. Br.J. Radiol., 59,1035-6. MazeronJ.J., Simon, J. and Crook, J. (1991) Influence of dose rate on local control of breast carcinoma treated by external beam irradiation plus iridium 192 implant. Int. J. Radial Oncol. Biol. Phys., 21,1173-7. Van Limbergen, E., Briot, E. and Drijkoningen, M. (1990) The source - skin distance measuring bridge: a method to avoid radiation telangiectasia in the skin after interstitial therapy for breast cancer. Int.J. Radial Oncol. Biol. Phys., 18,1239-44. McRae, D., RodgersJ.and Dritschilo, A. (1987) Dosevolume and complication in interstitial implants for breast carcinoma. IntJ. Radial Oncol. Biol. Phys., 13, 525-9. Saw, C.B., Suntharalingam, N. and Wu, A. (1993) Concept of dose nonuniformity in interstitial brachytherapy. Int. J. Radial Oncol. Biol. Phys., 26, 519-27. Metcalf, D.R., Lewinsky, B.S., Fingerhut, A.G. etal. (1988) A ratio of volumes technique for analyzing interstitial implants. Int.J. Radial Oncol. Biol. Phys., 15 (Suppl. 1), 143.

20 Brachytherapy in the treatment of head and neck cancer A.GERBAULETANDM.MAHER

20.1

HISTORICAL BACKGROUND

Since the discovery of radium in 1898 by Pierre and Marie Curie, there have been many advances in the use of radioactive sources for brachytherapy procedures. The first reported cases of interstitial therapy were published in 1914 from Dublin, Ireland [1-3]. Subsequent development of radium needles allowed easy implantation of skin tumors, lip tumors, and cancers of other accessible sites. Advances in dosimetry saw the development of units such as threshold erythema dose, millicurie destroyed and milligram-hours. In the 1930s Patterson and Parker devised a series of rules for single-plane, double-plane, and volume implants governing the use of radium needles. Milligram-hours were at that time the unit of measurement in common use for such applications [4,5]. In head and neck cancers the most common sites to be treated by such implants were lip, tongue, floor of mouth, and buccal mucosa. Radium needles had the disadvantage of significant radioprotective problems. Artificial radioactivity, however, was discovered by Irene Curie and Frederic Joliot in 1933 and shortly thereafter new materials suitable for clinical use became available. The introduction of iridium-192 wire brought with it greater flexibility and a major reduction in the hazards posed to both staff and patients by radium brachytherapy. From the 1960s onwards, the Paris school led by

Pierquin, Dutreix, and Chassagne [5-7] laid the foundations of the Paris system of implantation. Enormous clinical experience coupled with scientific endeavor resulted in what became known as the Paris System. This refers to a system of implantation and dosimetry which is predictive, reliable, consistent, and clinically safe [8,9]. With the development of linear accelerators in the 1950s and 1960s, the popularity of brachytherapy as a treatment modality began to decline. However, brachytherapy is currently undergoing a resurgence in use due to the widespread availability of isotopes which offer more flexibility and few radioprotective problems and the introduction of remote afterloading machines into many treatment departments [6,9].

20.2 PRETREATMENT ASSESSMENT AND INVESTIGATIONS

20.2.1

Primary tumor

Pretreatment assessment is without doubt the single most important step in any planned brachytherapy procedure. In order to be able to decide whether a brachytherapy procedure is appropriate, one must be able to define with confidence the limits of the tumor volume and the limits of the proposed target volume [1,5,7,9].

Treatment methods 285

In most instances, brachytherapy is contraindicated as an initial therapeutic procedure for T3-T4 cancers of the head and neck. On the other hand, brachytherapy is, in the majority of clinical situations, perfectly appropriate as an initial or indeed exclusive local therapeutic procedure for T1-T2 cancers of the head and neck. The key, therefore, to the correct and effective use of brachytherapy in head and neck cancers lies in the pretreatment assessment and investigations. Pretreatment assessment includes detailed history, full physical examination, appropriate investigations, and multidisciplinary consultation. With regard to the primary tumor, this process refers to loco-regional tumor evaluation, routine search for metastatic disease, investigation for synchronous second primaries and, in the case of oral cavity implants, gingival/dental examination and recommendations [5,10]. Loco-regional tumor evaluation defines the exact limits of the primary tumor, allowing the brachytherapist precisely to appreciate the tumor volume. This may be an entirely clinical assessment for lesions on the lip, buccal mucosa, floor of mouth, or mobile tongue. In some situations, however, further delineation is provided by computerized axial tomography (CAT) scanning and/or magnetic resonance imaging (MRI) scans, which may more accurately assess the primary tumor volume and the integrity of adjacent structures such as bone and cartilage [8,11-13]. 20.2.2

Neck assessment

For patients with oral cavity tumors for whom the planned treatment is brachytherapy, assessment of nodal neck disease is primarily clinical. Even if clinically negative, all such patients treated in Gustave-Roussy systematically undergo elective neck dissection provided they are deemed fit for general anesthesia and surgery. In situations in which patients are deemed to be unfit for general anesthesia, the draining neck nodes may be assessed clinically and by serial CAT scanning. 20.23

Dental assessment

Gingival and dental assessment is of vital importance prior to any brachytherapy procedure which will result in radioactive sources lying in close contact with the teeth, gums, or mandible. Teeth with extensive caries and gross gingival disease are better extracted prior to brachytherapy if osteoradionecrosis is to be avoided. Following extraction, sufficient time to allow adequate gum healing must elapse (usually 2-3 weeks) before the brachytherapy treatment is carried out. For patients with healthy teeth and gums, efforts must be made to protect the dentition. In our institution, a shielding system made of 2 mm of lead is used to cover the teeth and gums. An identical denture shield made of

acrylic resin, which is radiotransparent, is put in place when the orthogonal X-ray films for dosimetry are taken following the brachytherapy procedure. This allows reproduction of the actual source positions during irradiation with the dental radioprotective lead shield in place. This shielding system confers a reduction in dose of 50% to the teeth and mandible.

203

203.1

TREATMENT METHODS

lridium-192

Iridium-192 is the radioisotope used in our institution for head and neck low dose-rate (LDR) brachytherapy. Some institutions continue to use cesium needles in certain clinical situations, such as lip and tongue cancer. Iridium-192, however, is flexible, pliable, and can be cut to prerequisite lengths. It is available as a continuous wire coil of iridium-platinum alloy (25-75) and can be purchased in diameters of 0.3 or 0.5 mm, depending on the technique for which it will be employed. Iridium has a half-life of 74 days, is a gamma ray emitter with average energy of 0.35 MeV, and has a half value layer of 2 mm lead [4-7].

203.2

Iridium-192 hairpins

Iridium-192 is also available in the form of single pins or hairpins. The hairpin consists of two lengths of iridium wire connected by a bridge, rather like the three sides of a rectangle. The 'legs' can be cut to any desired length and the separation between them is a constant 12 mm, thereby assuring parallelism. This iridium has a diameter of 0.5 mm. Iridium hairpins are implanted using specially made stainless-steel guide gutters. These guide gutters have a similar geometric shape to the hairpin, but the 'legs' are hollow and bevelled. The bridge of the guide gutter is everted and can be gripped by a long-handled or shorthandled Pierquin forceps, which allows better leverage for accurate placement. Guide gutters/iridium-192 hairpins are ideally suited to brachytherapy for floor of mouth and lateral border of mobile tongue tumors. For implantation of such tumors, the patient sits in a dental chair and the procedure is carried out under local anesthetic. Ideally, the theater should be equipped with a Carm fluoroscopic X-ray control unit. The area to be implanted is anesthetized, the guide gutters are introduced, and their geometric arrangement is verified by fluoroscopy. When found to be in a satisfactory position, a silk suture is passed underneath the bridge of the guide gutter, taking in a generous amount of tissue. The active iridium hairpin is then slipped into the bevelled edges of the guide gutter and advanced until the bridge reaches the surface tissue. A skin hook is placed over the hairpin

286 Brachytherapy in the treatment of head and neck cancer

bridge to maintain its position while the guide gutter is being withdrawn. The silk suture is then tied to ensure the hairpin does not become displaced during the irridation. Orthogonal X-ray films are taken, with, if appropriate, the previously described acrylic dental protector in place. Dosimetry is determined by both computer and manual planning [5,7,8,14].

2033

Plastic tube technique

The plastic tube technique is an elegant system of implantation, but requires considerable operator skill and expertise. It is an afterloading technique which fixes the tissues encompassed by loops of plastic tubing. It is a technique of implantation which is suited to tumors of the floor of the mouth spreading onto the ventral surface of the tongue, and vice versa, for tumors of the lateral and posterior tongue, the tonsillar fossa, tonsillar pillars, soft palate, and uvula. The technique is described here in relation to a midline Tl tumor of the soft palate. Having confirmed the indication for brachytherapy treatment by preoperative assessment and investigations, the patient is given a general anesthetic. The procedure is carried out under aseptic conditions with the patient in the supine position. A small tumor of the midline of the soft palate is implanted by looping two hollow plastic tubes from the submandibular neck region on one side, through the tonsillar pillars, across the substance of the soft palate, and exiting by the tonsillar pillar route on the opposite side of the neck. Step 1 is to pass a hollow stylette vertically through the skin of the neck and posterior floor of the mouth, so that it exits intraorally at the foot of the posterior tonsillar pillar. A length of nylon monofilament is threaded through the hollow stylette from outside and is recuperated intraorally. The stylette is then withdrawn, leaving the monofilament in place. A length of hollow plastic tubing (which will eventually hold the radioactive iridium wire) is threaded over the monofilament and advanced to the skin entry point on the neck. This plastic tubing has an outer diameter of 1.6 mm and an inner diameter of 1.2 mm. Forceps are applied at the distal end of the monofilament, which is overlapped by the plastic tubing. The intraoral monofilament is thereafter carefully pulled through the tissues in vertical fashion until the plastic tubing emerges at the foot of the tonsillar pillar. Great care must be taken when pulling the monofilament/plastic tubing through the tissues so that tearing and subsequent bleeding are avoided. A Reverdin forceps (which is curved) is passed from the contralateral side through the substance of the soft palate to emerge at the superior pole of the posterior tonsillar pillar. The monofilament is gripped by the Reverdin forceps and pulled back through the soft palate. The plastic tubing is then carefully advanced through the soft palate tissue, following the same principles as before.

To exit the tubing and complete the loop, a hollow stylette is passed as before in vertical fashion from the submandibular neck area to emerge at the foot of the contralateral posterior tonsillar pillar. The monofilament is threaded through from inside to emerge externally and the stylette is then withdrawn. The plastic tubing is pulled through very carefully as before, and the monofilament is then withdrawn. The tubing is now in place, forming a loop which passes from one side of the neck through the posterior tonsillar pillar, across the substance of the soft palate, and emerging via the contralateral posterior tonsillar pillar to the opposite neck. The plastic tubing is flushed through with a heparin solution to ensure it remains patent. A second length of plastic tubing is implanted in exactly the same manner, but on this occasion the anterior tonsillar pillar is the intraoral point of entry and exit. Although the actual physical process of implantation has been described above, no mention has been made of the relation of the tubes to each other or, indeed, to the tumor. Obviously, these factors are of vital importance if the Paris System rules are to be observed. The loops must be implanted so that they comfortably sandwich the tumor between them, while simultaneously remaining equidistant and parallel with respect to each other. In terms of dosimetry, the optimal distance between the two tubes is approximately 12-15 mm. This distance is maintained externally as follows: plastic tube spacers which have been drilled with holes separated by a distance equal to the separation between the two hollow plastic tubes are passed over the free ends of the tubes and advanced so that they come to lie in contact with the skin of the neck. Dummy wire is then threaded through the plastic tubes and is held in place by lightly clamping metal buttons which slide over the plastic tubes. Orthogonal X-rays are taken for dosimetric purposes [4,5,15,16].

203*4

Hypodermic needle technique

Hypodermic needles are most often used for cancers of the lip and nose, for which an element of rigidity in the source carriers is required. They have an external diameter of 0.8 mm and are bevelled at both ends. When the target volume has been implanted and the positions are deemed satisfactory, the needles are kept in place by a template system. The templates, which are made of perspex, are cut and drilled to the implant requirements and are then slipped over the ends of the needles. Lead caps are placed over the bevelled ends of the needles on one side of the implant and are crimped to secure them. Appropriate lengths of radioactive iridium-192 wire are manually afterloaded into the opposite ends of the

Treatment planning 287

needles and lead caps are put in position and crimped as before [5,7,17].

203.5

high dose uniformity within the target volume, and a rapid fall-off in dose outside it [5,6,8,19].

Silk suture technique 20.4

This technique is used predominantly for small tumors on the skin and eyelids. Braided silk (4.0) into which 0.3 mm diameter iridium wire can be threaded is the vector for implantation. The silk thread is first canalized by a small steel wire and then hardened by dipping into an organic compound. The steel wire is withdrawn and replaced by iridium-192 of 0.3 mm diameter, which is maintained in position by a knot on the silk thread. The tumor to be implanted is treated by passing the silk thread through the target tissue so that the portion containing the iridium wire lies in an appropriate position. Depending on the size of the lesion to be treated, several silk sutures may be threaded through the target tissue, ensuring at all times that the rules of the Paris System are respected [6,18].

203.6

The Paris System

20.4.1

TREATMENT PLANNING General assessment

As previously emphasized, the general assessment includes an evaluation of the patient, the patient's tumor under consideration, and other relevant factors such as dentition. When a brachytherapy procedure is being proposed, consideration has to be given to the manner of anesthesia. Local anesthesia is quite adequate for well limited tumors of the lip, for small tumors of the floor of the mouth or lateral border of the tongue for implantation by the guide gutter technique. Advantages of local anesthesia are that normal muscle tonus is maintained and, with a conscious patient check, fluoroscopy screening is easily carried out. Patients undergoing intraoral brachytherapy procedures under general anesthesia must be intubated by the nasal route to allow adequate room for the brachytherapist to work [1,7-9].

To respect the rules of the Paris System, several criteria have to be observed. 1. The linear activity of the sources must be uniform for all the sources used and must be uniform throughout the length of each source. 2. Source must be implanted parallel and equidistant to each other. 3. The distance between the sources may vary from implant to implant, but, once decided, must be constant for each individual case. 4. The plane which passes through the midpoints of each source at right-angles to the axis of the implant is defined as the central plane and is used for calculating the basal dose rates. 5. The basal dose rate is the minimum dose rate between lines. When three straight lines are implanted for a small skin carcinoma on the cheek, there will be two basal dose rates. When three lines are implanted in triangular fashion for a small lip carcinoma, there will be just one basal dose rate. Depending on the number of active wires and their configuration, most head and neck implants can be subdivided geometrically into triangles. The basal dose rate for each triangle is calculated. The results are added and divided by the number of triangles, giving an average basal dose rate for the entire implant. 6. The reference dose rate is equal to 85% of the mean basal dose rate. This isodose envelops the target volume and is the isodose on which the treatment is prescribed. A good implant that follows the rules of the Paris System will give precise coverage of the target volume, a

20.4.2

Tumor evaluation

At first clinical assessment the brachytherapist can generally envisage the treatment method to be employed. In rare instances, the predicted implant technique may need to be modified due to further information gained from CAT scans or MRI scans. Guide gutter, hypodermic needle and silk suture techniques require immediate loading in the operating theater. The operator does this using long-handled forceps manipulated from behind lead screens. The plastic tube technique, on the other hand, is an afterloading system, which allows dosimetry to be calculated prior to loading of the active wire. All of these factors have to be kept in mind by the brachytherapist when planning the treatment. In this respect, the advantage of the Paris System can be exploited. With clinical assessment of the tumor volume to be encompassed, a knowledge of the Paris System of implantation allows for provisional estimation of the number of lines to be implanted, the separation between the lines, and the lengths/activity of iridium to be used. Tumor evaluation therefore includes the method, spacing, and length/activity of sources to be used in accordance with the size, shape, and position of the tumor. The tumor and a margin of security are enveloped by the target volume. The target volume is therefore the volume of tissue to which we intend to deliver the prescribed dose. The treated volume is that included by the 85% reference isodose curve, and should be at least equal to the target volume [5,10,20].


20.43 Geometric configuration When a series of loops or hairpins are implanted in precise geometric fashion, parallel and equidistant, the following volume applies: V=L x WxT

where V = volume, I = length, W= width, and T= thickness. Length treated = 0.8 x half total active length.

The activity of the radioactive source may have a bearing on ultimate outcome, and several studies have demonstrated a link between dose rate and local control. Such factors, therefore, impinge on the brachytherapist's therapeutic decisions. After-loading techniques such as the plastic tube method allow the brachytherapist to take great care over the geometry of the arrangement, thereby increasing the possibility of obtaining a perfect implant with uniform dose distribution [5].

Width treated = 1.55 x spacing. Thickness treated = distance between outermost branches + 0.5 x spacing.

As can be deduced from the above, the active wires must extend beyond the target volume at each end in order to compensate for dose fall-off at the limits of the implanted sources. The reference isodose dips sharply between the implanted wires or tubes at the ends of the implant due to the linear source strength of the iridium, and therefore the active ends must extend beyond the target volume to ensure the reference isodose curve equates with the volume to be implanted. Naturally, this results in a volume of tissue outside of the target volume receiving an appreciable dose of radiation, but this in turn is offset by the rapid fall-off in dose as one moves away from each source. With practice, the predictive dosimetry pertaining to each proposed implant can be envisaged, as can the influence of varying the number and spacings between the sources. Dosimetric planning consists of determining the dimensions of the target volume and choosing the method of implantation that best assures an optimal dose distribution within the treated volume. For single-plane implants, the three volume dimensions - length, width, and thickness - need to be considered. Length depends on the length of the iridium used, whereas width and thickness depend on the spacing between the sources.

20.4*4

Radioactive sources

For the specification of radioactive sources, the International Commission on Radiation Units and Measurements (ICRU) has recommended the use of kerma. The kerma rate defines the strength of a radioactive source and is measured in air at a distance of 1 m from the midpoint of the radioactive source. The unit of measurement for kerma rate is cGy rr1 m2. For LDR brachytherapy, radioactive sources must be of small diameter to allow them to be introduced into suitable carrier systems, such as plastic tubing. Sources must be to some degree pliable to conform to implant geometry and must not pose difficult radioprotective problems. Iridium is an element which fulfills these criteria.

20.5 20.5.1

TREATMENT Lip

For lip cancers, the hypodermic needle or plastic tube technique is generally used. Lip cancers are easy to assess clinically and allow one to visualize the implant technique and geometric arrangement prior to the procedure. Choice of technique depends on tumor volume, site, and anatomy. Large tumors and those involving the labial commissure are better treated by the plastic tube technique. Implantation follows the axis of the lip and preperforated templates may be introduced at both ends to maintain the geometric arrangement. General recommendations about dental protection apply and an appropriate shielding device should be worn by the patient during irradiation [1,4,5,7].

20.5.2

Nose

Cancer of the nasal vestibule may be implanted by plastic tubes, guide gutters/hairpins, or hypodermic needles. For large tumors infiltrating the columnella or nasal cartilage, plastic tubes may be used in a horizontal arrangement of several planes which transfix the nose and conform to the Paris System. Preperforated templates are used to maintain parallelism. Infiltration of the columnella may be treated by the guide gutter/hairpin technique [6,17,21].

20.5.3

Skin, ear, eyelid

The silk suture or the plastic tube techniques may be used for carcinomas of the skin, ear and eyelid. As the iridium contained within the silk suture has a diameter of 0.3 mm, this technique is suitable for areas such as the eyelid where the vector for the radioactive source needs to be of the smallest possible diameter. Carcinomas of the pinna and the external auditory canal can be treated by a mould system which conforms to the irregular anatomy [5,8,18,22].

The Institut Gustave-Roussy results 289

20*5.4

Mobile tongue

Carcinomas of the mobile tongue may be treated by either the guide gutter/hairpin or plastic tube technique. The guide gutter/hairpin method is suitable for small tumors and carries the advantage of avoiding general anesthesia. It is also a speedy procedure, which results in good parallelism and excellent dose distribution. The plastic tube technique is generally reserved for bigger tumors, requires general anesthesia, and transfixes the tongue/floor of mouth in its loops. As it is an afterloading system, there is less exposure to the operator and other personnel than that encountered by the guide gutter/hairpin technique, which requires 'live' loading in the operating theater. Choice of implant system is dependent on tumor site, volume, accessibility, and physician preference and experience [5,7,12,23-34].

20.5.5

Floor of mouth

Either the guide gutter/hairpin or the plastic tube technique can be used in the treatment of cancer of the floor of the mouth. As the separation between the 'legs' of the hairpin is a constant 12 mm, this method is reserved for small tumors. Care has to be taken that the active sources do not lie too close to the gingiva or mandible if subsequent late complications such as necrosis are to be avoided. As a general rule in this institution, brachytherapy is contraindicated if the implant demands that more than two radioactive lines lie in close contact with the mandible. The plastic tube technique can be equally applied in floor of the mouth cancers, but as this method transfixes the tongue and requires general anesthesia, the guide gutter/hairpin method is preferred providing tumor dimensions are appropriate [6,11 -13,27,39,40,42].

20.5.7

20.5.8 palate

Tonsil, tonsillar pillar, and soft

Nowadays, treatment of these sites by brachytherapy is confined almost exclusively to the plastic tube technique. Implantation follows the principles described earlier. For lesions confined to the tonsil, the loop may just involve the ipsilateral tonsillar bed. For central lesions of the soft palate, a looping system that passes from one side of the neck to the other may be used. In some instances, the loop may be fashioned in such a way that the tumor and the full width of the soft palate are enveloped by the loop, thereby confining the skin exit and entry points to one side of the neck [8,15,16,35,44].

Base of tongue

Whereas in the past the guide gutter/hairpin method was employed for base of tongue tumors, they are now treated by the plastic tube technique. The plane of implantation is generally sagittal (three loops) completed often by a frontal loop. In phase 1, the entire base of the tongue is the target volume when treating exclusively by brachytherapy. Phase 2 involves boosting the tumor and tumor bed volume by leaving the relevant sources in place for a longer duration of time, appropriate to the dose prescribed [14,19,35-38].

20.5.6

pin method is appropriate for non-infiltrating small tumors. The implantation of plastic tubes can be either in the vertical oblique or horizontal planes, depending on tumor orientation and infiltration [6,43].

Buccal mucosa

Again, the plastic tube or guide gutter/hairpin method can be applied. Choice of implant system is dictated by tumor dimensions and position. The guide gutter/hair-

20.5.9

Nasopharynx

Brachytherapy for nasopharyngeal carcinoma is a plesiotherapy technique. It is indicated in very few patients more often as a salvage treatment, as the maximum thickness of tissue that can be irradiated by this method without significant complications is 10 mm. Treatment involves taking an impression of the nasopharyngeal cavity using a very fine dental algate, and from the negative of this an individualized mould is constructed. The impression of the nasopharynx will reveal the position and dimensions of the tumor and from this the brachytherapist can decide where the plastic tubing source carriers should be positioned in the mould. The sources are afterloaded into the plastic tubes, which are appropriately positioned on the inside of the hollow acrylic applicator [6]. Tumor evaluation is of critical importance when this technique is to be considered. CAT scanning and/or MRI scanning are imperative in the assessment of the tumor dimensions.

20.6 THE INSTITUT GUSTAVE-ROUSSY RESULTS The following results are from experience at Institut Gustave-Roussy in treating head and neck cancers with LDR brachytherapy. In all cases, the rules of the Paris System were respected. The figures given are broken down into population base, age, sex, TNM status, implantation method used, and clinical results. Treatment protocol 'A refers to initial brachytherapy to the primary lesion ± (if indicated) cervical node dissection + (if indicated) external-beam irradiation.


Treatment protocol 'B' refers to initial external-beam irradiation followed by brachytherapy as a boost procedure [6].

20.6.1

Lip [6]

Population: 231 patients. Mean age: 65 years (range 28-90). Males: 85%; females: 15%. TNM distribution: TI = 82%; T2 = 13%; T3 = 3%; NO = 80%. Treatment protocol: A = 97%; B = 3%. Method: plastic tube technique = 40%; hypodermic needles = 56%; silk threads = 14%. Mean dose delivered = 76 Gy. Clinical results: overall 5-year disease-free survival = 66% local control rate at 5 years = 95%. Complications: mucosal necrosis = 13%.

20.6.2 Nose [6] Population: 36 patients. Mean age: 66 years (range 44-82). Males: 83%; females: 17%. TNM distribution: TI = 45%; T2 = 45%; T3 = 10%; NO = 93%. Treatment protocol: A = 93%; B = 7%. Method: plastic tube technique = 20%; hypodermic needles = 54%; guide gutters/hairpins = 40%; silk threads = 6%. Mean dose delivered: 72 Gy. Clinical results: overall 5-year disease-free survival = 68% local control rate at 5 years = 86%. Complications: grade 1 and 2 = 33%; grade 3 = 18%.

20.6.3

Mobile tongue [5,6,11]

Population: 269 patients. Mean age: 55 years (range 25-87). Males: 77%; females: 23%. TNM distribution: TI = 31%; T2 = 55%; T3 = 14%; NO = 81%. Treatment protocol: A = 72%; B = 28%. Method for protocol A: plastic tube technique = 21%; guide gutters/hairpin = 79%. Mean dose delivered: 71 Gy. Method for protocol B: plastic tube technique = 51%; guide gutters/hairpin = 49%. Mean dose delivered: 27 Gy. Clinical results: overall 5-year disease-free survival: A = 62%; B = 30% local control rate at 5 years: A = 87%; B = 49%

complications: mucosal necrosis = 11%; bone necrosis = 8%.

20.6.4

Floor of mouth [6,11-13]

Population: 206 patients. Mean age: 53 years (range 31-85). Males: 72%; females: 28% TNM distribution: TI = 42%; T2 = 50%; T3 = 6%; NO = 70%. Treatment protocol: A = 87%; B = 13%. Method for protocol A: plastic tube technique A = 21%; guide gutters/hairpin = 79%. Mean dose delivered: 65 Gy. Method for protocol B: plastic tube technique A = 19%; guide gutters/hairpin = 81%. Mean dose delivered: 27 Gy. Clinical results: overall 5-year disease-free survival: A = 74%; B = 30% local control rate at 5 years: A = 89%; B = 59%. complications: mucosal necrosis = 11%; bone necrosis = 21%.

20.6.5

Oropharynx [6,19,37]

Population: 312 patients. Mean age: 58 years (range 38-86). Males: 85%; females: 15%. TNM distribution: TI = 25%; T2 = 40%; T3 = 35%; NO = 50%. Treatment protocol: A = 11%; B = 89%. Method: plastic tube technique = 26%; guide gutters/ hairpin = 74%. Mean dose: 75 Gy (including external-beam radiation) Clinical results: overall 5-year disease-free survival: base of tongue = 26%; tonsil = 37%; anterior oropharynx = 40%; soft palate = 37%. Local control rate at 5 years: base of tongue = 68%; tonsil = 79%; anterior oropharynx = 69%; soft palate = 93%. Complications: grade 1 and 2 = 27%; grade 3 = 7%.

20.6.6

Nasopharynx [6]

Population: 47 patients. Mean age: 42 years (range 26-57). Males: 70%; females: 30%. TNM distribution: 33 patients treated as 'boost' following external irradiation (45 Gy); 14 patients treated for recurrence in previously irradiated area. Method: moulded applicator. Mean dose for 'boost' treatment: 30 Gy. Mean dose for salvage treatment: 60 Gy.

Future directions 291

Clinical results: overall 5-year disease-free survival for 'boost' treatment = 42% overall 5-year disease-free survival for salvage treatment = 17% local control rate at 5 years for 'boost' treatment = 74% local control rate at 5 years for salvage treatment = 50%.

20.6.7

Pediatric head and neck

malignancies [6] Population: 39 patients. Mean age: 5 years (range 3 months-15 years). Main tumor sites: nasolabial sulcus = 31%; oral cavity = 21%; neck = 15%; ear = 10%. Percentage of cases with rhabdomyosarcoma: 70%. TNM distribution: TI - 61%; T2 = 36%; TX = 3%; NO = 56%; NI = 41%; NX = 3%. Treatment protocol: for children, the approach was quite different from that with adults and included chemotherapy in most cases; external radiotherapy was given in 31% of cases. Brachytherapy procedure: brachytherapy was indicated in two different situations: first-line brachytherapy = 64%; salvage brachytherapy = 36%. Plastic tubes ± hypodermic needles and/or guide gutters: 95% Guide gutters ± hypodermic needles: 5% Brachytherapy performed per-operatively: 31%. Mean dose: first-line brachytherapy = 68 Gy; salvage brachytherapy = 56 Gy. Results: 5-year disease-free survival: first-line brachytherapy = 76%; salvage brachytherapy = 50% local control rate: first-line brachytherapy = 84%; salvage brachytherapy = 64%. severe complications: first-line brachytherapy = 24%; salvage brachytherapy = 21%.

20.7

LITERATURE REVIEW

A literature review and comparison of results are presented in classified tables (Tables 20.1, 20.2, and 20.3) according to the different tumor sites. In these tables, the following abbreviations are used: Results: O = origin, TS = tumor site, NP = number of patients, TP = treatment protocol, CND = cervical node dissection, EB = externalbeam irradiation, BT = brachytherapy, PS = Paris System LDR, LC = local control, CP = complications, STN = soft-tissue necrosis, ORN = osteoradionecrosis, SV = survival, OSV = overall survival, SSV: site-specific survival, DPS: disease-free survival; tumor sites: BM = buccal mucosa, BT = base of tongue, FM = floor of mouth, GPS = glosso palatine sulcus, L = lip, MT = mobile tongue, NP = nasopharynx, NV = nasal vestibule, OC = oral cavity, OP = oropharynx, P = pinna, SP = soft palate, TO = tonsil, ToPi = tonsil + pillars.

20.8

FUTURE DIRECTIONS

While the techniques of implantation described for LDR brachytherapy for head and neck carcinomas are well established, efforts have been made to further refine them. In an attempt to diminish the exposure to staff, automatic afterloading devices for LDR isotopes are now available. However, various technical problems have hampered their universal introduction and manual afterloading continues to be widely practiced. In particular, with a plastic tube technique that involves a loop, the source needs to be able to negotiate a curved path. Such technical problems require further investigation and refinement. Similarly, dosimetry pertaining to the Paris System is also well established and its precision is reflected in the high rates of local control and low rates of complications. However, with the advent of three-dimensional planning, there exists an opportunity to better define the treatment volume. Computerized dosimetric calculation with exact definition of the target volume may afford an opportunity to ameliorate the various source arrangement possibilities and thus arrive at an optimized dose distribution within a given volume. The generation of

Table 20.1 Nasal vestibule, pinna

Levendag, P.C. and Pomp, J. 21]

NV

MazeronJ.J. [17]

Nose

Debois,J.M.[22]

P

MazeronJ.J. [18]

P

63

T1 NO 36 T2 NO 24

EB + BT BT

OS 65 DPS 80

T1 97 T279

BT

PS Iridium

93.6

140

BT

Cesium

95

70

BT

PS

94

1676

I, II, III 6

20


Table 20.2 Oral cavity

MazeronJ.J. [17-19] FM

Pernot.M. [16]

FM

117

T1 47 T270

BT±CND +EB/N

PS

T1 NO 94 93.5 T2 NO 61 74.5 T2N1-N228 65

207 T185 T2 99 T316T44Tx3 NO 172

BT102 EB + BT105

PS

SSV T1 88 T2 47 T336

T197T272 T351

117,1112 III 6, IV 0.5

BT92 EB + BT 8

PS

DFS42 24

88 36

I, II 35 III 5

PS

DFS42 24

88 36

I, II 35 III 5

T1 94 T2 91 T371

STN20 ORN13

Volterrani, F. [41]

FM

175 T147T287 T319 T4 22

Benk,V. [24]

MT

110

II

BT±CND85 EB + BT25

Hareyama, M. [26]

MT

110

II

BT99 EB + BT25

MazeronJ.J. [17-19]

MT

166 T1 NO 70 T2 NO 83 T1-T2 N1-N213

Pernot, M. [29]

MT

147 T2 NO

Pernot.M. [16]

FM

207 T185 T2 99 T316T44TX3 NO 172

Iridium

PS

52 44 8

87 92 69

BT±CND70 EB + BT 77

PS

SS 62.2 34.7

89.8 50.6

BT102 EB + BT105

PS

SSV T1 88 T2 47 T336

T1 97 T2 72 T351

117,11 12,1116, IV 0.5

184 Ma 78 lib 72

Spf 85 Exoph 79 Infill 45

1138 1114

Shibuya, H. [30]

MT

370

I 90 Ma 196 lib 84

BT±CND EB + BT

Wang, C.C. [20]

MT

143

T1NO T2 NO

EB + BT

Wendt, C.T. [32]

MT

103 T1 NO 18 T2 NO 85

BT18 EB + BT 77 EB8

149

BT + ENI

Iridium

50 86 54

lOOorthoKv 100elec.eB

BT

Dearnaley, D.P. [25] MT FM Thomas L [31]

MT FM

Volterrani, F. [41]

OC

40 T1 NO T2 NO 406 T1 132.T2245, T329

29 T1/T2

BeitlerJ.J. [47]

TO

Matsuura K. [33]

MT

173

Fujita, M. [34]

MT

207 93 T1 114T2

Rudoltz, M.S. [42]

OC

55 T1 16 T226 T38 T45

75 Stage I 98 Stage 1 1

66 92 38 T1 T2 90

Iridium-cesium Radium

BT

52

65

T>20 mm

Radium

41.4

T1-279 T354

ORN22

BT+EB

Iridium 125

-

92

EB + BT 66 BTalone107

Iridium hairpins

Stage 1 93 (5 years) Stage II 78 (5 years)

EB + BT 82 BTalone125

Iridium hairpins

T193 T277

PS BT EB + BT3

EB + BT(HDR)

dose-volume histograms will, in time, allow correlations to clinical outcome, which should theoretically increase rates of cure and local control while simultaneously maintaining or diminishing current complication rates.

11.5

79 (2 years) 87forT1/2 47forT3/4

Other areas of worthwhile future investigation include biological studies involving proliferation rates, oncogene and tumor suppressor gene expression, which may, in time, better define the population base likely to benefit

References 293 Table 20.3 Oropharynx

Pernot, M. [10]

Esche, B.A. [15]

VT

361

SP

T190.T2141 T3119.T42, Tx91, NO 230

43

BT 18 EB + BT 343

EB + BT

80

PS

Specific SV

Iridium

63

PS

37

92

121,112, 1112, IV 0.2

GGPT Lusinchi.A. [37] Puthawala,A. [38]

BT

108

TO

80

T1 18T2 39 T3 51 111-IV81%

EB + BT

PS

26

T1 85, T2 50 T369

EB + BT

GGPT Iridium

72

84

from exclusive brachytherapy treatment. In our institution, the place of ultra-LDR brachytherapy is currently under investigation for patients suffering recurrence of previously irradiated head and neck cancers.

6

as serial reports confirm its usefulness in this regard [46].

REFERENCES 20.9

CONCLUSION

The aim of this chapter was not to be exhaustive but to try to show the efficacy of brachytherapy based on LDR technique. Taking into account the Institut Gustave-Roussy experience and most of the results collected from Group European Curietherapy (GEC) multicentric studies, two categories of patients can be identified: those treated with brachytherapy alone (60% of cases), in which the results are: disease-free survival (DPS) 65-75%, local control 80-90%, complications 10%; and those treated with brachytherapy boost: DPS 35-45%, local control 60-70%, complications 20%. To conclude, LDR brachytherapy plays a major role in the management of head and neck cancer: the local control rate is high, the complication rate is low. This treatment is well tolerated by the patient and can be delivered in a short time. However, successful brachytherapy depends much upon careful assessment of the patient, close collaborative efforts, and finally on the entire brachytherapy experience, which itself is based on precise planning and technique respecting the rules of the system used to implant and calculate the dose distribution, thus being able to report the results and compare them with those of other treatment approaches. It is likely that in the future, brachytherapy may be combined with chemotherapy in certain clinical situations or as an intraoperative endeavor [45]. In addition, it will continue to hold its proven role in the treatment of recurrent carcinoma in previously irradiated patients

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21 High dose-rate interstitial and endocavitary brachytherapy in cancer of the head and neck PETER LEVENDAG, CONNIE DE PAN, DICK SIPKEMA, ANDRIESVISSER, INGER-KARINE KOLKMAN, AND PETERJANSEN

21.1

INTRODUCTION

The development of manual afterloading techniques for radioactive sources and the introduction of artificial radionuclides have received considerable attention over the last few years and have contributed significantly to the renaissance of brachytherapy. The total elimination of radiation exposure to the nursing, medical, and physics staff as well as to patients' relatives by remote controlled afterloading devices was a logical extension of the manual afterloading concept. In 1961, the first high dose-rate (HDR) remote-controlled afterloader was introduced in the Memorial Sloan Kettering Cancer Center group, using high-activity cobalt-60 pellets. When the manufacture of small, cylindrical (l/iU Surg., 149,46-52. 15. Lerut,J.P.,Gianello, P.R.,Otte,J.B.and Kestens, P.J.(1984) Pancreaticoduodenal resection. Surgical experience and evaluation of risk factors in 103 patients. Ann. Surg., 199, 432-7. 16. van Heerden, J.A., Mcllrath, D.C., llstrup, D.M. and Weiland, LH. (1988) Total pancreatectomy for ductal

22.

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332 Brachytherapy in the treatment of pancreas and bile duct cancer

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74.

75.

T. and Nishimura, A. (1988) The role of intraoperative radiation therapy in the treatment of bile duct cancers. WorldJ.Surg., 12,91-8. Todorki, T., Iwasaki, Y. and Okamura, T. (1980) Intraoperative radiotherapy for advanced carcinoma of the biliary system. Cancer, 46,2179-84. Rich, T.A., Cacy, B., McDermott, W.V., Case, K.R., Chassey, J.T. and Hellman, S. (1988) Orthovoltage intraoperative radiation therapy: a new look at an old idea. Int. J. Radial Oncol. Biol. Phys., 10,1957-63. Busse, P.M., Stone, M.D., Shelton, T.A. etal. (1989) Intraoperative radiation therapy for biliary duct carcinoma. Results of a 5 year experience. Surgery, 10, 724-33. Son, Y.H., Nori, D., Leibel, S.A. etal. (1990) Biliary tree. In Interstitial Collaborative Working Group. Interstitial Brachytherapy, Programme and Abstracts. 7th International Brachytherapy Working Conference. New York, Raven Press, 153-6. Nunnerly, H.B.and Karani.J.B. (1990) Intraductal radiation. Radiol. Clin. North Am., 28,1237-40. Fletcher, M.S., Brinkley, D., Dawson, J.L et al. (1981) Treatment of high bile duct carcinoma by internal radiotherapy with iridium-192wire. Lancet,2, '\72-A. Molt, P., Hopfan, S., Watson, R, Botet, J.F. and Brennan, M.F. (1986) Intraluminal radiation therapy in the management of malignant biliary obstruction. Cancer, 57, 536-44. Johnson, D.W., Safai, C. and Goffinet, D.R. (1985) Malignant obstructive jaundice: treatment with external beam and intracavitary radiation therapy. Int.J. Radial Oncol. Biol. Phys., 11,411-16. Ede, R.J., Williams, S.J., Hatfield, A.R.W., Mclntyre, S. and Mair, G. (1989) Endoscopic management of inoperable cholangiocarcinoma using iridium-192. Br.y. Swrg., 76, 867-9. Levitt, M.D., Laurence, B.H., Cameron, F. and Klemp, P.F.B. (1988) Transpappilary iridium-192 wire in the treatment of malignant bile duct obstruction. Gut, 29,149-52. Herskovic, A.M., Engler, M.J. and Noell, K.T. (1985) Radical radiotherapy for bile duct carcinoma. Endocuriether./ Hypertherm. Oncol., 1,119-24. Nori, D., Nag, S., Rogers, D. etal. (1994) Remote afterloading high dose-rate brachytherapy for carcinoma of the bile duct. In High Dose Rate Brachytherapy: a Textbook, ed. S. Nag. Armonk, NY, Futura Publishing Co., Inc., 331-8. Merimsky, 0., Nori, D., Rogers, D. and Osian, A. (1995)

76.

77.

78.

79.

80.

81.

82.

83.

84.

85.

86. 87.

Conformal high dose-rate percutaneous transhepatic intraluminal cholangio-irradiation for unresectable cholangiocarcinoma. Endocuriether./Hypertherm. Oncol., 11,115-20. Robertson, J.M., Lawrence, T.S., Dworzanin, l.M.etal. (1993) Treatment of primary hepatobiliary cancer with conformal radiation therapy and regional chemotherapy. J. Clin. Oncol., 11,1286-93. Minsky B., Botet, J., Derdes, H.etal. (1992) Ultrasound directed extrahepatic bile duct intraluminal brachytherapy. Int. J. Radial Oncol. Biol. Phys., 23,165-7. Coughlin, C.T., Wong, T.Z., Ryan, T.P. etal. (1992) Interstitial microwave-induced hyperthermia and iridium brachytherapy for the treatment of obstructing biliary carcinomas. Int.]. Hyperthermia, 8, 57-71. Foo, M.L, Gunderson, L.L., Bender, C.E. and Buskirk, S.J. (1997) External radiation therapy and transcatheter iridium, in the treatment of extra hepatic bile duct cancer. Int.). Radial Oncol. Biol. Phys., 39(4), 929-35. McMasters, K.M., Tuttle, T.M., Leach, S.D. etal. (1997) Neoadjuvant chemoradiation for extra hepatic cholangiocarcinoma. Am.J. Surg., 174(6), 605-8, discussion 608-9. Kamada,T.,Saiton,H.,Takamura,A., Nojima.T. and Okushiba, S.I. (1996) The role of radiotherapy in the management of extra hepatic bile duct cancer; an analysis of 145 consecutive patients treated with intraluminal and/or external beam radiotherapy. Int.J. Radial Oncol. Biol. Phys., 34(4), 767-74. Montemaggi, P., Morganti, A.G., Dobelbower, R.R. et al. (1996) Role of intraluminal brachytherapy in extra hepatic bile duct and pancreatic cancers: is it just for palliation? Radiology, 199(3), 861-6. Vallis, K.A., Benjamin, I.S., Muaro, A.J.^o/.(1996) External beam and intraluminal radiotherapy for locally advanced bile duct cancer: role and tolerability. Radiother. Oncol., 41(1), 61-6. Leung, J.T. and Kuan, R. (1997) Intraluminal brachytherapy in the treatment of bile duct cncer. Aust. /tad/o/., 41 (2), 151^1. Schuricht, A.L, Spitz, F., Barbot, D. and Rosato, F. (1998) Intraoperative radiotherapy in the combined modality management of pancreatic cancer. Am. Surg., 64(11), 1043-9. Thomas, PR. (1996) Radiotherapy for carcinoma of the pancreas. Semin. Oncol., 23(2), 213-19. Dobelbower, R.R. and Montemaggi, P. (1996) Brachytherapy for pancreatic cancer: a review. Hepatogastroenterology, 43(8), 333-7.

23 Brachytherapy for treating endometrial cancer H. A. LADNER, A. PFLEIDERER, S. LADNER, AND U. KARCK

23,1

CLINICAL ASPECTS

During the last 30 years, technical advances as well as clinical developments have produced a significant change in the diagnosis and therapy of endometrial cancer. The increase in absolute numbers of endometrial cancers [1,2] and the increase of patients over 65 years of age cause a number of problems, including accompanying illness, appropriate radiation fractionation schedules and techniques [3,4]. Progress in anesthesiology and postoperative care now allows surgery in nearly all cases of endometrial carcinoma. As a result of these developments, staging can now be based on postoperative histopathological assessment. Relevant prognostic factors of endometrial cancer include stage (FIGO), depth of myometrial invasion, extrauterine extension, histological subtype, grade, ploidy, and levels of progesterone receptors. Pathogenetically, two different types are described [5,6]. The estrogen-dependent type A is characterized by a low histologic grade 1, high progesterone receptor value, endometrioid cancer in obese patients, and has an excellent prognosis. Type B cancers show no hormonal stimulation, are high-grade cancers [3] without progesterone receptor activity, and have a poor prognosis. A review of the recent literature shows almost general agreement that the cornerstone of curative treatment for endometrial carcinoma is abdominal hysterectomy, bilateral oophorectomy, and facultative lymphadenectomy [7]. Modern facilities now provide for surgery in obese, elderly women with vascular illness, which has dramatically reduced the number of 'inoperable' patients. Only a few patients with inoperable endometrial carcinoma now receive primary radiotherapy, with

a 5-year survival rate of about 20%. In 1995, Weiss et al. [8] reported only 21 patients who had undergone primary irradiation during the preceding 6 years. The changes in therapy, as described above, have developed slowly over the last 20 years. According to other authors [9,10], the difference in survival rate between surgical and radiotherapy treatment was, in the decade until 1985, of the order of 20% (i.e., 80% survival versus 60%), and it is difficult to evaluate the optimal indications for irradiation. Some of the management aspects are now described, together with the technical progress that has been made. In this context, it appears important to outline the best technical application of afterloading therapy in the future on the basis of the interesting review by Joslin [11].

23*1*1

Brachytherapy

There are three main requirements for the best appropriate use of brachytherapy: 1. Spatial dose distribution must be adapted to the individual anatomical situation. 2. Temporal dose distribution should be short enough to avoid clinical complications without reducing the therapeutic ratio. 3. The technique should be simple to apply and allow for reproducible source positioning. It should also be safe to use and allow for adequate radiation protection of staff. In the past, these requirements were not always satisfactorily met. The classic radium methods such as the Paris System, the Manchester System, and the method of Fletcher et al.

334 Brachytherapy for treating endometrial cancer

(1980) [12] involved protocols similar to those used for cervical carcinoma, with some degree of individualization. The Stockholm technique used flexible applicators which formed the basis of the classical Heyman packing technique of the uterine cavity with radium sources. It allowed the dose distribution to be adapted to the various shapes and sizes of uterine cavity in an optimal way, especially in cases with exophytic tumors. Furthermore, a relatively uniform dose distribution was delivered to the entire myometrium. High dose-rate (HDR) afterloading and its development for irradiation of endometrial carcinoma are associated with the name of Ulrich Henschke [ 13]. Following his guidelines for remote HDR treatment of gynecologic carcinomas, a variety of techniques in brachytherapy of uterine cancer was established in the following years [14-21,82]. Due to the use of combined treatments (brachytherapy and external-beam radiation therapy, EBRT), the situation was and still is complicated when looked at from the radiobiology viewpoint [11]. This is due to the fact that intracavitary irradiation is not delivered homogeneously throughout the treated volume. Further, in consequence of the steep dose gradient from the brachytherapy, the normal tissues outside the brachytherapy target volume receive relatively low doses of irradiation and the brachytherapy target volume is small in comparison to the external-beam target volume [11].

23.1.2 Dose rates and the choice of nuclide The reference dose rate according to the International Commission on Radiation Units (1985) is defined as follows: HDR treatment with more than 12 Gy h'1, medium dose-rate (MDR) treatment with 2-12 Gy h"1, and low dose-rate (LDR) treatment with less than 2 Gy h"1. There are different spatial arrangements of sources in use, such as a single oscillating source, a single source moving in steps (so-called train of different weighted pellets), or a train containing active sources and spacers. Simon and Silverstone [22] recommended a modified Heyman packing technique using hollow capsules, afterloaded by low-activity cesium-137 sources. However, they were confronted with the clinical consequences of a relatively long treatment time and lack of radiation protection for staff and visitors. A prerequisite for the achievement of optimal spatial and temporal dose distribution in combination with radiation protection and the advantages of Heymanstyle packing with remote HDR afterloading is the availability of small sources and computerized treatment planning. One good example seems to be the Wurzburg system, with small iridium-192 sources (diameter 1 mm) in conjunction with a MicroSelectron HDR afterloading machine, which allows for different kinds of dose opti-

mization when carrying out treatment planning (for technical details, see Herbolsheimer et al. [23]). Optimization according to the individual case can be performed by altering the dwell times of the six to 18 different capsules. When comparing the advantages of cesium-13 7, cobalt-60 and iridium-192 in regard to size, specific activity, and gamma energy, cesium-137 meets the special requirements best. This was reported in 1977 by Walstam [24], who suggested cesium-137 as the most suitable nuclide for brachytherapy in general.

23.2 MANAGEMENT AND CLINICAL PRACTICE The technique used by M. Herbolsheimer and K. Rotte in the U K F Wurzburg (Germany) is one which we advocate and now describe. One of the most important requirements for optimal brachytherapy is to be able to provide an individual dose distribution according to the size and share of the uterine cavity. A modified packing system such as the classical Heyman packing system using HDR afterloading can only be used when a sufficient number of small sources is available. This modified method was introduced by Herbolsheimer and Rotte (Wurzburg, Germany) in 1988. The use of small iridium-192 sources (diameter 1 mm) allows the uterine cavity to be packed with up to a maximum of 18 hollow plastic capsules, each capsule having a diameter of 4 mm. Following the placing of the capsules in the uterine cavity, orthogonal pelvic radiographs showing the distribution of the capsules, the measuring probes in the organs at risk and the bony structures are taken and digitized. A computer-controlled planning system provides the dose distribution in three dimensions and calculates the doses to the reference points of the organs at risk. In order to adapt the reference isodose to the uterine surface, the doses were prescribed to the so-called point 'MY' (myometrium) during the early years following the introduction of the system. 'MY' is situated 2 cm lateral to the central uterine axis and 2 cm below the most proximal capsule, which means 2 cm below the uterine fundus. Because the uterine shape is not visible on conventional radiographs and due to the fact that the point 'MY' is only an approximation, magnetic resonance tomography has been introduced into the planning procedure since 1993. Double-angulated slices (Figures 23.la and 23.Ib) are digitized and several reference points on the uterine surface are defined individually. In order to combine these points located on the serosa of the uterus by the reference isodose, it is necessary to distinguish each capsule from another and to assess them separately. A binary code of the dummies allows one to perform an optimization of the dose distribution. Five treatment fractions are given, each of 10

Management and clinical practice 335 Figure 23.1 Digitized slices from a scan illustrating the isodose distribution in relation to various reference points. Isodoses are in centigrays and axis scale dimensions are in centimeters.

Gy separated by 10 days. These treatments are scheduled within a course of megavoltage external-beam treatment to the pelvic lymphatics using bisegmental-biaxial arc rotation. Twenty-five fractions, each of 2.0 Gy, are delivered to the maximum dose point according to a threedimensional plan based on computer tomography. The 80% isodose should at least enclose the target volume. The total dose to the center of the pelvis, that is to say to the uterus, is delivered by brachytherapy alone, thus external-beam treatment is restricted to the lateral pelvic lymphatics. As a consequence, the mean dose to the tumor will be considerably higher in comparison to a treatment strategy using brachytherapy only as a boost after homogeneous irradiation of the whole pelvis. Moreover, the exposure of the organs at risk is lower. This has been shown by analysis of more than 200 patients [23]. The new Wurzburg results (1988-1994) demonstrate a 3-year actuarial survival rate of 82% in

FIGO stage I-III patients (n=68, 9% recurrence rate). In bulky tumors, which may be expected to contain a large fraction of hypoxic cells, non-restricted brachytherapy is used only as a boost. Compared with other afterloading methods, the advantage of this technique is that it provides for individual planning of doses.

23.2.1

Forms of applicator

Techniques based on the use of rigid applicators do not allow sufficient adaptation to individual anatomical situations. Only the applicators using iridium developed by Bauer et al. [25], the cobalt bulb techniques of Bjornsson and Sorbe [26], the flexible tube combined with vaginal ovoids [27], and the endouterine'umbrella' [21] provide a reasonable compromise with individual dose distribution because they use semi-flexible applicators. Other


authors perform uterine packing [17,28], sometimes combined with ovoids in the vaginal vault [29].

23*2.2

Remarks about dose rate

There is no general agreement about what provides the best remote-control brachytherapy method (low, medium, or high dose rate). An important advantage of LDR techniques remains the greater therapeutic ratio in comparison to HDR regimes based on the repair capacity of the tissues involved. Sublethal radiation damage recovery of normal-tissue damage may occur during the exposure time if the dose rate to any tissue or organ at risk is similar to classic radium therapy [30]. The reduced therapeutic ratio of HDR treatment in comparison with LDR brachytherapy requires adequate fractionation based on mathematical models which relate to time-dose relationships and take into account the time factors for repair of normal tissue [31,32]. The question of which treatment method is the most preferable, HDR or LDR afterloading, cannot be answered [33]. Both strategies have their specific advantages. In general, clinical studies comparing HDR and LDR treatments confirm that there is no significant difference between the two modalities of brachytherapy [10,28,34,35]. At present, there is a clear tendency in favor of HDR brachytherapy. However, LDR techniques still retain their place, which is not confined only to gynecologic tumors. It seems to be a question of habituation or availability of the afterloading machines. In Germany, many radiotherapy institutions prefer HDR brachytherapy because it is also possible to use the machine for nongynecological patients requiring HDR. There is no agreement in regard to the optimal dose rates.

23.23 Preoperative and postoperative irradiation Preoperative radiotherapy, partly combined with additional postoperative irradiation, has been used at several institutions [12,21,35,36]. The value of preoperative radiotherapy is discussed controversially [36,37]. Others, such as de Waal and Lochmuller [38] and Calais et al. [39], saw no improvement in the results after preoperative radium or brachytherapy of endometrial carcinoma compared to postoperative application. The timing of radiotherapy (brachytherapy and EBRT), i.e., preoperative versus postoperative, was not a significant factor in univariate or multivariate analysis [40,41]. The important question remains: for which group of patients will afterloading therapy lead to an improvement in overall survival? Several studies suggest that in some cases the application of adjuvant afterloading therapy in combination with EBRT will improve survival in patients exhibiting unfavorable prognostic factors such as low differentiation (grade 2), stage III disease, certain

histologic subtypes (e.g., clear cell adenosquamous and serous-papillary carcinoma), lymph node metastases, peritoneal spread, etc. However, controlled studies are missing. Further, it remains unclear whether adjuvant radiotherapy is helpful in cases of incomplete surgery. The results of therapy can only be evaluated by an exact analysis of recurrences and all forms of relapsing disease and metastases, including cases of complete failure. Recurrences in FIGO stage I or II disease are of particular interest. Following a review of a large number of recent publications, it is apparent that several reports suggest and discuss the benefits of adjuvant irradiation in endometrial cancer.

23.2.4 vagina

Postoperative brachytherapy of the

The incidence of vaginal recurrences after primary hysterectomy and bilateral salpingo-oophorectomy ranges from 5% to 20% if no postoperative radiation is performed [18,42]; the median rate is about 10% [43]. Many authors have reported a considerable reduction of this rate by including vaginal irradiation in the primary management using iridium, cesium, or cobalt [15,17-19,28,39,44-52), but there are also controversial opinions as to whether vaginal irradiation should be done. Sometimes its value is questioned: Malkasian et al. [53] reported 10% recurrences (stage I, EBRT for highrisk patients); Hording and Hansen (54) reported 19% recurrences (stage I, surgery without irradiation). Recurrences occur not only in the vaginal cuff, but also in the lower vagina, particularly in the suburethral area. Therefore, we also irradiate the lower vagina to the hymenal ring. A similar procedure is reported by others [42-44,52]. In contrast, Pipard et al. [55] and Pernot et al [21] do not recommend including the entire length of vagina because they foresee a potential risk to healthy tissues. Randall etal. [56] described the role of an intravaginal cuff boost of 30-50 Gy surface dose after adjuvant external-beam irradiation in early-stage disease treated from 1971 to 1983 with reduction of recurrence rates from 23% to 13% in those cases receiving a vaginal cuff boost.

23.2.5 Fractionation schemes and different dose rates Kob et al, using iridium, discuss fractionation regimes of: 4 x 10 Gy, 5 x 8 Gy, and 8 x 5 Gy at reference point A [34]. Sorbe and Smeds refer to 4 x 9 Gy, 5 x 6 Gy, 6 x 5 Gy, and 6 x 4.5 Gy [18]. Pettersson et al used cesium. Their reference dose to the rectum was 17 Gy or more, and since 1981 has been less than 17 Gy [49]. Kucera used iridium, giving a 10 Gy single dose since 1983: 3 x 7 Gy total dose to the surface of the vagina, and 2 x 7 Gy (at 2 cm distance from the applicator axis) in combination with EBRT [19]. Different LDRs are discussed by Haie-Meder et al [57].

Management and clinical practice 337

In the Freiburg data, vaginal recurrence was distinguished from the combination of vaginal and pelvic recurrence and from primary vaginal involvement, stage III or IV (FIGO, 1988). Recurrences within 6 months or failure of therapy was classified as progressive disease. Pelvic recurrence is defined as tumor growth limited to the pelvis, not involving the vagina, and occurring later than 6 months after primary treatment. The definition of distant metastasis is that of proven distant disease. The 5-year and 10-year survival rates use the data of Kaplan and Meier (SPSS program).

23.2*6 Disease recurrence rates after surgery and irradiation Table 23.1 demonstrates the recurrence rates after 5 years as published in the current literature. The differences in the quoted rates appear to originate from the fact that in some cases all stages were analyzed together, whereas in other reports only the early stages were included, i.e., only stage I [18]. Other confounding factors are differences in age structure of the patients and the incidence of accompanying illnesses. When looking at all stages together in an unselected population, a recurrence rate of about 10% appears to be achievable. Figures substantially higher than 10% ought to stimulate a re-evaluation of the therapeutic regimen used.

FREIBURG RESULTS

The prognosis of recurrent disease depends on the tissue site involved. Isolated vaginal recurrence (n=52) has a favorable prognosis, with a 5-year survival rate of 56.5% and at 10 years of 40%, whereas for patients who in addition had pelvic recurrence («=65), only 29% survived 5 years, which at 10 years was reduced to 17%. Similar results were obtained from cases with primary involvement, with a 5-year survival of 29% (n=67). Other 5-year survival results following radiotherapy for isolated vaginal recurrence have been reported (Table 23.2). These report results similar to our own. The application of brachytherapy, teletherapy, and vaginal surgery has been individualized [45,51,52,60]. Thus, results can be compared in order to assess the possible effects of differing therapeutic approaches which might become apparent. The Freiburg data suggest that the combination of hysterectomy and postoperative irradiation of the entire vagina (done in 925 patients, 76% of 1215 outpatients, 1969-1990) as primary management lowers the frequency of all types of recurrence (vagina: 1.5%, pelvis: 2%, distant: 5.4%) for all stages. In patients demonstrated to have distant metastases («=103) after the completion of primary therapy, there was a 5-year survival rate of 44.3% (at 10 years, 20%). This relatively high survival rate may be caused by the delay in the progression of distant metastasis following

Table 23.1 Frequency of recurrences following surgery and irradiation, as published in the current literature

Reference

5-year recurrence rate (%)

Poulsen and Roberts [62] Lancia no etal. [40] Kuceraeffl/. [19] SorbeandSmeds[18] Randal I era/. [56] Kleineefo/. [63] Petterssonefo/. [49] Calais efo/. [39]

14 10

2.2 4 16 8 10

23.2.7 Therapy and outcome of recurrent disease in Freiburg, Germany DEFINITIONS An isolated vaginal recurrence is a tumor up to 20 mm in size, limited to the vagina, occurring later than 6 months after primary therapy. The definition of isolated vaginal recurrences was adopted from Perez et al. [58] and slightly modified in later publications [46,52,59,60].

Table 23.2 Published 5-year survival rates after radiotherapy of isolated vaginal recurrence and mean follow-up time

3-19 4 4

M\dersetal. [46] (1984), 1960-1976, all stages Mandell etal. [43] (1985), 1969-1980, stage I Nori [17] (1987), 1969-1979, stage I Greven and Olds [66] (1987), 1970-1982, stages I and II Curran et.al. [59] (1988),* 1970-1985, all stages Kuten etal. [61] (1989),* 1959-1986, all stages Vavra etal. [51] (1993), 1973-1987, stage l-lll Elliott etal. [52] (1994),* 1964-1985, stages I and II

42 12 18 18 55 17 40 27

3(0 10

Searsetal. [60] (1994),* 1973-1991, all stages Ladner, UHW Freiburg (1995),* 1969-1990, all stages

45 52

7 11

226

5

Weighted mean, publications with * only

3-10 5 4.8

24 40 50 33 31 40 54 (3a) 23 10(10a) 44 56 40(10a) 41


primary therapy because, when looking at the 5-year survival rate after the diagnosis of distant metastasis, it goes down to 21% (at 10 years, 15%). These results also indicate that, in the majority of isolated vaginal recurrence cases, cure can be achieved by consequent brachytherapy and/or surgery. There is no reason for fatalism for patients suffering recurrent endometrial cancer.

23.2*8

Primary irradiation

For patients who are inoperable, for whatever reason, radiotherapy should be individualized. However, there are, today, few patients, whether due to age or to medical disorder, who should be considered inoperable. The mean ages of patients in various publications addressing this problem were68.5years [68],68years [69] and70years [70]. A comparison of 5-year survival data reported in the literature is difficult, because of patient selection, differences in technique and dosage, and inexact staging. In women who undergo combined brachytherapy and external-beam irradiation, the 5-year survival rates are now reported to range from 50% to 88% for stage I tumors and between 35% and 60% for stage II tumors; when all stages are combined, the 5-year survival rate averages about 55% (Table 23.3). A breakdown of the Freiburg results is given in Table 23.4. For patients undergoing primary irradiation, mortality rates after therapy due to intercurrent disease range between 36% and 60% [8,21,29,71,80,82]. These reports demonstrate the need to evaluate correct survival data [10,21,29,82]. 23*2.9

Recurrent disease

The published rates of pelvic recurrences and distant metastases after primary irradiation cover a wide range. According to Glassburn et al. [36], de Vita et al. [42], and Pernot et al. [21], who summarized the literature, disease

Table 233 The published 5-year survival rates following primary radiotherapy for stage I and stage II disease and for all stages

Stage I

Varietal. [71] Sorbertfl/. [73] Kucera ero/. [19,75] Rouaneteffl/. [69] Kupelianeffl/. [68] Petereiteffl/. [77] Ladnerefo/. (1996)

Iridium Cobalt

57 47 67 58

87(stagel-ll) 69 (3 years) 71 (see Table 23.4)

Stage II Grigsby et al. [72]

Taghianeffl/. [74] Booth by efo/. [76] Kucera [19,75] Ladnerefo/. (1996) All stages Taghianefo/. [74] Onnlsetal. [78] Pernot etal. [21] Vahrson[10] Rouanetefo/. [69] Rotte [79] Lad neretal. (1996)

71

Radium

56 36 47

Iridium Iridium

58 (see Table 23.4)

Cesium

52

Iridium

57 55 62 58 72

Iridium

55 (see Table 23.4)

relapses ranged from 8% to 25% for stage I and II disease: Boothby etal. [76], 19%, stage II; Kucera etal. [75], 12%; Huguenin etal [4], 19%; Kupelian etal. [68], 14%; Rouanet et al. [69] (for all stages), 31%. The rate of distant metastases was about 30-35%. Because of the high frequency of recurrent disease, several authors consider a higher total dose of irradiation or a higher number of fractions should be considered in an attempt to improve the outcome [19,75].

Table 23.4 Five-year and 10-year survival rates after primary irradiation with high voltage (HV) irradiation and/or brachytherapy (BT) in the FIGO Stages I-IV. UHW Freiburg, Germany, 1969-1990 (15% of all patients, 392/2530)

I

BT + HV BTonly

47 202

71.4 55.8

66.4 31.2

II

BT + HV BTonly

12 60

58.3 51.2

38.9 31.6

III

BT + HV BTonly

38 7

21.1 0

14.0 0

IV

BT+HV BTonly

10 5

30.0 0

30 0

I-IV

BT+HV BTonly

82 312

55.1 49.5

45.4 28.9

Conclusion 339

23.2*10

Complications

Fistulas involving the rectum or bladder, ureteric stricture, vaginal necrosis or stenosis, and contracted bladder are reported to affect from 3% to 19% of patients (Table 23.5). 23.2.11

Prognostic factors

Recently, we performed a retrospective analysis of all 2533 patients treated for endometrial carcinoma at the Freiburg University Hospital from 1969 until 1990 in order to identify risk factors for survival, recurrence, and adjuvant radiotherapy. Based on a profile of risk factors, patients were classified as either low risk (adenocarcinomas in FIGO stage la with grading 1 or 2, stage Ib only with grading 1) or high risk (all tumors with grading 3 or higher than Ib G2 and all non-adenocarcinomas) in an approach similar to that of the study of Shumsky et al (1997) [86]. The median follow-up for our patients was 12 years. In the Freiburg patients, we found surgical stage, grade, and patient age to be significant predictors (p 70, no involvement of corpus callosum, and maximum tumor diameter < 6 cm. Brachytherapy was given with one or more parallel catheters of temporary high-activity iodine-125 seeds. Median survival for the implant group was 13.8 months, compared to 13.2 for the no-implant group, which was not a significant improvement [26]. Re-operation was performed in 31% of the implant group and in 33% of the no-implant group. In both randomized studies, as in most retrospective series, patients who underwent a reoperation for a recurrence and/or necrosis after brachytherapy did significantly better than those without re-operation [15,21,22,25,26]. Other factors that improved survival were young age, high performance status, and smaller tumor size. Patients under the age of 30 particularly had an improved survival [22,27]. The pattern of recurrence and toxicity after interstitial boost treatment is an interesting secondary endpoint. Even after a combined interstitial and external dose of 100 Gy or more, recurrences after brachytherapy occurred in about 90% at the primary site [26,28-30]. A few studies reported lower local recurrence rates, but still about 70% [31,32]. However, the pattern of recurrence has changed. Distant relapses within the central nervous system are described in 22-28% of interstitially treated patients with a glioblastoma multiforme [28,32,33] compared to about 10% after external irradiation only [4]. In the randomized study there was a higher incidence of multifocal recurrences in the implant arm [26]. Studies from the Boston group described a higher incidence of marginal recurrences (37%), with only 35% failing within the brachytherapy volume [33]. However, it remains difficult to distinguish radiologically between marginal and local treatment failures. Smaller tumors (< 25 cm3) and 'adequate' implants were shown to have a higher local control rate [28,31,32]. The higher rate of marginal and distant relapses that occur when local treatment is improved confirms the fact that glioblastomas have a diffuse and widespread growth pattern. A dose-response relationship was demonstrated by Sneed et al., but interstitial doses of more than 50 Gy were also related to increased risk of life-threat-

ening necrosis [34]. Sneed recommended a conformal interstitial dose of 45-50 Gy in conjunction with conventional external-beam radiotherapy. The acute toxicity of brachytherapy in brain tumors is low. Overall toxicity of stereotactic management in midline brain lesions was found to be 4.2% [35]. The risk of arterial bleeding caused by the implantation of catheters is 0-2% [20,21,26,30] and infections are also rare. Late toxicity, however, is a clinical problem. Necrosis leading to a re-operation is a major problem in all series. We think that after doses of more than 100 Gy, with much higher doses in the center of the implant volume, necrosis can be viewed as integral to this procedure and not as a complication. The described incidences of re-operations of 35-64% [26,28,33] can be considered as an underestimation of the risk for brain necrosis because some of the patients do not live long enough to develop necrosis and others are in too bad a condition for re-operation. Median time to re-operation was about 40-50 weeks [21,28]. Apart from necrosis, histology after re-operation also showed, in most cases, vital tumor cells [28,31], confirming the fact that glioblastoma cells are highly radioresistant. Bernstein et al. reported severe vascular occlusion in 4% of their implant group [36]. In our series in the Academisch Medisch Centrum, Amsterdam (AMC), three out of 21 patients developed a sudden palsy 6-12 months after brachytherapy, mimicking a cerebrovascular accident within the implant volume [30]. The overall complication rate, excluding re-operation for necrosis, was about 25% in the randomized series, which is in the range of other series [10,24,30]. The effect of brachytherapy on quality of life should be an important endpoint. Gutin et al. described a continuing dependency on corticosteroids to combat the edema of focal radiation necrosis, which caused the reduction in mean KPS in their series [21]. In 13 patients from the same group who survived more than 3 years, mean Karnofsky had decreased from 95 at the time of brachytherapy to 75 at the time of last follow-up [28]. In the only published randomized trial, there was a significant increase in dexamethasone dosage for the implant group, but performance status did not differ between the implant and no-implant groups [26].

2633

Low-grade tumors

There are no randomized trials of brachytherapy for low-grade or benign brain tumors. The largest retrospective series comes from Freiburg in Germany, describing 455 patients with inoperable (often deepseated) low-grade tumors treated with temporary or permanent interstitial iodine-125 [37]. Selection criteria were signs of tumor progression, circumscribed tumors not exceeding 5 cm, KPS > 70, and no corpus callosum infiltration. Dose rates of preferably < 10 cGy h-1 were

References 377

given up to reference doses of 60-100 Gy to the outer rim of the tumor. The 5-years survival rates for pilocytic astrocytomas, grade II astrocytomas, oligoastrocytomas, oligodendrogliomas, and gemistocytic astrocytomas were, respectively, 85%, 61%, 49%, 50%, and 32%. These results are comparable with the survival data of the European Organization for Research and Treatment of Cancer (EORTC) study [38], taking into account the more favorable prognostic factors of the implanted group (smaller tumors, good performance). Radiogenic complications were observed in 39 out of 515 patients at the same institute. The most important risk factor was the volume of the 200 cGy isodose [39]. Good local responses were described with LDR implants in inoperable brainstem gliomas [40]. Brachytherapy can be considered as a treatment option for progressive, small, and inoperable low-grade gliomas.

Perez and L.W. Brady. Philadelphia, Lippincott-Raven, 777-828. 2. Walker, M.D., Alexander, E.Jr, Hunt, VJ.E.etal.(1978) Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas.J Neurosurg., 49,333-43. 3. Walker, M.D., Strike, T.A. and Sheline, G.E. (1979) An analysis of dose-effect relationship in the radiotherapy of malignant gliomas. Int.J. Radiat. Oncol. Biol. Phys., 5, 1725-31. 4. Wallner, K.E., Galicich, J.H., Krol, G., Arbit, E. and Malkin, M.G. (1989) Patterns of failure following treatment for glioblastoma multiforme and anaplastic astrocytoma. InLJ. Radiat. Oncol. Biol. Phys., 16,1405-9. 5. Salazar, O.M., Rubin, P., Feldstein, M.L and Pizzutiello, R. (1979) High dose radiation treatment of malignant gliomas; final report. Int.J. Radiat. Oncol. Biol. Phys., 5, 1733^0. 6. Sheline, G.E., Wara, W.M. and Smith, V. (1980) Therapeutic irradiation and brain injury. Int.J. Radiat. Oncol. Biol.

26.4

FURTHER DEVELOPMENTS

To further improve local tumor control in glioblastoma multiforme, some centers started to combine interstitial radiation with interstitial hyperthermia, using the same catheters. A randomized trial comparing brachytherapy boost alone versus brachytherapy boost plus interstitial hyperthermia in patients with newly diagnosed glioblastoma multiforme demonstrated a small but significant improvement in median survival of 9 weeks for the hyperthermia group [41]. Further technical developments can improve the level, homogeneity, volume, and control of the temperature in the target volume and thus could improve the clinical results [42]. A phase I-II study is ongoing in the AMC, Amsterdam, with this new technique for newly diagnosed glioblastoma multiforme patients. Dose escalation by focused stereotactic external radiation (radiosurgery) has become available and the advantages in dose distribution with this technique can be compared with brachytherapy. The first clinical comparisons between radiosurgery and brachytherapy in newly diagnosed and recurrent brain tumors resulted in a similar survival for both treatment options [43,44]. Radiosurgery has the advantage of being an outpatient, non-invasive therapy, with the possibility of fractionation. A phase III trial is being conducted in Europe randomizing between conventional radiotherapy with or without a stereotactic external boost in newly diagnosed, selected glioblastoma multiforme patients. REFERENCES

Phys., 6,1215-28. 7. Battermann,J.J.(1980) Fast neutron therapy for advanced brain tumours. Int.J. Radiat. Oncol. Biol. Phys., 6(3), 333-5. 8. Mundiger, F. and Weigel, K. (1984) Long-term results of stereotactic interstitial curietherapy. Acta Neurochir., 33 (Suppl.), 367-71. 9. Willis, B.K., Heilbrun, M.P., Sapozink, M.D. et al. (1988) Stereotactic interstitial brachytherapy of malignant astrocytomas with remarks on postimplantation computed tomographic appearance. Neurosurg., 23, 348-54. 10. Salcman, M., Sewchand, W., Amin, P.P. and Bellis, E.H. (1986) Technique and preliminary results of interstitial irradiation for primary brain tumours.J Neurooncol., 4, 141-9. 11. Rostomily, R.C., Halligan, J.B., Keles, G.E., Spence, A.M. and Berger, M.S. (1993) Management of adult recurrent supratentorial gliomas. Neurosurgery, 3,219-52. 12. Harsh, G.R., Levin, V.A., Gutin, P.H., Seager, M., Silver, P. and Wilson, C.B. (1987) Reoperation for recurrent glioblastoma and anaplastic astrocytoma. Neurosurgery, 21,615-21. 13. Dirks, P., Bernstein, M., Muller, P.J. and Tucker, W.S. (1993) The value of reoperation for glioblastoma. Can.J. Surg., 36,271-5. 14. Leibel, S.A., Gutin, P.H., Wara, W.M. et al. (1989) Survival and quality of life after interstitial implantation of removable high-activity iodine-125 sources for the treatment of patients with recurrent malignant gliomas. Int.]. Radiat. Oncol. Biol. Phys., 17,1129-39. 15. Halligan, J.B., Stelzer, K.J., Rostomily, R.C., Spence, A.M., Griffin, T.W. and Berger, M.S. (1996) Operation and permanent low activity 125I brachytherapy for recurrent high-grade astrocytomas. Int.J. Radiat. Oncol. Biol. Phys.,

1. Wara, W.M., Bauman, G.S., Sneed, P.K., Larson, DA and Karlsson, U.L (1997) Brain, brain stem and cerebellum. In Principles and Practise of Radiation Oncology, ed. C.A.

35, 541-7. 16. Bernstein, M., Laperriere, N., Glen, J., Leung, P., Thomason, C.and Landon,A.E. (1994) Brachytherapy for

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31. Schupak, K., Malkin, M., Anderson, L, Arbit, E., Lindsley, K. and Leibel, S. (1995) The relationship between the technical accuracy of stereotactic interstitial implantation for high grade gliomas and the pattern of tumour recurrence. Int.J. Radiat. Oncol. Biol. Phys., 32, 1167-76. 32. Loeffler, J.S., Alexander, E., Hochberg, f.H.etal.(1990) Clinical patterns of failure following stereotactic interstitial irradiation for malignant gliomas. Int. J. Radiat. Oncol. Biol. Phys., 19,1455-62. 33. Wen, P. Y., Alexander, E., Black, P.M. et al. (1994) Long term results of stereotactic brachytherapy used in the initial treatment of patients with glioblastomas. Cancer, 73, 3029-36. 34. Sneed, P.K., Lamborn, K.R., Larson, D.A. et al. (1996) Demonstration of brachytherapy boost dose-response relationships in glioblastoma multiforme. IntJ. Radiat. Oncol. Biol. Phys., 35,37-44. 35. Zamorano, L, Ausman, J.I., Chorni, D. and Dujovny, M. (1992) Stereotactic management of midline brain lesions. Stereotact. Funct. Neurosurg., 59,142-50. 36. Bernstein, M., Lumley, M., Davidson, G., Laperriere, N. and Leung, P. (1993) Intracranial arterial occlusion associated with high-activity iodine-125 brachytherapy for glioblastoma.y. Neurooncol., 17,253-60. 37. Kreth, F.W., Faist, M., Warnke, PC., Rossner, R., Volk, B. and Ostertag, C.B. (1995) Interstitial radiosurgery of lowgrade gliomas. J. Neurosurg., 82,418-29. 38. Karim, A.B.M.F., Maat, B., Hatlevoll, R. et al. (1996) A randomised trial on dose-response in radiation therapy of low-grade cerebral glioma: European Organization for Research and Treatment of Cancer (EORTC) Study 22844. IntJ. Radiat. Oncol. Biol. Phys., 36, 549-56. 39. Kreth, F.W., Faist, M., Rossner, R., Birg, W., Volk, B. and Ostertag, C.B. (1997) The risk of interstitial radiotherapy of low-grade gliomas. Radiother. Oncol., 43,253-60. 40. Mundinger, F., Braus, D.F., Krauss, J.K. and Birg, W. (1991) Long-term outcome of 89 low-grade brain-stem gliomas after interstitial radiation therapy./ Neurosurgery, 75, 740-6. 41. Sneed, P.K.,Stauffer, PR., McDermott, M.W.etal.(1998) Survival benefit of hyperthermia in a prospective randomised trial of brachytherapy boost ± hyperthermia for glioblastoma multiforme. IntJ. Radiat Oncol. Biol. Phys., 40,287-95. 42. Crezee, J., Kaatee, R.S.J.P., van der Koijk, J.F. and LagendijkJ.J.W. (1999) Spatial steering with quadruple electrodes in 27 MHz capacitively coupled interstitial hyperthermia. IntJ. Hyperthermia, 15,145-56. 43. Stea, B., Rossman, K., KittelsonJ. et al.(1994) A comparison of survival between radiosurgery and stereotactic implants for malignant astrocytomas. Acta Neurochir., 62,47-54. 44. Shrieve, D.C., Alexander, E., Wen, P.Y. et al. (1995) Comparison of stereotactic radiosurgery and brachytherapy in the treatment of recurrent glioblastoma multiforme. Neurosurgery, 36,275-82.

27 Interstitial brachytherapy in the treatment of carcinoma of the cervix A.M.NISARSYEDANDAJMELA. PUTHAWALA

27.1

INTRODUCTION

It is estimated that approximately 16000 new cases of invasive carcinoma of the cervix were being diagnosed in the United States in 1996, with an estimated 4900 deaths as a result of cervical cancer. The death rate per 100 000 population due to cervical cancer decreased by almost 50% from 1960 to 1990. The relative 5-year survival improved from 58% in 1960 to 69% in 1989 among whites, and from 47% in 1960 to 57% in 1989 among blacks [ 1 ]. The prognosis for patients with cervical cancer mainly depends upon their age, the clinical stage, nodal status, tumor volume, and lymphovascular invasion [2-5]. The overall 5-year survival in patients with stage I and IIA disease is 85-90% [6-9], but only 30-50% with stage III disease. As the tumor volume increases, so does the risk of nodal metastases with poor prognosis. The risk of pelvic recurrence is 8-10% in patients with stage I and IIA disease, as compared to 45-50% in patients with stage III disease [10,11]. Lociano et al [12] reported, from the Patterns of Care Study, an increased risk of in-field failure and poor survival with increasing tumor bulk within stage. Among 1558 patients treated between 1973 and 1978, Perez et al. [13] reported that the tumor size as a single variable was directly related to pelvic failure rate and inversely related to disease-free survival. Lowrey et al. [14] found that tumor size was a

strong independent predictor of pelvic control, distant relapse, and disease-free survival. Although surgery or primary irradiation, or a combination of both, yields 70-90% cure rates in patients with stage I and IIA disease; in locally advanced stage IIB, III, and IVA carcinomas, which are surgically unrespectable, external irradiation with conventional intracavitary application fails to provide an adequate dose to the target volume without extensive bladder and rectal doses. Waterman et al [15] in 1947 and Prempree and Scott [16] in 1978, reported transvaginal interstitial radium needle implant technique in the treatment of cancer of the cervix stage IIIB, with 31% 5-year survival and 78% loco-regional control, respectively. This technique had the disadvantage of excessive exposure to personnel and higher complication rates. We have reported an afterloading technique of interstitial-intracavitary implants using the 'Syed-Neblett' template in the treatment of carcinoma of the cervix [17-20] 27.2

PRETREATMENT WORK-UP

The following is an optimal work-up to determine the histology, tumor grading, volume, local tumor invasion, lymphovascular invasion, staging, etc., for designing appropriate treatment. 1. History and physical examination.

380 Interstitial brachytherapy in the treatment of carcinoma of the cervix

2. Pelvic examination, cystoscopic and proctosigmoidoscopic examination, preferably under anesthesia. 3. Complete blood count (CBC), liver function tests, and serum electrolytes; additionally, a human immunodeficiency virus (HIV) test for patients younger than 25 years of age. 4. Chest X-ray. 5. Intravenous pyelogram and/or computed tomographic (CT) scan of the abdomen and pelvis. 6. Biopsy of cervical tumor. 7. Bipedal lymphangiography and/or retroperitoneal pelvic and para-aortic lymph adenectomy, only for patients on specific protocols.

273 TECHNIQUE The interstitial-intracavitary implant technique utilizes an intracavitary tandem (whenever possible), as in conventional intracavitary applications, but the conventional intravaginal ovoids have been replaced with interstitial ovoids, i.e., transperineally implanted multiple guide needles through the paravaginal and parametrial tissues [17-20]. The interstitial-intracavitary Syed-Neblett applicator consists of a perineal template, vaginal obturator, 17-gauge hollow guide needles, and a tandem (Figure 27.1). The template is made of silicone and has a 2-cm diameter central hole to accommodate the vaginal obturator, and 34 holes drilled 1 cm apart in concentric circles to accommodate the guide needles. The vaginal obturators are 2 cm in diameter and have three different lengths, 12, 15, and 18 cm. The vaginal obturator has a central tunnel to accommodate a tandem and six longitudinal grooves on the surface for guide needles, and an embedded screw at its distal end to secure the tandem. The guide needles are 17 gauge and 20 cm in length. Each needle has the proximal end tapered and closed for easy penetration of the skin and tissues, and a met al ring close to the distal end to prevent

Figure 27.1 Assembled Syed-Neblett applicator.

it from sliding through the template and being left in the tissues when the implant is removed. The pre-implant preparation of the patient is the same as for the conventional intracavitary procedures, i.e., nothing by mouth after midnight and a Fleet's enema on the morning of the procedure. The procedure is performed either under general anesthesia or, more frequently and preferably, under epidural block so that the patients can control the pain following the procedure themselves. The patient is placed in the lithotomy position and an abdominal-pelvic examination is performed to determine the size and extent of the residual tumor and/or metastases, and any anatomical distortions. A proctosigmoidoscopic examination is performed to evaluate any abnormalities and radiation reaction, and also to clean out the feces from the rectum. The perineum and vagina are prepped with Betadine solution and the area is draped as for any surgical procedure. A Foley catheter is inserted into the bladder and the balloon is filled with 7 ml of Hypaque for X-ray localization films. The cervix and vagina are visualized with a vaginal speculum and two gold marker seeds are implanted into the cervix at the two and eight o'clock positions, and another at the lower end of the vaginal extension of the tumor, using an MD Anderson marker applicator. The endometrial canal is sounded and the length measured. The endocervical and endometrial canals are then dilated using Hank or Hegar dilators. A Fletcher or Henschke tandem is inserted into the endometrial canal with the met al flange fixed at the appropriate level according to the length of the endometrial canal. First, a guide needle (which has no guard ring at the distal end) is inserted into the remains of the anterior or posterior lip of the cervix to a depth of 3.5-4 cm. The distance between the distal end of the tandem and the first guide needle is measured, as this distance has to be maintained at the completion of the procedure. The vaginal obturator is inserted into the vagina while the tandem is threaded through its central canal. The template is held against the perineum and the vaginal obturator with the tandem, and the guide needle is threaded through its central hole. A rubber O-ring 2 cm in diameter is threaded over the vaginal obturator and placed into the groove on the template to secure the obturator and the first needle into position. An appropriate number of needles are implanted through the perineal template transperineally on both sides to encompass the initial extent of the tumor, i.e., 20 to 36 needles. The depth of insertion of these guide needles is the same as that of the first guide needle [20] (Figure 27.2). Lateral pressure is exerted on the needles between the perineum and the template while the needles are implanted to prevent central coning of the needles. The needles are dipped in alcohol for easy insertion through the template as alcohol acts as a lubricant for the template material.

Loading and unloading of radioactive sources 381

Figure 27.3 Implant completed for carcinoma of the cervix, stage IVA.

27.5 LOADING AND UNLOADING OF RADIOACTIVE SOURCES

Figure 27.2 Tandem, vaginal obturator, and perineal template are positioned (a), and guide needles are implanted (b).

The tandem is now pushed into the uterus and secured in position by tightening the screw at the distal end of the vaginal obturator with an Allen wrench. The template is secured in position by 2-0 silk sutures through the perineal skin and anterior two corners of the template. The space between the perineum and the template is filled with vaginal gauze, usually soaked in antibiotic cream or saline. A piece of vaginal gauze soaked in barium paste, or a rectal marker, is then inserted into the rectum for X-ray localization films (Figure 27.3).

27.4

LOCALIZATION FILMS

The tandem and the guide needles are loaded with inactive dummy sources, and anteroposterior and lateral orthogonal X-rays are obtained for computerized dose distribution plotting and volume analysis (Figure 27.4).

The tandem is loaded with radioactive cesium-137 and the parametrial guide needles with iridium-192 sources in the patient's room, with usual radiation precautions. The tandem is usually loaded with three sources of cesium-137 of 10 mg Ra-eq at the tip, and two sources of approximately 5 mg Ra-eq each distally, with appropriate spacers according to the length of the endometrial canal. Each of the guide needles is usually loaded with a plastic ribbon containing seven seeds of iridium-192 sources spaced 1 cm apart, having an activity of 0.3-0.45 mg Ra-eq each. The dose to the parametria can be optimized either by differential unloading of tandem and central guide needles or by using a higher activity of iridium-192 sources in the lateral guide needles. The dose can be optimized by utilizing 'remote afterloads' with a single iridium-192 source with their software and computer treatment planning systems for continuous low dose rate (LDR), pulse low dose rate (PDR), medium dose rate (MDR), or high dose rate (HDR). It is desirable to keep the dose rate to the medial parametria, ie, Point A, under 80 cGy h-1 in LDR treatment protocols to minimize complications. The radioactive cesium-137 and iridium-192 source ribbons are unloaded from the tandem and parametrial guide needles after the desired dose is delivered. The radioactive sources are placed in an appropriate lead container, or withdrawn by the remote afterloader, and taken to the isotope storage room.


The patient and the room are surveyed with the Victoreen survey meter for any radioactivity and the implant is then removed. The patient receives morphine

sulfate 10 mg intramuscularly 15 min before removal of the implant. The packing and the perineal sutures are removed. The screw holding the tandem to the vaginal obturator is withdrawn. The guide needles and tandem are removed in one motion by pulling the template from the perineum. The minimal bleeding from the perineum usually stops with the use of gentle pressure with gauze. The Foley catheter is removed and the patient is ambulatory within an hour.

27.6 TREATMENT PROTOCOL Patients receive external irradiation to the pelvic nodes, cervix, and vagina to 5040 cGy in 28 fractions, or 5000 cGy in 25 fractions, 180 or 200 cGy per fraction and five fractions per week, usually with the four-field technique. The rectum and bladder are shielded after 4000 cGy or 3960 cGy, using a midline block. The first interstitial-intracavitary implant is usually performed 1 week following completion of the external irradiation. The second application is performed 2 weeks following the first implant.

27.7 DISCUSSION In cervical cancer, the tumor size, even in the early stages of disease, has been found to be the most significant independent prognostic factor in multivariate analysis in several series [3,5,11].

Figure 27.4 (a) Anteroposterior X-ray localization film with isodose distribution plot overlaid, (b) Lateral X-ray localization film with isodose distribution plot overlaid.

Discussion 383

The treatment of choice for patients with locally advanced cervical cancer, i.e., stages IIB, III, and IVA, is radiation therapy with or without systemic chemotherapy and possible pelvic exenteration for patients with stage IVA disease. However, a combination of external and conventional intracavitary irradiation results in 40-50% pelvic failures, with significant complications. However, in most series, pelvic failures increased proportionately, i.e., 40-60%, with advanced stages of disease treatment with a combination of external and conventional intracavitary irradiation [11,21-23]. These treatment failures have essentially been due to large tumor volume and inadequate doses delivered by the intracavitary applicators. The radioactive sources in the tandem and ovoid could not deliver high enough doses to the target volume without excessive doses to the rectum and bladder. Anatomical distortions, even in early disease, i.e., narrowing of vagina, obliterated fornices, or inability to use tandem, can also cause failure to deliver adequate doses to the tumor volume. Waterman et al. [13,24] reported a 31% 5-year survival for patients with stage IIIB carcinoma of the cervix using a transvaginal interstitial radium needle implant technique. Prempree and Scott [16] reported 78% local tumor control using a similar technique in 1978 in stage IIIB carcinoma of the cervix. This technique of interstitial implant has several inherent technical and radiationexposure problems. We reported the technique of interstitial-intracavitary applicators using the 'Syed-Neblett' template with preliminary results in advanced carcinoma of the cervix in 1978 [17-20]. This technique involves the use of an intracavitary tandem and interstitial ovoids, i.e., multiple guide needles inserted into the parametria transperineally through the template. The technique is easily reproducible and provides excellent dose distribution to the tumor volume with relative sparing of critical structures, i.e., rectum and bladder.

The technique lends itself to HDR treatments utilizing commercially available remote afterloaders. Table 27.1 reflects the results during the evolution of the technique by several authors. Geddis et al. [25] reported, in 1983, a 14% rate of severe complications. These higher complications occurred during the evolution of the technique and have been mainly due to: (1) extensive necrotic tumors; (2) lack of availability of computer dosimetry, so the dose was based on milligram-hours, thus delivering much higher doses; (3) high dose rates, i.e., 120-200 cGy h~', to point A; and (4) point A received a total of 10000-14000 cGy by a combination of external and interstitial irradiation with higher doses to the rectum and bladder. Aristizabal et al. [26] reported 76% and 74% pelvic control in stages IIB and IIIB, respectively, and reduced the complication rate from 33% to 6% by modification in implant geometry and reduction of total milligram-hours. Ampuero et al. [27] reported 38% local recurrence and 29% complications in 24 patients with stage IIB and IIIB cervical cancer. Martinez et al [28] published results of 70 patients with locally advanced cervical carcinoma treated by transperineal implants using the Martinez Universal Perineal Implant Template (MUPIT) and achieved 66% local control and 14% severe complications. We reduced the dose rates and also the doses to the rectum and bladder by dose optimization and by differential unloading or using higher activity sources in the lateral parametrial needles (0.4-0.5 mg Ra-eq) and lower activity sources (0.2-0.3 mg Ra-eq) in the medial parametrial needles. The complication rate in subsequent series of patients has been reduced to 3% while maintaining the loco-regional control at 78% in stage IIB, III, and IVA carcinomas of the cervix (Tables 27.2 and 27.3). This finding is supported by others [33] who report that grade IV complication rates can be reduced from 14% to 3% when dose rates are reduced to below 70% cGy h~' without jeopardizing disease control rates.

Table 27.1 Interstitial irradiation (afterloading technique) for carcinoma of the cervix

Pitts and Waterman, 1940

IIIB

Prempree and Scott (1978) [16]

IIIB

110

49

31 (5-year)

13

60 (median 24 months)

8

78

Feder, Syed and Neblett (1978) [18] IIIB

Syed-Neblett

38

Geddisrto/. (1983) [25]

I, II, III, and IV

Syed-Neblett

84

71

Aristizabal et al. (1983)

Advanced Hand IIII

Syed-Neblett

21

85

Ampuero et al. (1983) [27]

IIBandlllB

Syed-Neblett

24

72

29

Aristizabaltfo/. (1985) [26]

Advanced Hand IIII

Syed-Neblett

118

75

21

Syed et al. (1986) [20]

I, II, III, and IV

Syed-Neblett

60

78

' Severe complications include severe proctitis, cystitis, rectovaginal fistula and/or vesicovaginal fistula.

14 58

58

35

3


Table 27.2 Carcinoma of the cervix, Syed-Neblett template: complications

IB IIAandllB IIIAandlllB IVA

6 23 26 0

0 2 1 0

0 2 1 0

0 0 2 0

0 0 0 0

All

60

3(5%)

3(5%)

2(3%) 0

RV, rectovaginal; W, vesicovaginal. Table 27.3 Carcinoma of the cervix, Syed-Neblett template: patterns of failure

IB IIAandllB IIIAandlllB IVA

6 23 26 5

0 2(+2Y 4 1

0 2 4 0

0 5 5 3

All

60

9 (1 5%)

6(10%)

13(22%)

'Two patients had only central recurrence; the other two failed only in the parametria.

cumulative dose of 7706 cGy at point A using a standard Fletcher-Suit technique. The interstitial group received a mean external dose of 5050 cGy and two interstitial implants using a transperitoneal Syed-Neblet template with a mean tumor dose of 2239 cGy and 1942 cGy for each application, respectively. No statistical difference could be detected in survival for stage III and IVA patients, but for stage II patients the intracavitary results were better, with more relapses in the interstitial group. However, the intracavitary group received a larger dose than the interstitial group (4608 versus 3504 radium milligram-hours equivalent) because a tandem was only used in 24% of the interstitial implants. Complications occurred in 21% of patients in each group. We have published the guidelines to be followed while employing the Syed-Neblett template technique to minimize the complications and maximize the local tumor control [20]. Bloss et al. [31] reported improvement in local control by utilizing the interstitial-intracavitary applicator with radiofrequency hyperthermia for radiopotentiation in patients with locally advanced and necrotic cervical cancers. The following are our conclusions and current indications for the use of interstitial-intracavitary applications:

1. Interstitial-intracavitary application using the SyedNeblett technique is safe and easily reproducible. The clinical outcome for HDR interstitial brachyther2. Loco-regional control of 70-77% can be achieved in apy in combination with external-beam irradiation [34] stage IIB and III cancers, with less than 4% severe has also reported satisfactory local and regional control complications. results. Six fractions were used of 5.5-6.0 Gy interstitial 3. This technique lends itself to manual, continuous therapy in combination with external-beam irradiation, LDR, pulse LDR, MDR, and HDR utilizing remote with central shielding, to a dose of 50 Gy to the pelvic afterloaders. side walls. The patients chosen had locally advanced dis4. Interstitial hyperthermia, i.e., radiofrequency or ease which precluded satisfactory tandem and ovoid microwave, can be utilized with the template insertion. This is perhaps an indication for interstitial technique for radiopotentiation. treatment that requires further consideration. 5. It is preferrable to use this technique in patients Hockel and Muller [29] modified the Syed-Neblett with: (a) cervical cancer stages IIB, III A, IIIB, and template for HDR brachytherapy of gynecological IVA, and in patients with stage IB and IIA with malignancies to reduce the rectal and bladder doses. The distorted anatomy, i.e., narrow vagina and template's assembly allows cystoscopic and rectoscopic obliterated fornices; (b) inability to use tandem in all control of needle positions. Wolkov et al. [30] constages; (c) carcinoma of the cervical stump; and (d) cluded, from the results of 14 patients with locally recurrent carcinoma of the cervix who have not advanced cervical cancer and review of the literature, been properly selected. that the loco-regional recurrence rate utilizing a transperineal template technique is approximately 50% less than the traditional intracavitary irradiation, with an REFERENCES overall complication rate of 18%, comparable to that reported by the Patterns of Care Study for similar stages 1. Parker, S.L., Tong, T., Bolden, S. and Wingo, P.A. (1996) of cervical cancer. Cancer statistics, 1996. CA Cancer J. Clin., 46, 5-10. Monk and colleagues [32] have reported different 2. International Federation of Gynecology and Obstetrics results. They carried out a retrospective assessment of (1991) Annual report on the results of treatment in the experience of two institutions, one of which used gynecological cancer. Int.J. Gynaecol. Obstet, 36(Suppl.), intracavitary brachytherapy in combination with 27-30. teletherapy and the other used interstitial brachytherapy 3. KovalicJ.J., Perez, C.A., Grigsby, P.W.etal.(1991) The with teletherapy. Patients from the two groups were simeffect of volume of disease in patients with carcinoma of ilarly matched. The intracavitary group received a mean

References 385

the uterine cervix. Int.J. Radial. Oncol. Biol. Phys., 21, 905-10. 4. White, CD., Morley, G.W. and Kumar, N.B. (1984) The prognostic significance of tumor emboli in lymphatic or vascular spaces of the cervical stroma in stage IB

17. Syed, A.M.N. and Feder, B.H. (1977) Technique of afterloading interestitial implants. Radiolog. Clin., 48, 458-75. 18. Feder, B.H., Syed, A.M.N. and Neblett, D.L (1978) Treatment of extensive carcinoma of the cervix with the 'transperineal parametrial butterfly:'a preliminary

squamous cell carcinoma of the cervix. Am.J. Obstet. Gynecol., 149,342-9. 5. VanBrommel, P., VanLindert, A., Kock, H.et al. (1987) A review of prognostic factors in early stage carcinoma of the cervix (FIGO IB and MA) and implications for treatment

report on the revival of Waterman's approach. Int. J. Radial Oncol. Biol. Phys., 4,735-42. 19. Syed, A.M.N. and Neblett, D.L. (1997) Interstitialintracavitary applicator in the management of gynecologic malignancy. Proceedings of the Pacific

strategy. Eur.J. Obstet. Gynecol. Reprod. Biol., 26,69-84.

Endocurietherapy Society, Winter Meeting, December

6. HorrotJ.C, PyneuxJ., Pourquier, H.et al. (1988)

5-7, Mazatlan, Mexico.

Radiotherapy alone in carcinoma of the intact uterine cervix according to GH Fletcher guidelines: a French cooperative study of 1383 cases. Int. J. Radial. Oncol. Biol.

20. Syed, A.M.N., Puthawala, A.A., Neblett, D.L et al. (1986) Transperineal interstitial-intracavitary 'Syed-Neblett' applicator in the treatment of carcinoma of the cervix.

Phys., 14,605-11.

Endocuriether./Hyperlherm. Oncol., 2,1-13.

7. Komaki, R., Brickner, T.J., Hanlon, A.L, Owen, J.B. and Hanks, G.E. (1995) Long-term results of treatment of cervical carcinoma in the United States in 1973,1978 and 1983: patterns of care study (PCS). Int.J. Radial. Oncol. Biol. Phys., 31,973-82. 8. Liebel, S., Bauer, M., Wasserman, T. et al. (1987)

21. Aristizabal, S.A., Giever, R.J., Duque, A. and Surwit, E. (1981) Invasive carcinoma of the cervix treated primarily with radiation therapy - University of Arizona experience. Ariz. Med., 38,613-16. 22.

Molina, J., Guillen, R., Rodriguez, E. and Velasquez, J.

Radiotherapy with or without meconidazole for patients

(1980) Radioterapia en cancer cervico uterino en etapa

with stage 1MB or stage IVA squamous cell carcinoma of

clinica 1MB (Spanish). ResulladosaCincoAnos GinecObstet Mex,47,419-31.

the uterine cervix: preliminary report of a Radiation Therapy Oncology Group randomized trial. Int.J. Radial. Oncol. Biol. Phys., 13, 541-9.

23.

9. Runowicz, C.D., Wadler, S., Rodriguez, L et al. (1989) Concomittant cisplatin and radiotherapy in locally advanced cervical carcinoma. Gynecol Oncol., 34,395-401. 10. Jampolis, S., Andras, J. and Fletcher, G.H. (1975) Analysis

Kapp, D.S., Fischer, D., Gutierrez, E. et al. (1983) Pretreatment prognostic factors in carcinoma of the uterine cervix: a multivariate analysis of the effects of age, stage, histology and blood counts on survival. InlJ. Radial Oncol. Biol. Phys., 9,445-55.

of sites and causes of failure of irradiation in invasive

24. Waterman, G.W. and Raphael, S.I. (1952) The role of interstitial radium therapy in the treatment of cancer of

squamous cell carcinoma of the intact uterine cervix. Radiology,115,681-5.

25. Geddis, D., Morrow, C.P., Klement, V., Schlaerth, J. and

the cervix uteri. Am. J. Roentgenol., 68, 58-62.

11. Montana, G.S., Martz, K.L and Hanks, G.E. (1991) Patterns

Nalick, R.H. (1983) Treatment of cervical carcinoma

and sites of failure in cervix cancer treated in the USA in 1978. IntJ. Radial Oncol. Biol. Phys., 20,87-93. 12. Lociano, R.M., Won, M. and Hanks, G.E. (1992) A reappraisal of the International Federation of Gynecology

employing a template for transperineal interstitia!192lr brachytherapy. Int.J. Radial Oncol. Biol. Phys., 9, 819-27. 26. Aristizabal, S.A., Valencia, A., Ocampo, G. and Surwit, E.A.

and Obstetrics staging system for cervical cancer: a study

(1985) Interstitial parametrial irradiation in cancer of the

of the patterns of care. CA Cancer J. Clin., 69,482-7.

cervix stage MB and 1MB: analysis of pelvic control and complications.Endocuriether./Hypertherm. Oncol.,'1,

13. Perez, C.A., Kurman, R.J., Stehman, F.B. et al. (1992) Uterine cervix. W.J. Huskins, C.A. Perez and R.C. Young. In Principles and Practice of Gynecologic Oncology, ed.

41-8. 27. Ampuero, F., Doss, L.L, Khan, M., Skipper, B. and Hilgers,

W.J. Huskins, C.A. Perez and R.C. Young, Philadelphia,

R.D. (1983) The Syed-Neblett interstitial template in

JBLippincott Co., 591-662. 14. Lowrey, G.C., Mendenhall, W.M. and Million, R.R. (1992) Stage IB or IIA,B carcinoma of the intact uterine cervix treated with irradiation: a multivariate analysis. Int.J. Radial Oncol. Biol. Phys., 24,205-10. 15. Waterman, G.W., Dileone, R. and Tracy, E. (1947) The use of long interstitial radium needles in the treatment of cancer of the cervix. Am. J. Roenlgenol., 57,671 -8. 16. Prempree, T. and Scott, R.M. (1978) Treatment of stage 1MB carcinoma of the cervix: improvement in local

locally advanced gynecological malignancies. InlJ. 28.

Radial Oncol. Biol. Phys., 9,1897-903. Martinez, A., Cox, R.S. and Edmundson, G.K. (1984) A multiple site perineal applicator (MUPIT) for treatment of prostate, anorectal and gynecologic malignancies. Int.J. Radial Oncol. Biol. Phys., 10,297-305.

29. Hockel, M. and Muller, T. (1994) A new perineal template assembly for high-dose rate interstitial brachytherapy of gynecologic malignancies. Radial Oncol., 31,262-4. 30. Wolkov, H.B., Manjat, J., Ordoridca, E. and Trelford, J.

control by radium needle implant to supplement the

(1987) Interstitial templates for locally advanced cervix

dosetotheparametria. Concur, 42,1105-13.

cancer. Med. Dosimetry, 12(1), 21-4.

386 Interstitial brachytherapy in the treatment of carcinoma of the cervix 31. Bloss, J.D., German, M.L, Syed, A.M.N. et al. (1992) Treatment of advanced carcinoma of the uterine cervix with interstitial radiotherapy and hyperthermia. Endocuriether./Hypertherm. Oncol., 8,145-50. 32. Monk, B.J., Tewari, K., Burger, R.A., Johnson, M.T., Montz, F.J. and Berman, M.L (1997) A comparison of intracavitary versus interstitial irradiation in the treatment of cervical cancer. Gynecol. Oncol., 67(3), 241-7.

33. Gupta, A.K., Vicini, F.A., Frazier, A.J. et al. (1999) Iridium192transperineal interstitial brachytherapy for locally advanced or recurrent gynaecological malignancies. Int. J. Radial Oncol. Biol. Phys., 43(5), 1055-60. 34. Demanes, D.J., Rodriguez, R.R. and Ewing, T.L (1999) High dose ratetransperineal interstitial brachytherapy for cervical cancer: high pelvic control and low complication rates: Int.J. Radial Oncol. Biol. Phys., 45(1), 105-12.

28 Interstitial brachytherapy in the treatment of carcinoma of the anorectum AJMELA. PUTHAWALAANDA.M. NISARSYED

28.1

INTRODUCTION

Surgery has played a dominant role in the definitive treatment of carcinoma of the lower rectum and anus, which has typically required abdominoperineal resection with permanent colostomy. However, over the past two decades a more conservative approach has been sought in an attempt to preserve the organ and its function. This is especially true for carcinoma of the anus, for which a combined modality, i.e., radiation therapy and systemic chemotherapy, has yielded up to 85% local control and preservation of the sphincter function in 65% of patients [1-5,22,23]. Newer surgical techniques, i.e., using an endorectal staple gun or pull-through procedure, as well as laser fulguration of the lower rectal cancers allow the preservation of the sphincter function [6-10]. The use of preoperative radiation therapy as well as chemotherapy has also facilitated organ preservation for borderline cases which would otherwise require abdominoperineal resection and permanent colostomy [11-13]. As early as 1915 Cade [14] reported the use of an intracavitary radium applicator for lower rectal cancers. In 1975, Papillon [15] reported a large series of patients who were treated successfully using endocavitary radiation for early-stage cancer of the lower rectum. In 1982, his updated results were published in the book entitled Rectal and Anal Cancers. Conservative Treatment by Irradiation: an Alternative to Radical Surgery [16]. For the past two decades we have used definitive radia-

tion therapy with a combination of external-beam irradiation and interstitial iridium-192 afterloading implants in the treatment of carcinoma of the anus and lower rectum in lieu of surgery [ 17,18]. Our experience is based on treating most of the patients with large bulky disease who were considered unresectable and/or inoperable because of advanced age and medical problems. We reported in 1982 the treatment results of 40 such individuals who underwent a combination of external-beam irradiation and interstitial iridium-192 implant [19]. Seventy percent of the patients achieved local tumor control with median follow-up of 36 months. Since then, at our institution, we have extended the use of definitive radiation therapy to include patients with relatively early stages of cancer as an alternative treatment to abdominoperineal resection. In 1987, Papillon and Montbarbon [20] reported a 3-year local control rate of 80% among 276 patients with epidermoid carcinoma of the anal canal treated by a combination of external-beam and interstitial iridium-192 implant radiation. Ninety percent of these patients had retained normal anal function. 28.2 PRETREATM ENT ASSESSM ENT AN D INVESTIGATIONS The pretreatment work-up should include complete history and physical examination, assessment of the regional lymph nodes, proctosigmoidoscopy, biopsy, as well as metastatic work-up including chest X-ray, liver

388 Interstitial brachytherapy in the treatment of carcinoma of the anorectum

function studies, complete blood count, urinalysis, coagulation profile, and serum human immunovirus. Transanorectal ultrasonography may be useful to evaluate the thickness of the lesion and penetration of any pelvic organs. Computer tomographic (CT) and magnetic resonance imaging (MRI) may be useful in some cases.

283

TREATMENT PROTOCOL

For epidermoid carcinoma of the anal canal, if there is no contraindication for systemic chemotherapy, these patients should first be treated with a combination of external-beam irradiation and continuous 5-fluorouracil intravenous infusion for 3-5 days, starting with the first day of external irradiation, with or without mitomycin-C or Cisplatin. All patients, except patients with early stage Tl tumors of the anorectum, receive a minimum dose of 4500 cGy delivered on megavoltage unit using anteroposterior (AP) and posteroanterior (PA) parallel opposing ports to encompass the primary disease and the draining lymphatics, using 1.8-2 Gy per fraction, five fractions per week. Patients with recurrent tumors after definitive surgery who have not received either preoperative or postoperative adjuvant radiation therapy should also be treated with external irradiation as above.

28.4

INTERSTITIAL BRACHYTHERAPY

The patient should have at least a 2-3-week rest period after completion of external-beam irradiation. One or two applications of interstitial brachytherapy may be required, depending upon the bulk of the original lesion. Each implant application may deliver a total tumor dose of 15-25 Gy over 30-60 h. Preferable dose rate for the anorectal implant is 0.4-0.5 Gy h'1. If two implants are planned, then the interval between implants should be at least 3-4 weeks. The implants are usually performed under general anesthesia; however, epidural or spinal anesthesia is preferable and the indwelling epidural catheter could also be left in for the duration of the implant for pain management.

28.5

EQUIPMENT

The equipment includes the following: Syed-Neblett disposable rectal template (Figure 28.1), a set of 15-20 cm long 17-gauge, hollow, stainless-steel needle guides, number 36 rectal tube or, preferably, plastic chest tube, marking pen, ruler, non-radioactive gold marker seeds, wire stylette, one 20 cm long 17-gauge open needle for marking seed insertion, 1-0 silk suture with non-cutting Gl needle, 2-inch roller gauze, 5 ml of Hypaque, triple sulfa cream, and Foley catheter 16 French, as well as alcohol to soak the template and to lubricate the guide

Figure 28.1 Syed-Neblett disposable rectal template (right) and classic (multiple use) rectal template (left).

needles so they can be easily inserted through the template (the needles are locked into position in the template after complete evaporation of alcohol). If the non-disposable template is used, then Allen-head screws should be loosened to allow the needles to pass through the template. After insertion of all the needles, screws should be tightened to fix the needles in place [13]. 28.6 INTERSTITIAL BRACHYTHERAPY TECHNIQUE After induction of satisfactory anesthesia, the patient is placed in the lithotomy position. The abdomen and perineum are prepped and draped in the usual fashion. The patient is then catheterized with a Foley catheter with the bulb inflated with 5 ml of Hypaque for localization of the bladder. The Foley catheter should be attached to the drainage tube and to the collecting bag. For male patients, the scrotum and penis should be pulled up with gauze and should be held by the abdominal drape with an Alice clamp. Prior to prepping and draping of the patient, a proctosigmoidoscopy should be carried out to ensure the satisfactory evacuation of the rectosigmoid colon and, more importantly, to register any undue reactions to the previously given radiation, as well as to locate the tumor and to take the measurements, i.e., extent of the tumor along the longitudinal axis in relation to the anal verge as well as circumferential involvement along the lumen. A bimanual examination should also be carried out and the tumor location should be marked on the perianal skin in relation to its circumferencial involvement (Figure 28.2). Gold marker seeds are then inserted transperineally with the finger in the rectum to define the superior-most and inferior-most extent of the palpable tumor as well as the lateral-most extent of the tumor. Usually, four marker seeds are implanted to help define the tumor volume on the radiographs. The first guide needle is then inserted transperineally through the perianal skin, guiding it with the finger in the rectum, keeping the needle just under the mucosa. The first needle should be placed approximately

Interstitial brachytherapy technique 389

at the center of the tumor on the longest extension of its vertical axis. The tip of the needle should be advanced at least 2-3 cm beyond the palpable lesion. The depth of insertion of this needle should then be measured from the perineal skin (Figure 28.2) and a Kelly clamp should be placed on the needle near the skin. The rectal tube or, preferably, a number 36 French plastic chest tube, is then

inserted in the rectum to a depth of at least 10-12 cm. A1 -0 silk suture should then be taken through the perianal skin and through the tube to secure the implant in place. The sutures should be placed opposite to the implant area so the suture will not be cut off while the needles are being inserted. A disposable Syed-Neblett rectal template is then placed against the perineum, letting the first guide needle pass through the appropriate hole in the innermost circle and the rectal tube pass through its large central hole (Figure 28.3). The template is then held against the perineum in a fixed position, and two or three more needles are inserted to a similar depth on the side of the perineal area where the tumor extension was marked on the skin earlier. In the second circle encompassing the circumference with a 1-cm margin on either side should be completed, i.e., six to nine guide needles, and in the third circle, again, six to eight needles are inserted to a similar depth through alternate holes. The needles should be dripping wet with alcohol to facilitate their passage through the template. 1-0 silk sutures are then taken through the perineal skin and the upper outer corner holes on the template to keep it in position. Two-inch roller gauze impregnated with triple sulfa cream is then applied lightly between the template and the perineal skin (Figure 28.4). The patient is then sent to the recovery room.

Figure 28.3 Plastic tube (No. 36 French) in rectum, and first guide needle through the template which is held against the perineum.

Figure 28.4 Template is sutured to the perineal skin after insertion of all required afterloading guide needles.

Figure 28.2 Tumor location is marked on the perineal skin. The first guide needle is placed with the finger in the anorectum. Total depth of insertion is measured from the anal verge.


Prior to starting the interstitial implant, it is recommended that the patient receives 1 or 2 g of a broadspectrum antibiotic intravenously, and antibiotics should be continued for the duration of the implant. AP and lateral orthogonal X-rays with dummy sources in all

guide needles are taken for computer dosimetry. The number of iridium-192 seeds to be loaded in each guide needle is decided in the operating room after taking the measurements, with usually a 2-3 cm margin given superiorly and inferiorly. If the tumor extends through the perianal skin, the sources are usually brought down beyond the skin; otherwise, the sources should be kept under the skin to avoid a brisk, moist skin reaction. The implant is then loaded with iridium-192 ribbons, either manually or using the remote afterloading device. The computerized isodose distribution on both the X and Z axes at 5-mm intervals is obtained. The X and Z axes are usually placed through the center of the implant. The isodose planes at X = 0 and Z - 0 are then directly overlaid on the AP and lateral orthogonal radiographs (Figure 28.5). The isodose line encompassing the tumor volume adequately is chosen as minimum dose rate [21]. The dose-volume histograms are also obtained (Figure 28.6). The duration of the implant is then calculated by dividing the total dose to be delivered by dose rate. At the completion of interstitial irradiation, the radioactive sources are removed, again either manually or by remote afterloading device. The sutures are removed from the perineal skin and the template is removed by pulling it away from the perineum so all the needles will be removed at once. Betadine solution is then applied to the skin and light pressure is exerted with dry gauze for a few minutes to stop the bleeding. The applicator, the patient, and the room should be checked with a Geiger counter to ensure that all sources have been removed and placed in the lead container. If the patient has no continuous epidural pain medication, intramuscular Demerol (meperidine hydrochloride), 50-100mg, should be given at least 10-15 min prior to removal of the implant. Figure 28.5 Anteroposterior (a) and lateral (b) orthogonal radiographs with computergenerated isodose distribution overlaid for dose calculation.

Results 391

Figure 28.6 Dose-volume histogram.

28.7

AFTERCARE

The patient should be advised to take sitz baths once or twice a day for the first week to 10 days. The patient may also need steroid cream or Cortifoam enema to help alleviate the pain and discomfort from ensuing proctitis. Usually, acute proctitis subsides in 2-3 weeks on conservative management.

tion of this treatment had extensive tumors (T3 or T4) or they were treated for recurrent cancer (Table 28.2). Local tumor response has been assessed on clinical examinations, including proctosigmoidoscopy and repeat biopsies, if indicated. Most lesions resolved 2-3 months after completion of this treatment. Occasionally, induration or mucosal thickening may persist for a long time at the site of the original tumor secondary to fibrosis. In the past, some of these patients had undergone repeated biopsies because of concern about persistent or recurrent tumor and had developed ulceration and necrosis. Most recurrences or persistent disease are clinically manifested by 12-18 months and, rarely, after 24 months following this treatment. Histologic grade and type had no significant impact on the rate of local tumor control. The overall complication rate has been 19.6% (Table 28.3). The most common complication of this treatment is rectal ulceration or necrosis. Tumor-associated necrosis usually resolves on conservative management if treatment is successful. Hyperbaric oxygen therapy is usually successful in patients who develop persistent ulceration and necrosis. It is advisable for these patients to undergo temporary Table 28.1 Anorectal carcinoma stage distribution

T1 T2 T3-4 Recurrent Total

28.8

15 50 38 60 163

RESULTS Table 28.2 Anorectal carcinoma local control at 3 years

One hundred and sixty-three patients with a diagnosis of carcinoma of the anorectum were treated between 1974 and 1992: 103 patients were treated for primary cancer and 60 patients were treated for recurrent cancer (Table 28.1); 132 patients had adenocarcinoma and 31 patients had squamous cell carcinoma. A cumulative local tumor control was achieved in 130 (80%) of 163 patients at 3 years of follow-up (Figure 28.7). Most patients who had either persistent or recurrent disease after comple-

n T2 T3-4 Recurrent

15/15(100%) 46/50 (92%) 30/38 (79%) 39/60 (65%)

Total

130/163(80%)

Table 28.3 Anorectal carcinoma complications

Rectal ulceration and necrosis Anal stricture and fibrosis (with or without incontinence) Hemorrhage Perianal infection or ischio-rectal abscess RectovaginaI fistula Total Figure 28.7 Cumulative local control. REC, recurrent.

19/163(11.7%) 7/163(4.3%) 2/163(1.2%) 3/163(1.8%) 1/163(0.6%) 32/163(19.6%)a

'24/163 (14.7%) patients required colostomy because of complications.


colostomy, and they should also have no evidence of persistent or recurrent disease proven on biopsy. Anal stricture and fibrosis with incontinence are rare complications and are often associated with circumferential implants. Twenty-four (14.7%) out of 163 patients required palliative colostomies following treatment because of persistent ulceration, necrosis, or anal stricture and tenesmus. Most of these patients had already been treated for extensive disease. This treatment-related complication rate can be minimized if patients are selected carefully who have limited disease which does not require more than half the circumference implant and active length of more than 7 cm. Salvage surgery is feasible for a substantial number of patients who may fail this treatment regimen. It often requires abdominoperineal resection with permanent colostomy. In our series, five (42%) out of 12 patients who failed this regimen were salvaged by abdominoperineal resection. The ideal lesions to be treated with definitive radiation therapy using a combination of external-beam irradiation and interstitial brachytherapy: (1) are located within 8 cm from the anal verge; (2) involve less than half the circumference of the lumen; (3) measure less than 3 cm in thickness and less than 6 cm in length; (4) have no complete fixation to the pelvic bones or visceral invasion; and (5) have no extensive ulceration.

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interstitial implant. Radiology, 128,199-203. 18. Syed, A.M.N. and Feder, B.H. (1977) Technique of afterloading interstitial implants. Radiol. Clin., 46,

2. Cummings, B.J., Thomas, G.M., Kean,T.J.ef al. (1982) Primary radiation therapy in the treatment of anal canal carcinoma. Dis. Colon Rectum, 15,778-82. 3. Nigro, N.D. (1984) An evaluation of combined therapy for squamous cell cancer of the anal canal. Dis. Colon

458-75. 19. Puthawala, A.A., Syed, A.M.N., Gates, T.C. and McNamara, C. (1982) Definitive treatment of extensive anorectal carcinoma by external and interstitial irradiation. Cancer, 50,1746-50.

Rectum, 27,763-6. 4. Sischy, B. (1985) The use of radiation therapy combined

20. Papillon, J. and Montbarbon, J.F. (1987) Epidermoid carcinoma of the anal canal: a series of 276 cases. Dis.

with chemotherapy in the management of squamous cell

Colon Rectum, 30,324-33.

carcinoma of the anus and marginally resectable adenocarcinoma of the rectum. Int.J. Radial Oncol. Biol. Phys.,! 1,1587-93. 5. John, M.J., Flam, M., Lovalvol, L.J.etal.(1987) Feasibility of non-surgical definitive management of anal canal carcinoma. Int.J. Radial Oncol. Biol. Phys., 13,299-303.

21. Neblett, D.L, Syed, A.M.N., Puthawala, A.A., Harrop, R., Frey, H.S. and Hogan, S.E. (1985) An interstitial implant technique evaluated by contiguous volume analysis. Endocuriether./Hypertherm. Oncol., 1,213-22. 22. Sandhu, A.P., Symonds, R.P., Robertson, A.G., Reed, N.S., McNee, S.G. and Paul, J. (1998) Interstitial iridium-192 implantation combined with external radiotherapy in

6. Bacon, H.E. (1956) Abdominoperineal proctosigmoidectomy with sphincter preservation: Sand 10

anal cancer: ten years experience. Int.J. Radial Oncol.

years after 'pull through' operation for cancer of the

Biol. Phys., 40(3), 575-81.

rectum.JAMA, 160,628-34. 7. Rich, T.A., Weiss, D.R., Mies, C. et al. (1985) Sphincter preservation in patients with low rectal cancer treated

23.

Broens, P., Van Limbergen, E., Penninckx, F. and Kerremans, R. (1998) Clinical and manometric effects of

with radiation therapy with or without local excision or

combined external beam irradiation and brachytherapy

fulguration. Radiology, 156, 527-31.

for anal cancer. Int.J. Colorectal Dis., 13(2), 68-72.

29 High dose-rate brachytherapy in the treatment of skin tumors CAJOSLINANDA. FLYNN

29.1

INTRODUCTION

Epidermal skin in fair-skinned people is particularly at risk of developing skin cancer. In recent times, the risk has greatly increased with changes in social habits such as increased exposure to sunlight [ 1,2]. The frequency of skin cancer approaches 10% of all cancers, depending upon the country and its ethnic population. The risk increases as age increases [3], the commonest age group affected being 60 years and older. The site and extent of the disease, the histology, and the medical fitness of the patient can determine the type of treatment used. Basal cell carcinomas (or rodent ulcers) most commonly affect the skin of the head and neck regions, remain localized, and require local radical treatment. Less commonly, rodent ulcers occur in sites other than around the head. Squamous cell carcinoma may also involve the skin of the head and neck region, but more commonly involve the skin over the dorsum of the hand, particularly when these areas are exposed to ultraviolet light over long periods [1,2]. Radiation therapy can be an effective and satisfactory treatment for the majority of cases of non-melanoma skin cancer. In a review of the literature, Halpern advised that, with efficient methods of dose fractionation and delivery of radiotherapy, skin cancers could be controlled in over 90% of cases treated [4]. He also advised that, in general, the cosmetic appearance and function are better preserved under most circumstances. How-

ever, other forms of treatment such as curettage and cautery are effective against small rodent ulcers in the majority of patients. Surgery may also be used, but this can cause disfigurement in larger lesions, although sometimes a combination of surgery and radiotherapy is indicated. The type of radiotherapy and method of application are often determined by their practicability and the risk of exposure to staff and other people. One method in use for many years involved surface treatment moulds loaded with radium-226 as the active material [5]. More recently, radium-226 has been replaced by cesium-127 or iridium-192. However, there remains the potential radiation hazard arising from preparation of the sources, the loading of the mould, and also from nursing the patient during treatment. Because of this, the use of manually preloaded surface moulds went out of fashion, and nowadays most treatment is given using either superficial X-rays or low-energy electrons [4]. However, when the treatment volume includes cartilage and tendons, where the superficial tissues are thin and overlie bone, or the treatment area is large, a case for using surface mould therapy can be made. This will particularly apply when the only alternative treatment is to use superficial X-ray therapy when the absorbed dose to bone will be greater than in muscle. With the advent of remotely controlled afterloading equipment, the potential radiation hazard can be virtually eliminated and the place for using a surface treatment mould needs further consideration. The purpose

394 High dose-rate brachytherapy in the treatment of skin tumors

of this chapter is to discuss the use of afterloaded treatment moulds rather than superficial X-rays or electrons for treating skin cancer, particularly with regard to high dose-rate (HDR) remotely afterloaded surface moulds. However, when indicated and for completeness, reference will be made to other brachytherapy systems. The authors' experience was originally gained with the use of surface mould therapy using sources of radium226, gold-198, cesium-127 or iridium-192 placed on individually made shells or wax blocks. The spatial distribution and quantity of the radioactive sources were determined by the Paterson-Parker Rules [5-7]. The amount of radioactive material depended on the size of the treatment area and the distance between the plane of the sources and the treated surface. For large treatment areas, considerable amounts of source activity were needed, with consequent restriction on the amount of time that could be spent positioning the device on the patient and on nursing and visitors' time spent with the patient. In particular, the technical staff who prepared the mould before application, and dismantled it after use, could be exposed to a significant radiation hazard. The use of a remote afterloading machine offered a possible solution to those difficulties [8], and subsequently other reports of this technique were published [9-11]. A recent literature search has shown that there continues to be an interest in the technique [13-20].

Figure 29.1

Percentage depth dose characteristics of a 40 mm

diameter surface mould (SM) at 10 mm and 30 mm treating distances (TD): curves SM 10 mm TD and SM 30 mm TD. For comparison, superficial X-rays of 2 mm aluminum half value layer (Al HVL) and 8 mm Al HVL at a focus-to-skin distance (FSD) of 150 mm are also shown: curves X-ray 80 kV and X-ray 140 kV. (Data from references [7] and [12].;

29.2 HIGH DOSE-RATE AFTERLOADING SYSTEMS One author (CAJ) described a suitable remotely controlled system in 1969 [9], which was also being developed by the second author (AF), in conjunction with Dr A.J. Ward, in another center (Cookridge Hospital, Leeds) at about this time. Both these treatment systems used an HDR cobalt-60 unit, the Cathetron, previously described [8]. However, the methods used are adaptable to any afterloading machine with suitable small sources and source delivery system. More recently, Selectron-LDR (low dose-rate), microSelectron-HDR, and pulsed doserate (PDR) machines have been adopted for use in afterloading surface moulds [13-15,17-20].

293

ABSORBED DOSE DISTRIBUTION

Due to the short source to skin distance, which is typically between 5 mm and 30 mm, a rapid fall-off in dose with depth from the skin surface of the applicator occurs. Figure 29.1 shows a typical depth dose profile for a source to skin distance of 10 mm and 30 mm, for a 40 mm diameter applicator. The curves shown are for radium-226, but are not substantially different for other isotopes in common use. Also, for comparison, depth

dose data for 150 mm focus-to-skin distance (FSD) superficial X-rays at 80 kV and 140 kV are shown, the data being taken from the British Journal of Radiology, Supplement 26 [12]. In the case of a surface mould, the reduction in dose with depth within the irradiated tissues is principally due to the increase in distance from the radiation source(s), and the relative effect of tissue attenuation and scatter is small. In contrast, absorption and scatter, depending upon the quality of the beam, will be more important for superficial X-rays. The net result is that for water (or muscle tissue) the depth dose characteristics of the two modalities are similar, despite the differences of photon energy and source to skin distance/FSD. However, for tissues of higher atomic number, such as cartilage and bone, the photoelectric effect will dominate in the case of superficial X-ray therapy, but not in the case of a surface mould when using an isotope emitting high-energy photons. When these tissues are included in the treatment volume, there will be a relatively greater absorption of energy for superficial X-rays than for a surface mould, which may lead to a greater absorbed dose than that prescribed. This, in turn, will increase the risk of severe late normal-tissue injury, which the higher energy radiation from a surface mould will largely avoid.

Mould production 395

29,4

SELECTION OF TREATMENT DISTANCE

depth of the tumor. The fall-off in dose from the skin surface is greatly affected by the treatment distance. Figure 29.1 shows that, for a treating distance of 10 mm, using cobalt-60, the percentage depth dose falls to 20% at 30 mm beneath the skin surface. This needs to be taken into consideration when prescribing treatment which, for skin tumors, has historically been prescribed to the skin surface. With the elimination of exposure risks to staff, it may be tempting to improve the dose homogeneity by increasing the treating distance to 20 mm or 30 mm. Care should be taken if this is intended, because the usual method of treatment delivery does not normally provide any form of collimation. While improved collimation can be achieved to some extent by surrounding the treatment area with appropriate lead shielding, this may produce practical problems because of the weight of lead required and the need to provide some sort of supporting structure.

As shown in Figure 29.1, the depth dose characteristics of a surface mould depend strongly on the treatment distance, a greater distance giving a higher relative depth dose. Before any part of the mould device is actually constructed, it is necessary to decide on the appropriate treating distance. This will depend mainly on the thickness of the tumor to be treated and the dose required at the deepest part of the target volume. Whilst it would normally be necessary to construct a full treatment plan for the mould when all of the parameters have been decided, it is useful initially to choose a treatment distance based on the information contained in the Paterson-Parker tables [7]. Although these tables are calculated for radium-226 sources, the depth doses that may be obtained from them are sufficiently accurate for this purpose when using other nuclides such as cobalt60, cesium-137, or iridium-192. The choice of treatment distance is a compromise between conflicting requirements, and usually a distance of 10 mm or 20 mm is chosen. A treatment distance of less than 10 mm may produce unacceptable dose variation on the skin surface if the latter has undulations that cannot be accurately followed by the source applicators. A treating distance greater than 20 mm may lead to long exposure times and to a wide penumbra effect outside the edges of the intended treatment area. This may result in a clinically meaningful dose to critical organs such as the eye. To some extent these effects can be overcome by suitable shielding at the edges of the mould, as illustrated in Figure 29.2 and discussed in references 9-11. An additional consideration is the thickness of the tumor. There is an approximate relationship between the diameter of a skin cancer and its thickness. Lesions that are up to 25 mm diameter are, in general, no more than 5-6 mm thick. This is an important relationship because a cancericidal dose will be necessary at the maximum

The first step in the production of a mould is to take a cast of the affected area. If a flat area is involved, the traditional plaster of Paris can be used. However, for more detail on an undulating surface it may be better to use one of the modern alginate impression materials. A close-fitting, transparent plastic shell is made from the cast, usually by vacuum forming. If the area to be treated is on a limb extremity, such as the dorsum of the hand, the shell can be attached to a baseplate to provide stability; otherwise, straps can be used to attach it to the patient. The area to be treated is marked on the skin and superimposed on the shell (Figure 29.3).

Figure 29.2 Cathetron HDR afterloading surface mould, showing lead shielding around the irradiated area.

Figure 29.3 HDR afterloading surface mould, with the area to be treated marked on the skin.

29.5 29.5*1

MOULD PRODUCTION Providing a cast


29.5.2

Disposition of sources

The proposed arrangement of the sources and dwell positions should be determined. Our usual procedure is to use the Paterson-Parker distribution rules as a guide to the arrangement of the source positions around the periphery of the treated area and, when necessary, in a line or series of parallel lines over the area itself. For some afterloading machines, the number and configuration of the source trains available are restricted. These may be used if the source train length matches the required treatment length; otherwise, a single active source can be stepwise positioned along the line of the treatment. With some current afterloading machines, the stepping source arrangement offers greater flexibility, providing for any active length that may be required, and allows the dose distribution to be optimized if required. This can be of particular value when irradiating an irregular surface or where the treatment area is not flat (Figure 29.4). 29.5.3

Applicator supports

Having decided on a provisional source(s) arrangement, the construction of the mould may be completed. On

our early moulds using the Cathetron machine, we used a Perspex frame to support the (then rigid) treatment catheters (Figure 29.5), but later we developed flexible catheters. These are now superseded by using 6-French bronchus-type catheters with the microSelectron, or similar. The catheters are supported by Perspex catheter supports of the appropriate height, attached to the surface of the shell. These supports have a hole drilled in them to accommodate the flexible catheters, as appropriate. They are of the correct height to provide the required treatment distance, allowing for the thickness of the shell material. The supports at the end of each catheter position contain a recess rather than a complete hole. This provides an end-stop to define the longitudinal position of the catheter and to prevent any catheter movement. It also ensures that the catheters are inserted in the correct position for treatment. In some cases, lead shielding is placed around the treated area to help to protect nearby critical organs, as already mentioned and illustrated in Figure 29.2. There are, of course, alternative methods of supporting the applicators, such as embedding them in a wax or acrylic sheet of the appropriate thickness.

29*5*4

Provisional treatment times

A provisional set of treatment times for the various source positions is then drawn up. This should be done by referring to appropriate data on the dose rate(s) and distribution(s) for the available source trains. For the microSelectron-HDR and other similar afterloaders, the calculation can be performed on the brachytherapy treatment planning system. The use of a dwell time optimization program may be considered to improve the dose homogeneity on the treated surface, but in practice we found this difficult to use as the position of the dose calculation points cannot easily be defined, particularly for a curved surface. For a small mould with only a few treatment applicators, we found it just as easy to adjust

Figure 29.4 MicroSelectron HDR afterloading surface mould, showing the source catheters (applicators) in parallel lines over the irradiated area. (Courtesy of Nucletron BV.)

Figure 29.5 Cathetron HDR afterloading mould, showing the catheter support Perspex frame.

Clinical practice 397

the dwell times empirically, in conjunction with dosimetry measurements, as described below.

29.5.5

Dosimetry measurement

The dosimetry should be checked before treatment is started by thermoluminescence dosimetry (TLD) or other suitable dosimetry system. Our own experience is with TLD. A number of thin sachets containing lithium fluoride crystals are taped to the underside of the shell on the treated surface, and the space beneath this is filled with a tissue-equivalent material. The mould is exposed according to the provisional treatment times, and the dose to the treated area is determined. A correction to the dose measured is made to allow for the thickness of the sachet, based on the depth dose characteristics as previously calculated. The treatment times are then adjusted as necessary. The dose distribution is regarded as being satisfactory if the range of doses measured is within ±10% of the mean. This is the range suggested in the Paterson-Parker Rules, which can often be improved on in practice.

29.6

CLINICAL PRACTICE

Most of our experience has been gained from treating patients who were diagnosed with basal cell carcinoma, squamous cell carcinoma, or intraepidermal carcinoma. However, a few cases of less common soft tissue sarcoma have been treated postoperatively, including a case of recurrent malignant melanoma in a young man and a primary malignant melanoma of the pinna in a geriatric patient. A variety of body sites were treated, including the scalp, dorsum of hand, chest, abdominal wall, and lower leg. The main constraint from a technical point of view has been that the treated area should not be so curved as to restrict the movement of the source train through the catheters. This restriction is less critical for current machines which use small stepping iridium-192 sources, such as the microSelectron-HDR; whereas, for machines for which the size of the radioactive source(s) is relatively large, the minimum radius of curvature will be restricted. One other constraint has been the need to restrict the radiation dose received by any critical normal tissue(s) adjacent to the target volume.

29.6.1

Dose fractionation schedules

For soft tissues, the fall-off in dose with distance below the skin surface is similar whether superficial X-rays or cobalt-60 treatment moulds are used. If a similar dose fractionation regime is used for HDR treatment moulds as for superficial X-rays, any difference in tissue effect(s) will be principally dependent on the radiation quality

alone. This is of particular importance where bone or cartilage underlies a tumor, when it is clearly advantageous to use high-quality radiation. In order to achieve a radiobiological effect in muscle similar to that used in time-established superficial X-ray treatment, the dose per fraction for cobalt-60 will need to be increased by about 10%. Compared to muscle, bone will absorb about four to five times more energy per gram from superficial X-rays as compared with cobalt-60, with obvious advantages in favor of cobalt-60. For many treatment situations, small treatment areas less than 3.0 cm in diameter should be restricted to a dose of 45 Gy in ten fractions. When treating areas larger than 3.0 cm diameter, increased fractionation is necessary if the risk of late normal-tissue damage is to be minimized. Among the situations in which careful consideration of the dose fractionation regime used is necessary, is treatment to areas with minimal subcutaneous thickness such as skin overlying the shin bone.

29.6.2

Dorsum of the hand and lower arm

The commonest tumor is an invasive squamous cell carcinoma. These tumors are more often seen in older patients who have already suffered skin changes due to chronic exposure to sunlight. The majority of lesions are flat and do not exceed 20 mm in diameter at presentation. Typical dose regimes are 45 Gy in ten fractions and 50 Gy in 15 fractions. Usually, a source to skin treating distance of 10 mm or 15 mm is suitable. Others have reported using a short-distance cobalt unit to give 55 Gy in 15 fractions over 3 weeks to fields less than 3.0 cm in diameter. They referred to lesions on the dorsum of the hand being radioresistant, with a higher recurrence rate compared to other sites. The skin overlying the treated area may become thin and atrophic. Such changes can be aggravated in a situation where skin damage is already present due to previous chronic exposure to sunlight. Problems may also arise in a patient who, following treatment, is exposed to a risk of traumatic skin injury. We have seen such a case in a sailor who suffered a skin laceration through the treated area 2-3 years following radiation which required plastic surgery. In the older patient with thin atrophic skin, increased fractionation is advisable and the alternative treatment by plastic surgery should be carefully considered. Occasionally, multiple lesions may be unsuitable for surgery or small-field radiotherapy. A technique using a large treatment field to deliver 60 Gy in 2.0-Gy fractions to an area covering more than half the circumference of the forearm has been described by Rudoltz and others [20]. They used a thermoplastic mould 5.0 mm thick with 22 silicone-rubber catheters longitudinally placed 20 mm apart. The given dose was prescribed to 8 mm depth in tissue, treatment being delivered using source


dwell positions at 1-cm intervals and the mould covered with a lead shield. The results were reported as satisfactory, the disadvantage being the extended treatment time and concern about radiation exposure to staff. This latter problem emphasizes the need to deliver treatment within a radiation-protected room, the purpose of lead shielding being to reduce whole-body irradiation to the patient.

29.63

Face and scalp

When treating sites in this area, it is important to pay particular attention to appropriate shielding of surrounding normal tissues. Treatment distances should be short in order to reduce the exposure time of the radioactive sources. If shielding cannot be easily provided, it is preferable to consider using electron-beam or photon-beam therapy. The areas most applicable to surface mould therapy are the forehead and temporal areas. Where areas are situated close to the hairline and because of the wide penumbra, the risk of alopecia is high and appropriate shielding should be used where possible.

29*6.4

Pinna

Carcinoma of the skin of the pinna will overlie cartilage and the benefits of high-energy photon radiation will particularly apply for the reasons discussed earlier. HDR afterloading using cesium-137, cobalt-60, or iridium192 is especially suitable. Treatment can be given using a single-plane applicator at a treatment distance of 10-20 mm (although the authors have found 15 mm to be the most practical distance) to a prescribed dose of 45-50 Gy in eight to ten fractions. The pinna is amenable to the protection of adjacent structures, which is important if hair loss is to be minimized. However, the use of radiation shielding of adjacent tissues may involve the practical problems of physically supporting a lead shielding block [10]. For thick lesions of the helix, a double-plane applicator can be used and planned according to the Parker-Paterson Rules, but the practicalities of protecting surrounding tissues may prove difficult.

29.6.5

Legs

In general, skin healing following radiation, particularly overlying the anterior tibia, is poor. Of 20 cases treated with 45-47.5 Gy in 10 or 11 fractions, poor healing affected three cases, with superficial necrosis affecting three other cases (one following injury). Considerable care is therefore necessary when considering dose fractionation regimes for this site, and increased fractionation is advisable. A review by Podd [21] reported an overall recurrence

rate of 4.6% and a radionecrosis rate of 9.2% when treating squamous and basal cell cancers of the lower limb in older patients. The treatment given was to areas less than 30 cm2, which corresponded to a 6 cm diameter applicator. Although either superficial or orthovoltage X-rays to a dose of 40 Gy in ten fractions were used, allowing for the difference in radiation quality, these reported findings were similar to our own series. The treatment of a large area carries an increased risk of failure to obtain complete skin healing. However, in a case report of LDR treatment in an elderly patient, a treatment area of 8 x 8 cm, extending over half the circumference of the leg, was considered more acceptable than either a single external-beam field or a parallel opposed pair of fields, particularly as the latter would have treated more than half the leg thickness [12]. We support reserving treatment of lesions of the lower limb using a treatment mould to situations for which alternative treatments have been carefully assessed and eliminated.

29.6.6

Trunk

The skin of the lower abdominal wall is generally more sensitive than that of the upper trunk to the effects of radiation. However, because of the rapid fall-off in dose beneath the skin surface, surface moulds can be extremely useful for confining the effects of radiation to within the abdominal wall tissues. For the treatment of skin tumors or secondary skin nodules, this form of therapy can be useful where the treatment of a relatively large surface area is indicated. The technique employed is similar to that for radium loaded chest wall moulds as used historically. Where large areas are to be treated, increased fractionation is necessary and, in general, this form of treatment application has been superseded by electron therapy. However, optimized treatment can provide better dose homogeneity over curved surfaces [10] than from abutted electron fields [13]. When using spatially positioned sources, by altering the position of the source pencils and adjusting treatment times for different source positions, it is possible to treat surface areas up to 200 cm2 without loss of uniformity of dose [11]. Others have since described the use of an HDR (iridium-192, 370 GBq) remotely loaded applicator for treating Kaposi sarcoma lesions. This entailed using a custom-built, ceiling-mounted immobilization device that secures the applicator on the surface of the patient. The applicators were made of tungsten/steel, 1, 2, or 3 cm diameter. The treatment distance was 15 mm and treatment sites included the head and neck and extremities, as well as the torso. The applicators required a plastic cap to eliminate electron contamination. For treating Kaposi sarcoma lesions, an optimal surface dose of 10-15 Gy in a single fraction, depending on the thickness of the lesion, was recommended [19].

References 399

29.7

CONCLUSION

11. Joslin, C.A.F. (1972) Afterloading methods in radiotherapy. In Recent Advances in Cancer and Radiotherapeutics, ed. K. Hainan. Edinburgh, Churchill

The majority of skin tumors are amenable to treatment by conventional means, including superficial X-rays, electron therapy, and surgery. This chapter has reviewed the literature and, coupled with our own experience, has identified and discussed the use of afterloaded treatment moulds in situations in which they offer potential treatment advantages to the patient.

for use in radiotherapy. Br.J. Radiol., 26. 13. Kitchen, G., Dalton, A.E., Evans, M., Pope, B. and Smith,

REFERENCES

14. Kitchen, G., Dalton, A.E., Pope, B.P., Smith, P.O. and Powner, M. (1991) Surface applicator for basal cell carcinoma of the right pinna: a case report. Activity [Selectron Activity Journal], 5,140.

1. Gloster, H.M.and Brodland, D.G. (1996) The epidemiology of skin cancer. Dermatol. Surg., 22(3), 217-26.

Livingstone. 12. Supplement 26 BJR. (1996) Central axis depth dose data

P.O. (1990) Selectron-LDR mould for large area basal cell carcinoma; a case report. Activity [Selectron Activity Journal], 4,72.

15. Perrozzo, M., Stabile, L, Ross, R., Moorthy, C, Tchelebi, A. and Hilaris, B.S. (1992) HDR remote afterloading as an alternative to electrons for therapy of superficial

2. Strom, S.S. and Yamamura, Y. (1997) Epidemiology of nonmelanoma skin cancer. Clin. Plast. Surg., 24(4), 627-36.

tumours. Activity [Selectron ActivityJournaf], 6,11. 16.

3. Wei ,Q. (1998) Effect of ageing on DMA repair and skin

superfractionated skin irradiations using large

carcinogenesis: a mini review of population based

afterloading moulds. lnt.J. Radial Oncol. Biol. Phys., 36(1)147-57.

studies.J Investig. Dermatol. Symp. Proc., 3(1), 19-22. 4. Halpern, J.N. (1997) Radiation therapy in skin cancer. A historical perspective and current applications. Dermatol. Surg., 23(11), 1089-93. 5. Paterson, R.P. and Parker, H.M. (1934) Dosage system for gamma ray therapy. Br.J Radiol., 7, 592. 6. Paterson Rand Parker H M. (1938) A dosage system for

17. Leung, J.T. (1997) Extensive basal cell carcinoma treated with the mould radiotherapy technique. Australas. /tad/o/.,41,20-1. 18. Svoboda,V.H.J., KovarikJ.and Morris, R(1995) High dose-rate microSelectron moulds in the treatment of skin tumors./ Radial Oncol. Biol. Phys., 31,967-72.

interstitial radium therapy. Br.J. Radiol., 9,252 and 313. 7. Meredith, W.J. (ed.) (1967) Radium Dosage. The Manchester

19. Evans, M.D., Yossa, M., Podgorask, E.B., Roman, T.N., Schreiner, L.J.andSouhami, L. (1997) Surface applicators

System. ES Livingstone, Edinburgh and London. 8. O'Connell, D., Howard, N., Joslin, CAR, Ramsey, N.W. and

for high dose rate brachytherapy in A.I.D.S related Kaposi sarcoma. lnt.J. Radial Oncol. Biol. Phys., 39(3), 769-74.

Liversage, W.E. (1965) A new remotely controlled unit for the treatment of uterine cancer. Lancet, 18, 570-1. 9. Joslin, C.A.F., Liversage, W.E. and Ramsey, N.W. (1969)

Fritz, P., Hensley, F.W., Berns, C., Schraube, P. and Wannenmacher, M.(1996) First experiences with

20.

Rudoltz, M.S., Perkins, R.S., Luthmann, R.W. et al. (1998) High-dose rate brachytherapy with custom surface mold

High dose-rate treatment moulds by afterloading

to treat recurrent squamous cell carcinoma of the skin of

techniques. Br.J. Radiol., 42,108-12.

the forearm./ Am. Acad. Dermatol., 38,1003-5.

10. Joslin, CAR and Smith, C.W. (1970) The use of high

21. Podd, T.J. (1992) Treatment of lower limb basal cell and

activity cobalt 60 sources for intracavitary and surface

squamous cell carcinomas with radiotherapy. Clin. Oncol.,

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4,44-5.

30 Hyperthermia and brachytherapy PETER M. CORRY, ELWOOD P. ARMOUR, DAVID B. GERSTEN, MICHAEL J. BORRELLI, AND ALVARO MARTINEZ

30.1

INTRODUCTION

Brachytherapy provides an obvious and sometimes ideal setting for combining hyperthermia with radiation therapy. Such combination therapy has been carried out in the past primarily using microwave technology, multiple antennae being placed intratumorally through plastic catheters previously inserted for this purpose [1,2]. There are a number of situations, particularly in the head and neck region, where this methodology is useful, but it does not lend itself easily to automation and does not adapt well to the simultaneous application of hyperthermia or to the use of radioactive source afterloaders. Another situation in which hyperthermia can and has been applied [3-5] is for implants that involve stainlesssteel needles to contain the radioactive materials. This approach is usually done in conjunction with a cutaneously attached template guidance apparatus [6]. In this case, radio-frequency (RF) power is applied directly to the stainless-steel needles themselves. Other approaches include needles heated with resistive electrical heating elements or hot water [7,8] ferromagnetic seeds contained within plastic catheters [9], and RFdriven, capacitively coupled, plastic-coated catheters [10]. Ultrasonic interstitial and intracavitary applicators promise more functionality and versatility, but are not yet in widespread clinical use [11]. From a clinical historical perspective, there have been

several randomized, prospective, clinical trials carried out in Europe over the past few years [12] which have demonstrated benefit associated with the addition of hyperthermia to conventional radiation therapy. The only similar clinical trial combining hyperthermia with brachytherapy, conducted by the Radiation Therapy Oncology Group (RTOG) in the USA, showed no such benefit [13]. Unfortunately, this trial, which was fraught with several quality assurance issues, was designed and mostly conducted prior to the development of the quality assurance guidelines which are now known to be essential to a positive result [14]. Only one patient of 86 in this study received what was considered an 'adequate' hyperthermia session. 30.2

BIOLOGICAL FACTORS

Over the past 20 years, the biological effects of elevated temperatures (40-43 °C) and their implications in cancer therapy have been extensively investigated. The following points summarize these investigations and constitute the rationale for the application of elevated temperatures in this setting. • Hyperthermia kills tumor cells directly and preferentially kills cells in macroscopic tumors. • If sufficient exposure is given, hyperthermia supraadditively sensitizes cells to the action of ionizing

Biological factors 401

radiation with a thermal enhancement ratio (TER) up to 3, and chemotherapeutic drugs with a TER up to 10. • Hyperthermia eliminates dose-rate effects by the inhibition of repair phenomena (Figure 30.1) [15]. This is particularly important in application with brachytherapy because the biological effects of low dose-rate (LDR) radiation and high dose-rate radiation (HDR) should be approximately the same in heated tumor tissues. In cooler normal tissues, however, LDR should have an advantage in terms of lesser toxicities. • Recently, other investigators have shown that temperatures in the 41-42°C range, when applied to solid tumors in rodents, can have a profound effect on tumor oxygenation and/or reoxygenation [16,17]. This reoxygenation greatly reduces the hypoxic fraction, significantly enhancing the effects of ionizing radiation in addition to the direct hyperthermic effects. Similar observations have been made in human tumors [18]. • Hyperthermia acts in a complementary manner to ionizing radiation and chemotherapeutic drugs. Those cells most resistant to radiation or drugs are the most sensitive to hyperthermic killing and sensitization. For many years, the existence of a phenomenon known as thermal tolerance was thought to contraindicate closely spaced heat fractions and the administration of chronic protracted heating. In fact, several publica-

Figure 30.1 Dose-rate effects in rat 9L gliosarcoma cells in culture. (Data adapted from reference 15.)

tions (e.g., [19-21]) support the contention that few, perhaps only 10%, of a tumor's cells are killed by hyperthermia and that number can be expected to vary by at least an order of magnitude in any clinical setting. These reports also support the notion that, while thermal tolerance develops, it is not a clinically limiting factor. Furthermore, hyperthermia is rarely, if ever, used as single-agent cancer therapy. Recent randomized clinical trials using the combination of hyperthermia and conventional fractionated radiation therapy have shown positive benefit to the addition of hyperthermia (e.g. [12]) demonstrate T90 values between 39°C and 41°C: temperatures far too low to accomplish any significant direct cytotoxicity. What has been shown by authors quoted above, as well as others, is that such temperatures for protracted periods of time continue to affect thermal radiosensitization (TERs of 1.6-2.0) and that such sensitization is essentially independent of the development of chronic thermal tolerance. Whereas the intrinsic thermal sensitivity of human cells varies over several decades of survival from cell line to cell line at these temperatures, thermal radiosensitization seems to be affected to only a minor degree, if at all. In addition to thermal radiosensitization, thermal intratumoral reoxygenation and hypoxic cell fraction reduction are probably playing an important role as well. Irrespective of the clinical heating methodology, acute pain associated with power application has been reported as the primary limiting factor in achieving temperature distributions with T90 greater than 41 °C for protracted periods [22-25]. This pain is often associated with elevated temperatures themselves, as well as direct power deposition within the involved tissues. This has been found to be the case for tumors with nerves encompassed by the tumor and is a particularly significant factor for advanced malignancies in the pelvis and abdomen. Fortunately, several publications (e.g., [15, 26-28]) have demonstrated that 41 °C for long durations can yield TERs between 1.5 and 2 (Figure 30.2) as well as the elimination of dose-rate effects. This is more often than not the maximum temperature achievable clinically. All but one of the clinical brachytherapy studies to date applied hyperthermia for 1 h at a target temperature of 43 ° C before beginning the LDR radiation, and for 1 h after completion of the radiation therapy course, usually 48-72 h. This was not done because those regimens have been demonstrated to be optimal, but was dictated solely by the practical limitations of the systems used for tumor temperature elevation. As may be easily seen on consideration of the data in Figure 30.3 little added benefit in terms of antitumor effect should be expected from this regimen. Consideration of the above data and observations yield several conclusions. The negative findings, relative to the addition of hyperthermia, of the RTOG randomized clinical trial came about because of two factors:

402 Hyperthermia and brachytherapy

Figure 30.2 Enhancement of LDR in rat 9L cells, at a dose rate of 50 cGy h~1, by continuous simultaneous heating at41°C. The acute X-ray dose was delivered at approximately 3 Gy min~\ (Data adapted from reference 27.)

(1) extensive thermometry was not employed and the actual thermal distributions were not known to an adequate degree of certainty, and (2) hyperthermia was administered only for 1 h before and after the interstitial radiation. Sparse thermometry has previously been shown to yield a false sense of intratumoral heating adequacy [22]. If the data of Figure 30.3 are representative of what is occurring intratumorally, little or no supraadditive enhancement of radiation cytotoxicity should be expected. Other important observations relative to thermal reoxygenation are: (1) at least a 1-h exposure at 41-42°C is required to optimally reduce the hypoxic fraction; (2) reoxygenation effects disappear between 12 and 24 h after the hyperthermic exposure; and (3) at higher temperatures, 43-44°C, reoxygenation is not observed due to intravascular coagulation. This last observation (intravascular coagulation) might seem to suggest that lower temperatures are better because more reoxygenation is observed. It must be remembered, however, that for each degree increase in temperature above 42 ° C, direct heat killing as well as thermal radiosensitization to radiation increase by approximately a factor of 2. One scenario that would explain clinical results, where broad temperature distributions from 39°C to 44 °C are the rule rather than the exception, is that in those portions of a tumor that are poorly heated (39-42 °C), thermal radiosensitization by reoxygenation predominates.

Figure 30.3 Effects of 1-h 43 °C heat exposures both before, after and before, and after LDR irradiation in rat 9L gliosarcoma cells in culture at a dose rate of 50 cGy h-1 There is no significant difference in the slopes of any of these plots. The thermal enhancement ratio for all three hyperthermia regimens is slightly less than 1.0, suggesting that there was no supraadditive interaction between the heat and radiation for these regimens.

In those portions of the tumor that are heated well (41-44°C), thermal radiosensitization by repair inhibition predominates. In the 41-42°C range, both effects are operative. This is a fortuitous situation because tumors have proven to be remarkably refractory to uniform heating, even with interstitial and intracavitary technology. Taken together, these factors lead to the conclusion that, for optimal antitumor effect, hyperthermia should be administered continuously and simultaneously during LDR irradiation. The use of pulse dose-rate (PDR) and HDR irradiation technology requires some further consideration. For PDR, the hyperthermia requirements are essentially identical [28]; however, because the radiation for PDR is administered in short pulses, perhaps 1 min h'1, it is not essential that hyperthermia be administered during the actual irradiation period. This factor may be of considerable practical importance. In the case of HDR procedures, in which radiation fractions are spaced over days or weeks, hyperthermia should be administered for at least a 1-3-h period immediately prior to irradiation and, if practical, during irradiation [29].

A system for simultaneous hyperthermia and brachytherapy 403

303

THERMOMETRY REQUIREMENTS

Quality assurance criteria and the need to control temperatures in three dimensions at some prescribed level dictate thermometry requirements. The prescription should be expressed in terms of the temperature distribution throughout the treatment volume and not in terms of a given temperature at any given point within the volume. A convenient way of describing the distribution is the percentage of intratumoral temperature points at or above a given index temperature [22,30]. The software operating the system must have the capability of computing and displaying this type of information in real time, providing the operator with the ability to assess compliance with the prescription continuously. This type of real-time analysis also permits alteration of the power deposition pattern to comply with the prescription if necessary. The RTOG in the USA has developed comprehensive quality assurance guidelines for interstitial hyperthermia which are sufficiently extensive to permit this type of analysis and control [14]. Table 30.1 summarizes the approximate recommended number of sensors as a function of tumor volume. Table 30.1 Recommended implanted sensors

5 10 50 100 200 500

12 15 18 24 30 48

These publications also outline the guidelines for placement of the sensors. Catheters containing multiple sensors or within which a single sensor will be scanned along its length must be placed to represent accurately the central and peripheral aspects of the tumor as well as sensing temperatures in tumor tissue central to the arrays of heating entities. It must be stressed again that these figures are recommended minima for quality assurance purposes and for many systems additional sensors will be necessary to achieve adequate threedimensional power deposition control. Clearly, systems of the future will require expanded data acquisition capabilities over those of the past. A 32-point measurement capability appears to be the minimum required number and, for versatility, 64 is highly desirable.

30.4

SYSTEMS CONSIDERATIONS

The primary considerations in the design of systems for the administration of hyperthermia and brachytherapy are based on the biological factors and thermometry

requirements discussed above, as well as on practical considerations. The following criteria are recommended for an ideal system: • It should be possible to deliver hyperthermia simultaneously prior to and throughout the course of radiation, irrespective of the brachytherapy modality in use - LDR, PDR, or HDR. • Compatibility with LDR after-loaders as well as PDR and HDR source loaders is required for optimal flexibility in source handling and to reduce exposure to personnel. • The thermometry system should have at least 32 temperature-measuring channels. Preferably, 64 should be available. The design should permit temperature measurements in tissue between heating elements if sensors are built into the heating elements themselves. • The system should permit dynamic alteration of the power deposition pattern in three dimensions throughout the course of treatment. • Power deposition control and data acquisition must be fully automated. Because prolonged exposures of hours to days may be required, remote monitoring and control are highly desirable. • For practical reasons, set-up complexity should be minimized. • For optimum utility, the system should be portable or at least easily movable. In practice, there are no systems that are available commercially or prototype systems that have been developed in research laboratories that can satisfy all of the above criteria. It is also highly unlikely that any one system will be appropriate for all anatomic locations. For example, while local current flow (LCF) technology, such as that described below, works well for tumors in the deep pelvis with transperineal template guidance, it adapts poorly to tumors in the head and neck. Ultrasound and microwave systems permit wider element spacing, and as a result fewer elements, than other technologies and provide superior three-dimensional control, but do not adapt well to simultaneous administration with radiation. Capacitively driven systems are very flexible and adaptable to irregular shapes and to tumors in the head and neck, but power deposition control is more difficult and simultaneous administration is precluded for most systems. In all cases, trade-offs have been required. As a result, there is no ideal system or method available for hyperthermia administration at present.

30.5 A SYSTEM FOR SIMULTANEOUS HYPERTHERMIA AND BRACHYTHERAPY To test the hypothesis that simultaneous administration of hyperthermia throughout the course of


brachytherapy administration should yield superior results to protocols applying heat only before and after radiation, a new system was designed. This first step was the Martinez Universal Perineal Implant Template (MUPIT) [6], used to guide implants to incorporate printed circuit boards as integral components to effect connections to the needles. This hyperthermic universal perineal implant template (HUPIT) is shown in position in Figure 30.4 after the operative procedure for a patient under treatment. There are 59 positions, at 11 mm separations, for stainless-steel needles in a seven wide by nine high array, with one needle missing at each corner. Each needle connects both to the afterloader to insert/retract the radioactive isotope, as well as to the power-generating circuitry to induce hyperthermia. There are 48 positions centrally located between these needles for dedicated thermometry catheters. Connection to the power generator is via two miniature connectors, one at each end of the template (29 wires each). The microprocessorcontrolled power generator has the capability of applying the RF power to any, all, or none of the needles

simultaneously, and each needle can be connected at an RF phase angle or either zero or 180 degrees. By varying the pattern and phase angles of the connections, any desired power deposition pattern can be achieved, at least in two dimensions. As areas of the tumor warm to the set point, the duty factor for needles in the immediate proximity to the sensors is varied to maintain the desired temperature. The inherent flexibility of this approach minimizes the information necessary prior to doing the implant. Treatment planning software is used after the implant is done to determine the initial power deposition patterns, however. All parameters are under operator control at all times during therapy and can be varied to account for factors such as blood flow and patient tolerance which cannot be accurately determined in advance. This system satisfies all of the design criteria outlined above except one. Because the stainless-steel needles are not segmented, power is controlled only in two dimensions rather than the more ideal situation in which it would be controlled in three dimensions. To have control in three dimensions it would be necessary to develop needles that are segmented along their length. This system was used to treat a variety of tumors in 19 patients to test the feasibility of the approach. The goal was to achieve an intratumoral temperature distribution with a T90 of 41 °C and to maintain that distribution throughout the course of treatment (continuous mild hyperthermia, CMH). Prior to finishing the development of the technology necessary for CMH, 14 patients were treated with acute fractionated hyperthermia (AFH), which consisted of hyperthermia for 1 h before and 1 h after the interstitial irradiation. Clinical response data for the two groups of patients were compared. Figure 30.5 shows the therapy set-up for the patient in Figure 30.4. The distribution of anatomic sites for the tumor in all 34 patients is given in Table 30.2. Figure 30.6 shows a composite integral distribution of intratumoral and normal tissue temperatures for all 19 patients undergoing CMH. A similar distribution (not shown) for patients who underwent AFH did not differ significantly from that of those who underwent CMH. For comparison, the results of a prior study, with a system

Table 30.2 Patient characteristics

Figure 30.4 Electronic template shown fixed in position after the operative procedure was completed on a patient being treated for recurrent cancer of the uterine cervix. The stainlesssteel needles (N) connect to remote afterloaders to insert and retract the radioactive sources. These needles are also connected to the hyperthermia power source by spring-loaded collars (not shown) that in turn connect to the 37 pin connectors (C), mounted at each end of the template. In this instance, six dedicated thermometry catheters (T) were implanted and a total of 30 thermocouple sensors were inserted. V = vaginal cylinder.

Endometrium Cervix Colorectal Prostate Urethra Vagina Anus Breast Total

7 4 5 2 1 2 1 1 23

7 1 1 2 11

Females, 28; males, 6. Mean age, 64 years; age range, 34-88 years.

A system for simultaneous hyperthermia and brachytherapy 405

Figure 30.5 Thermobrachytherapy set-up in the brachytherapy treatment room for the patient shown in Figure 30.4. The box with the connectors (copper-constantan thermocouples) at the upper left is the thermometry system, with 32 individual channels. Located immediately below the thermometry system is the treatment control computer, which is connected to the institution-wide computer network for control and monitoring purposes. The two large tubes at the lower left are the umbilici for two afterloaders, each of which can contain 15 iridium-192

that did not permit power control at the single-needle level [22] are shown. The error bars in Figure 30.6 represent one standard deviation of the 19 points for each index temperature. Normal tissue temperatures within 1-2 cm of the tumor periphery averaged 1.5-2.5°C below those in the tumor itself. The results of clinical follow-up, which varied in duration from 6 months to 3 years, are summarized in Tables 30.3 and 30.4, and the observed toxicities for all 33 patients are summarized in Table 30.5. The definitions for complete response (CR), partial response (PR), and no response (NR) are those that are conventionally used in cancer treatment. The radiation dose for the 33 patients ranged from 15 Gy to 39 Gy and was dictated by prior radiation exposure of the treated region. There was no significant difference between the dose range for AFH and for CMH. The number of implanted needles ranged from 14 to 30, the maximum number being limited by the aggregate number of available sources provided by two afterloading systems (30). The number of thermometry sensors inserted into the implant varied from 18 to 32 and was limited by both the number of catheters implanted (three to six) and the number of channels available (32).

ribbon sources. Smaller tubes (electrically non-conducting) extend from the ends of the umbilici to the template itself. The

Table 30.3 Overall response rates

patient remains in this configuration for 48-72 h. On demand, patient-controlled analgesia is used to control discomfort and pain.

CR PR NR CR+PR

14/19(74%) 4/19(21%) 1/19(5%) 18/19(95%)

7/14(50%) 1/14(7%) 6/14(43%) 8/14(57%)

AFH, acute fractionated hyperthermia; CMH, continuous mild hyperthermia; CR, complete response; PR, partial response; NR, no response. Table 30.4 Responses by tumor volume

CR PR NR

88(7) 120(1) 254(6)

36-100 120 90-432

143(14) 138(4) 122(1)

8-450 45-288 122

* Tumor volume was computed as the product of the three measured dimensions of the tumor multiplied by Pi/6. For abbreviations, see Table 30.3. Table 30.5 Toxicities

Figure 30.6 Temperature distributions.

Pain during treatment Pain after treatment Drainage Perineal reaction Fistula

6 (22) 3(11) 5(18.5) 4 (14.8) 2(7.4)


30.6

DIRECTIONS FOR THE FUTURE

Over the past few years, LDR technology has been, for the most part, replaced with HDR systems. These systems provide numerous benefits, which are outlined in other chapters of this text and will not be elaborated upon here. In practice, the adaptation of HDR to application with hyperthermia is simpler than that for LDR technology. Because the dose is delivered in short pulses (a few minutes), the need for protracted hyperthermia application is lessened. The heat dose can be delivered prior to and after irradiation without the absolute requirement for simultaneous delivery. Eliminating hyperthermia for the short interval during irradiation should have inconsequential biological effect. We have adapted the LDR system described above to HDR applications, but insufficient clinical data and follow-up are available to evaluate this approach objectively. The hyperthermia/brachytherapy setting also provides an ideal scenario for the testing and application of gene therapy in cancer treatment. Because the procedures are already invasive, access to deliver the interventional product is guaranteed. To assess the potential efficacy of such an approach, a series of experiments was initiated to mimic the use of the truncated human heat shock promoter (designated AHSP) controlling a reporter gene, the green fluorescent protein (enhanced green fluorescent protein, EGFP), when delivered by a viral vector, Adenovirus 5 (Adv), in this setting. The following experiments were carried out in collaboration with Dr Mark Dewhirst and Dr Rod Braun of Duke University, Durham, North Carolina. Figure 30.7 shows the results of two experiments varying the effective heat dose (30, 60, 90 minutes at 42 °C, assayed 21-23 h later) and the time after heating (0-42 h). These data clearly show a relationship between heat dose and expression as well as time after exposure. Quantitation of gene expression from the digitized video frames for the Adv-AHSP-EGFP samples is expressed as the ratio of the fluorescent signal in the sample to the control after subtracting out baseline autofluorescence. For the dose-response data (panels E-H: A, 0, 30, 60, 90min at 42°C), the values were 3, 28, 102, and 177 respectively. For panels C and D, the values were 165 and 204 for 21 and 42 h post-heating, respectively. Other experimental data show that, ideally, heat shock should be delivered 12-24 h after viral administration, that the heat-induced expression of recombinant products tapers off over the following 24 h, and that it may be reexpressed by heat pulses spaced at 24 h. These parameters adapt admirably to a 3-4-day course of HDR with four to six fractions of administered radiation. These results demonstrated that gene expression could be controlled over a significant range of expression and heat doses in a predictable manner. Also of significant importance was the fact that, in the absence of heat shock, gene

product from the virally introduced recombinant DNA was undetectable. There are few other systems available which permit conformal control of foreign recombinant DNA expression in such a predictable manner.

30.7

CONCLUSIONS

Whereas hard and fast conclusions are difficult with the limited number of patients described above, we believe that the trends in the data are encouraging. The response data for AFH in Table 30.3 show a pattern that is consistent with historical controls for brachytherapy alone. The response rates for CMH showed an improvement from a CR rate of 50% for AFH to 74% for CMH. The overall objective response rate improved from 57% to 95%. Striking differences are also seen when the data are stratified according to tumor volume for each response category. For AFH, there is a clear dependence on tumor volume, a characteristic of all studies that involve radiation as single-agent therapy. For CMH, however, there was no such pattern. The CR category actually was characterized with a wider range of tumor volume than the other two response categories. Statistically, no significant differences could be determined for the ranges of tumor volume in the various response categories; however, this could easily be a result of the small numbers involved. Nevertheless, the elimination of the tumor volume effect requires a TER in the neighborhood of three. While the numbers are small and the assumptions used to calculate the required TER can certainly be challenged, the possibility of obtaining radiation dose modification of this magnitude encourages enthusiasm. Observed toxicities were acceptable and did not vary significantly from what would be expected for brachytherapy alone, with the exception of treatment-related pain. In one case, pain after treatment was protracted for 3 months but subsequently resolved without intervention. To some degree, intra-treatment pain was noted for all patients and in six cases (22%) this pain limited the power that could be applied and required aggressive pain management. The temperature distribution data shown in Figure 30.6 show an improvement in the direction of an ideal distribution, uniform heat dose in the tumor and none outside it. When compared to a previous study in which dynamic control of the power deposition pattern at the level of a single needle was not available [22], more of the tumor is adequately heated and less is overheated. Unfortunately, parts of the tumor remain below the target temperature of 41 °C (10-20%) and a few points as high as 46 °C were observed. These temperature distributions probably will not improve until three-dimensional control of the power distribution pattern can be achieved. This shortcoming points out the need for further instrumentation and systems development.

Conclusions 407

Figure 30.7 Epifluorescence photomicrographs of rat MAC tumors grown in a window chamber and topically infected with Adv-AHSP-EGFP viral preparations. Panels A-D are for the same tumor and track EGFP expression and fluorescence as a function of time after heating for 90 min at 42 °C. Panels E-F are for three different tumors (rats) for heat exposures of 0, 30, 60, and 90 min at 42°C. (A) Immediately prior to infection; (B) 29 h post-infection and immediately prior to heating at 42°Cfor 90 min; (C) 21 h post-heating; and (D) 42 h post-heating; (E) 28 h post-infection, immediately prior to heating at 42 ° Cfor 30 min; (F) as in (E) but 23 h postheating; (G) 23 h post-heating at 42°Cfor 60 min; and (H) 27 h post-heating at 42°Cfor 90 min. The scale in the lower left portion of panel A shows a 1-mm scale photographed through the microscope. All photographs are at the same magnification and aspect ratios are preserved. In panel D, very intense fluorescence in the top portion saturated the video camera, causing underexposure in the remainder of the photograph. All photomicrographs were taken at identical fluorescence excitation levels and magnification.

As stated in the introduction, brachytherapy often provides an ideal setting for combination with hyperthermia. The invasive nature of brachytherapy itself reduces objections to the requirement for invasive thermometry. In the system described above, the needles required for introduction of the radioisotope are also used for hyperthermia, without the need for the introduction of additional invasive elements, other than for thermometry. The ability to administer hyperthermia simultaneously optimizes intratumoral sensitization to radiation both for direct hyperthermic sensiti/ation and from reoxygenation, both of which are required to optimize the antitumor efficacy. While the system described

above is effective for our purposes, particularly for transperineal templates, it is poorly adaptable to other anatomic areas, such as head and neck, where other systems and principles must be employed. Although the results described here are encouraging, multiinstitutional randomized trials with stringent quality assurance criteria and strict patient selection criteria are essential to accurately assess efficacy and benefit to the patient. Finally, this combined modality may provide an ideal setting for testing new modalities such as heatactivated, controllable gene therapy using bacterial proteotoxins and cytokines as well as hypoxic cell radiation enhancers such as the inducible nitric oxide synthases.


ACKNOWLEDGMENT This work was supported in part by grant CA-44550 from the US National Cancer Institute.

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31 The costs of brachytherapy GRAHAM READ

31.1

INTRODUCTION

Healthcare costs have shown a consistently rising trend worldwide during the last three decades. Thus, in the USA healthcare spending, expressed as a percentage of the gross national product (GNP), rose from 6% in 1965 to over 14% in 1992 and to 14.9% in the year 2000 approximately $1.5 x 1012 [1]. There is naturally, therefore, an increasing interest in cost-effectiveness and cost containment [2,3]. This will particularly focus on cancer as, if present trends continue, cancer will soon surpass cardiovascular disease as the leading cause of death in the USA, with an estimated annual cost of $82 x 109, approximately 20% of all healthcare costs [4]. In the UK, the National Health Service (NHS) reforms of 1991 [5] were driven by a vision of a cost-efficient healthcare system based upon an efficient contracting and purchasing process [6]. This has subsequently been replaced by a looser system of service and financial frameworks (SaFFs) to be supported by clinical governance and performance indicators, with regulatory bodies such as the National Institute for Clinical Excellence (NICE) and the Commission for Health Improvement (CHI) [7]. In Canada, the previously unchallenged healthcare system has recently come under close evaluation and financial scrutiny [8].

31.2

RADIOTHERAPY COSTS

Radiotherapy has been perceived, incorrectly as this chapter will show, as an expensive treatment modality [9,10]. Analyses of the costs of radiotherapy have generally been directed at treatments involving linear accelerators [11,12]. Although this in itself presents considerable difficulties, the costing of brachytherapy is even more complex. Firstly, there is a greater variation in the modalities used: some having a high capital component, such as high dose-rate (HDR) brachytherapy, while others have a high revenue cost, such as interstitial seed insertion. Secondly, there has been a greater change in practice with the abandonment of early techniques such as those employing radium and cobalt and the adoption of newer procedures, usually involving some form of remote afterloading. These changes have occurred, in many cases, for sound clinical reasons, for example the re-evaluation of different forms of radiotherapy or a movement to other forms of management such as surgery. Changes may also be brought about, however, for reasons other than clinical. For example, amendments and greater stringency in protection regulations have led to a greater use of afterloading methods as opposed to those involving the handling of live sources. In some instances, certain types of radioactive source have become unavailable. Lastly, as with the costs of cytotoxic drugs, there have been large

Principles of costing 411

changes in the costs of some sources: for example, the cost of gold seeds rose approximately ten times between 1980 and 1990. However, the principal difficulty in assessing the costs of brachytherapy remains the lack of published information available.

313

PRI NCI PLES OF COSTING

313.1

Variables

Costs may be divided into those which are fixed, semivariable or variable. Fixed costs remain unchanged regardless of the level of activity (Figure 31.1). These include many aspects of the basic administration of a hospital such as the provision of financial, catering, and general maintenance services. Semi-variable (semi-fixed or step) costs remain constant only for a certain level of activity (Figure 31.2). These include most of the staffing costs and also items of capital expenditure such as afterloading equipment. Thus, one low dose-rate (LDR) or HDR machine may be adequate for a certain number of patients, above which a further unit would be required. Variable costs vary in direct proportion to the level of activity (Figure 31.3). These include drugs and disposable sources such as iodine seeds.

313*2

Capital costs

Capital costs are the initial costs of any item of equipment and those which arise subsequently, namely interest and depreciation. Because costs and benefits in any department accrue at different rates over different periods, investment appraisal is generally taken into account by the use of investment procedures, or discounting. The object of these procedures is to enable costs and benefits to be evaluated as if they had occurred at the same point in time. Thus, the initial capital costs can be converted into a series of annual payments by using a given interest or discount rate. These annual payments are referred to as equivalent annual costs (EAC). The EAC can take into account situations in which different components of capital expenditure have differing lifetimes: thus, an item of after-loading equipment may be amortised (paid off) over a period of 15 years, whereas a building may have a lifetime of 60 years. Since 1991, all providers in the UK have been required to keep capital asset registers of items valued in excess of £1000 and pay interest and depreciation charges at the recommended discount rate for public sector projects of 6%, in accordance with UK Treasury guidelines [13]. Frequently, an item of equipment has little alternative use (when it could give rise to an opportunity cost) and is then referred to as a sunk cost. Sunk costs should not be included amongst annual capital costs.

3133

Revenue costs

Revenue or operating costs include all those costs which recur annually. In the case of afterloading equipment, these include maintenance on the equipment and renewal of sources. These costs are fixed, because they will be unchanged irrespective of the number of patients treated. The costs of source replacement clearly relate to the half-life of the source used and are, therefore, higher for machines employing iridium in comparison to those using cesium (Table 31.1). Other operating costs will be

Table 31.1 Fixed costs for LDR and HDR afterloading equipment

Machine3 Gynecological applicators

285077

14182

7191

First-year sources

40878

81756

20000

283293

396000

312268

42984

81887

223483

326277

477887

535751

Sources and service"

Variable costs.

299862

7191

Total initial costs

Total fixed costs

Figure 31.3

235224

"Prices relate to Nucletron equipment. Discounted at 5% over 8 years. Data in Canadian dollars (1992) from Jones et al. [36].

412 The costs of brachytherapy

variable, including operating room costs, admissions costs, overheads, and consumables. STAFF (LABOUR) COSTS These generally account for a substantial proportion of all costs - thus, in the UK, approximately 70% of all National Health Service costs relate to starring and, in the USA, Perez et al. calculated that they were 66% of their facility's global costs [ 14]. In the UK, general management, senior medical and nursing staff are regarded as fixed costs, and junior medical, nursing, physics, portering, and technicians are regarded as semi-fixed [15]. In contrast, in the USA, direct labor costs are regarded as variable. Staff costs are particularly important as brachytherapy procedures are complex and labor intensive. Thus, Perez et al. calculated that an intracavitary insertion required an average of 195 min of medical time, and an interstitial implant 263 min, in contrast to times for external-beam treatment planning of 23-45 min and simulation 29-45 min. 31.3.4

Marginal costs

Although estimates of average costs have frequently been used in healthcare accounting, it may be more useful in some circumstances to estimate the marginal costs; that is, those costs associated with a small change in healthcare activity [16]. The marginal costs incurred in treating, for example, one additional patient on an HDR machine will normally be very much smaller than those measured by using average cost estimates. Conversely, the savings made, for example, by reducing the number of fractions will be much smaller than an average cost estimate. Consequently, the amount of money saved by making small changes in clinical practice is often overestimated. Thus, many procedures will result in a reduction of the length of stay for inpatients, but the savings made will only be the marginal rather than the average costs. Substantial savings are only made in the rare situations in which it is possible to lay-off machines and staff and close wards. 31.3.5

Inpatient or outpatient costs

During the last decade, there has been a progressive trend to outpatient care. It has been estimated that

85-90% of all cancer care is now administered on an outpatient basis [17]. This has occurred because of the recognition of the high costs of inpatient care and, in the USA, because of changes in healthcare legislation which have affected patterns of reimbursement [18]. The relative costs of inpatient and outpatient treatments may have a significant effect in cost minimization analyses, for example when comparing HDR with LDR, as discussed below (Table 31.2). The relative benefits of outpatient treatments are so far poorly documented. For example, Yokes et al. found that, while outpatient chemotherapy was 53% less expensive than inpatient care, a significant proportion of patients refused outpatient care because of fear of malfunction of the equipment or inconvenience due to frequent clinic visits or restrictions in daily home activities [19].

31.3.6

Other costs

Although the focus of costing falls naturally on those services provided by the health service or healthcare provider, many costs are borne by patients and their families or carers. These include direct costs such as travel or absence from work, which may be considerable. Thus, in a study in the west of Scotland [20], the time patients receiving radiotherapy spent away from home each day varied from 35 min to 7 h, with a mean of 2 h 50 min; 16% had a relative who had to take time off work. Indirect costs may also result from psychological distress or the 'knock-on' consequences of loss of work and production.

31.3.7

Costs of failure

Further considerations which are frequently ignored are the costs evoked by either not treating the patient or by failing to cure. It is often assumed that the costs of supportive care are low in comparison with the costs of active treatment. This has been shown not to be the case. Perez demonstrated that the costs of curing a patient with a stage A2 (Tib - UICC TNM stage classification) carcinoma of the prostate with radiotherapy were

Table 31.2 Costs of LDR and HDR

Staff costs Variable costs Capital

1833.73 383.98 3327.78

Total

5545.49

33.1 6.9 60.0 100

Costs per patient C$1997 from reference [38].

1277.38 103.42 3173.03 4553.83

28.1 2.3 69.7 100

Charging for healthcare 413

$199320000' compared with $199347000 if the treatment was unsuccessful [21]. It is interesting to note that the equivalent surgical costs were $199325 000 and $199349 307, respectively.

31.4

CHARGING FOR HEALTHCARE

A simple question which is often asked is, 'How much does procedure x cost?' (Note this is not the same question as 'What is the price of procedure *?') Unfortunately, there is rarely a simple answer. In countries such as the UK where there is state funding or insurance, the overall costs of a department will be known, but the costs of individual procedures may be difficult to calculate. Where healthcare is charged directly to the patient or via an insurance company, some estimate of the costs of different procedures will have been performed to enable a charge to be made. This may not necessarily represent the true costs because there may be an element of profit included or the charge may subsidize or be subsidized by other costs. Payment patterns may have been arbitrarily set up over a period of years independent of cost factors. Thus, Perez et al. found that brachytherapy accounted for 10% of technical costs, but only 4% of revenue [14]. Costs for individual procedures may depend upon how quickly it is intended to recoup the initial capital expenditure (for an example, see Bastin et al. [22]).

31.4.1

UK funding

In the UK, no charging existed for several decades after the inception of the NHS and therefore costing was poorly developed and ill-understood. The 1990 National Health Service and Community Care Act split District Health Authorities (DHAs) in the UK into purchaser units which purchase services for patients from their own hospitals, from other authorities' hospitals, from self-governing trust hospitals, or from the private sector, and provider units, usually representing their district general hospitals (DGHs), which provide patient services. A further innovation was the creation of fundholding general practices which, with money top-sliced from the DHAs, were able to buy services from those provider units which in their view offered the best services. With a change of government in 1997, a further major revision has been initiated, with the creation of primary care groups (PCGs) of general practitioners serving approximately 100 000 people. Four possible levels of function of PCGs are envisaged, with the highest being a trust having total purchasing power for its population. 1

For simplicity all monetary amounts have been left in their original currencies with a suffix denoting either the year in which the calculations were made where this is stated in the original articles or else the year of the article.

Certain services, such as specialist cancer services, will again be purchased by Regional Health Authorities (RHAs), restoring some functions which had been previously eroded - indeed they had been merged into eight units in 1994 and complete abolition had been scheduled for 1996. Despite these reforms, the basic purchaser/ provider division has been retained. However, without adequate information on costs and outcomes, their ability to make informed decisions is limited. The 1991 reforms and the creation of an internal market have forced a change from management accounting to financial accounting. NHS Trusts have an obligation to: (a) deliver 6% return on their capital assets; (b) balance their budget; and (c) live within their external spending limit. This has led to very stringent financial control. Costs have had to be assigned to different procedures, usually on the basis of inadequate data, in order to draw up contracts. Financial management was previously carried out on a purely departmental basis, which meant that the costs of any one procedure were usually unknown. This sort of budgeting is known as an input budget and has no regard for the level of activity, or outputs, in a department. In order to make an estimate of the costs of a procedure, estimates have to made of the direct operating costs, including staff and consumables, and the indirect operating costs, such as cleaning and portering. The calculation of indirect costs will vary depending upon the method of recharging used, and capital costs will depend upon whether the procedure uses a purpose-built protection suite or areas shared with other users. Clearly, there will be considerable differences amongst centers and countries.

31.4.2

USA funding

In the USA, there was a progressive shift away from 'out of pocket' payments to funding from Federal Government or private insurance. The Social Security Act Amendments of 1983 shifted Medicare reimbursement away from retrospective payments to a prospective payment system based upon diagnosis-related groups (DRGs). In 1989, cost-effectiveness was proposed as a criterion of funding by the Health Care Financing Administration [23]. Increasingly, purchasing cooperatives have been formed with extensive databases on performance and cost. They have attempted to maintain or lower costs by the use of clinical protocols, disease and case management, and outcomes research [24].

31.4.3

Healthcare resource groups

The DRG system is now being emulated in the UK with the development of healthcare resource groups (HRGs) [25]. These are intended to define patient groups which are both clinically relevant and consume similar levels of resources [26]. Provisional groupings developed for


radiotherapy and chemotherapy were tested at three sites in 1992 [27] and, after further piloting at eight additional sites, definitive recommendations have now been published for use commencing April 2000 [28]. The proposed groups for brachytherapy are shown in Table 31.3. Table 31.3 UK healthcare resource groups in brachytherapy (version 1)

Mechanical afterloading

HDR LDR

Manual afterloading Live source

31,5 31.5.1

COSTS OF BRACHYTHERAPY Cost areas

The principal areas are shown in Table 31.4. Capital costs will include the costs of the afterloading equipment and applicators. Increasing attention is being given to treatment planning and optimization. As the systems used frequently form part of a larger system for external radiotherapy planning, the actual costs are frequently hidden. Other important areas include operating theater costs, hospitalization and staff costs. Hospitalization costs are usually derived from estimates of the average cost of an inpatient day. The cost reduction from using brachytherapy, particularly HDR therapy, will often result from the savings of such costs. Whether these costs are actually realized will depend upon the alternative uses to which the bed is put, and cost savings should, therefore, be restricted to marginal rather than average costs. These savings should include the reduction in the number of specialized nurses necessary to supervise inpatient treatments. 31.5.2

Costs of manual techniques

These include both the insertion/implantation of active sources and the use of afterloading techniques. A

significant feature of the cost is that of the isotope. Unlike the older radionuclides radium and cobalt, which could be kept in stock and used for a large number of patients over a long period of time, newer isotopes have relatively short half-lives and may require a new order for each patient. The length of theater time will depend upon the type of procedure and the experience of the operator. An iridium implant might occupy an hour of theatre time, whereas a prostatic iodine seed implant may require two or three. Telliffe [29] estimated the cost of a breast implantation using iridium-192 wire to be £1990689. The major component of this expenditure was the cost of the iridium wire (£1990280) and hospitalization for 2 days (£1990240). One hour of operating time was included, but this estimate really represents only the marginal costs of the procedure as detailed estimates of the true operating theater and accommodation charges (which may include a purposebuilt protection suite) were not made. The duration of stay would clearly have a significant effect on the overall costs.

31.5.3

Costs of afterloading techniques

These differ significantly amongst LDR, medium doserate (MDR), and HDR machines. This is due, firstly, to the difference in the half-lives of the sources. Source costs may be included as part of the initial capital cost if the isotope is long lived. Short-lived isotopes may be included with revenue costs. Example costs for Nucletron HDR and LDR machines, building, and maintenance are shown in Tables 31.1 and 31.5. Secondly, LDR and MDR techniques require hospitalization, with its associated costs. Costs will also depend upon the operating room costs and the type of anesthesia or sedation employed. Jelliffe [29] also estimated the costs of brachytherapy using afterloading techniques in breast cancer patients on the basis of 100 patients per annum. Again, no allowance was made for building costs, and it is not clear whether the annual maintenance charge included depreciation of capital. He estimated the cost of an LDR implant using cesium-137 to be £1990618, of which £1990273 was attributed to the costs of the Nucletron LDR

Table 31.4 Cost areas in different brachytherapy treatments

Capital Isotope/source Anesthetic/theater Hospitalization Mould room Staff costs

++

++

+ + +

+

++

+

+

+

+

+

++ ++ +

+

+

Economic evaluation 415

Table 31.5 Fixed costs for afterloading equipment

Estimated cost Capital investment-initial HDR afterloading equipment Verification system options Treatment room Miscellaneous

300000 100000 50000-100000 5000

Capital investment-annual Maintenance Sources Supplies Verification system maintenance Total (7-year)

12000 16000 75000 10000

633500-798000

Data in American dollars (1993) from Bastin et al. [22].

machine based upon an initial cost of £1990180000, including 30 cesium-137 source trains and an annual maintenance cost £199010 340 after the first year. Two days' hospitalization was costed at £1990240 and 1 h operating theater time was allowed at £199080. Treatment with an HDR unit was estimated to cost £1990435. The cost of the HDR machine was taken as £1990280, based upon an initial cost of £1990140000, but with replacement iridium192 sources at £19906000 per annum. The difference in the costs of the LDR and HDR techniques was mainly accounted for by the lack of hospitalization with HDR. These average costs are clearly heavily dependent upon the number of patients treated per annum. Benn [30] attempted to calculate and compare costs in two hospitals with a differing workload. Again, building and depreciation costs were not included. He estimated the cost of a single LDR to lie between £1990510 and £1990672. He found the cost of an HDR fraction to lie between £199049.5 and £1990117. Bastin et al. [22] estimated that an HDR application should be charged at $19931008, but this was dependent upon the rate at which the initial capital costs were recovered.

31.6

ECONOMIC EVALUATION

A number of methods of analysis seek to relate the costs and consequences of healthcare programs. Some of these expressions are used as 'umbrella' terms to cover any form of cost analysis, e.g., cost-effectiveness or cost benefit. However, the more precise meanings defined below are generally accepted. Although cost analyses have been increasingly reported in medicine, the number relating to cancer is relatively few. Not unnaturally, because of the high costs, procedures in medical oncology have attracted the largest number [31] of studies, whereas those in brachytherapy are extremely few in number at the present time.

Some have argued that cost analyses are inappropriate in medicine [32]. Indeed, in brachytherapy, one may be faced with the situation in which, for example, the costs of an implantation may be greater than those of an equivalent external-beam treatment, but the benefits, such as improved cosmesis, may be very difficult to quantify in monetary terms.

31.6.1

Cost minimization

The method compares the total costs of two different strategies which have the same outcome. Unfortunately, in clinical practice it is rare to find two modalities which differ significantly (and therefore have significantly differing costs) for which there is general agreement that the outcomes are the same. In general, comparisons of modalities in the literature have focused on survival and side-effects and only in recent years has the specific issue of cost comparison been addressed. MANUAL VERSUS REMOTE AFTERLOADING BRACHYTHERAPY

Jelliffe [29] estimated the cost of a manual breast implantation using iridium-192 wire to be £1990689, compared to £1990435 and £1990618 for the HDR and LDR implants. Ostrowski [33] compared manual and remote afterloadine techniaues. LDR VERSUS HDR BRACHYTHERAPY

A number of studies have sought to compare LDR with HDR brachytherapy. Leaving aside considerations as to whether the clinical outcomes are truly similar, there remains considerable controversy as to the optimal technique [34]. Because the numbers of applications of each modality required to achieve the same endpoint may vary considerably [35], this has an important consequence upon the cost-minimization analysis. Thus, Bastin et al. [22] compared LDR in gynecological cancer consisting of two applications with 3 days' hospitalization with an HDR of five outpatient applications. The costs of LDR were 244% higher, primarily due to hospital and operating theater costs. The cost estimates of Jelliffe and Benn show, however, that the comparison is not simple. Taking only average patient costs into consideration, the cost will depend upon the number of patients treated. Furthermore, the number of fractions used varies. Considering the marginal costs, these are clearly smaller in the case of HDR than LDR. In a detailed analysis, Jones et al. [36] compared the costs of HDR and LDR machines using Nucletron LDR-3, LDR-6, and HDR units. They found that the total fixed cost of the HDR unit was C$1992209 474 greater than the cost of the LDR-3 unit and C$,99257 864 more than the LDR-6 unit (see Table 31.1). However, analysis of the operating costs showed that, for various schedules of


LDR and HDR, the operating costs per patient were less for HDR than for LDR, except for the comparison of one LDR insertion with four HDR insertions. Savings increased in favor of HDR over LDR as the annual case load increased (Figure 31.4). They also concluded that, for small units treating up to 40 patients per year, the LDR-3 unit was the most cost-effective machine. In general, for a greater number of patients, HDR would be recommended, but they produced algorithms allowing more precise assessments to be made depending upon the annual number of patients, the ratio of LDR to HDR insertions, and other practical considerations. Their calculations assumed that the machines were used only for gynecological insertions. Cost sharing, for example for the treatment of cancer of the esophagus, lung, or breast, would affect the calculations significantly. Chenery et al. estimated that HDR would lead to a cost avoidance of C$19841700000, based upon an annual patient load of 85 cervical and 60 endometrial cancer patients over a period of 20 years [37]. More recently, Pinilla [38] calculated that an HDR regimen (two fractions) was 22% less expensive compared to an LDR (one fraction) regimen amounting to C$991.66 per patient (see Table 31.2). However, if LDR maintenance was done in house, then the LDR cost fell to 98% of the HDR cost. Konski et al. [39] carried out a meta-analysis of six options in stage I endometrial cancer based upon costs paid, and concluded that LDR was the most costeffective treatment, with no evidence of any difference in disease-free survival. Thus, a simple choice between LDR and HDR cannot be made as it depends upon the number of fractions used, the number of patients treated, and the maintenance costs. However, there appears to be a general agreement that, except for in the smallest centers, HDR is likely to prove more cost-effective than LDR.

BRACHYTHERAPY AND EXTERNAL-BEAM THERAPY

In many instances in oncology, it will be clear from the extent or site of the tumor that external-beam radiotherapy is the treatment of choice. In some instances, a brachytherapy insertion may be added at the conclusion of the external-beam treatment to supplement the radiation dose to an area of special risk. Here, the issue will be whether or not this treatment, and the implied additional cost, confers a benefit in terms of improved local control or survival. BRACHYTHERAPY AND ELECTRON THERAPY

Jelliffe compared the cost of a five-fraction electron boost to that of an interstitial implant [29]. His estimate of the cost of electron therapy was £1990200, which compared favorably with costs of £1990435-£1990689 for the implants, but he noted that the poor cosmetic results from electrons might justify the higher costs of the implant. BRACHYTHERAPY AND SURGERY

Comparisons between the use of brachytherapy and surgery are often highly controversial and fraught with difficulty. Patients treated surgically are frequently younger and fitter. The surgical modality may, by its very nature, provide more accurate staging information, rendering stage-by-stage comparison difficult. For example, Farndon et al. [40] reported that surgical resection in esophageal cancer was more cost-effective than other methods of treatment, including brachytherapy. However, as the survival amongst surgical patients was significantly greater, it is unlikely that the patients' staging was comparable. Although it is possible to compare

Figure 31.4 Annual cost differences in Canadian dollars (1992) for LDR compared with HDR for different numbers of patients (from Jones et al. [36]). Positive values indicate cost balance in favor of LDR, negative in favor of HDR.

Economic evaluation 417

the costs of the initial procedures, these frequently do not take into account the costs associated with failure of treatment or of any complications which may arise. External-beam radiotherapy as an outpatient treatment has been shown to be less expensive than comparable surgical procedures for a number of common cancers because of the avoidance of hospital, anesthetic, and operating theater costs [41]. Hanks and Dunlap determined the costs of treating prostate cancer by radical prostatectomy, lymph node dissection with iodine-125 implant, and external-beam radiotherapy [42]. The median cost of radical prostatectomy was $198614000, of lymph node dissection and iodine-125 implantation $198612000, and of external-beam radiotherapy $6750 before 1984 and $5600 after 1984. These costs were derived from the hospital fees, professional fees, and other major expense items as charged and are therefore highly influenced by the method of charging as well as by the true costs of the procedures. Thus, the apparent change in the cost of radiotherapy was entirely due to changes in billing. It is interesting to note that bills for apparently the same procedure varied by up to 82%, indicating the inherent flaws in this method of determining costs. By reviewing the current literature, they concluded that none of the methods showed a superior outcome.

cost of a city bus ride!). This was one or more orders of magnitude different from the costs of a year gained by, for example, coronary bypass (C$19926698), renal dialysis (C$199267345), or school testing for tuberculosis (C$199269634) [44].

31*63

Although cost-effectiveness analyses may be very useful, they are unable to compare different diseases or strategies where the outcomes cannot be measured in a common unit. This may arise where, for example, a healthcare purchaser wishes to decide between, say, allocating money to cataract surgery or cancer chemotherapy. Cost utility relates the cost of different medical procedures to the increased utility (the amount of wellbeing) they produce in terms of improved quantity and quality of life. In order to measure utility, various quality-of-life scales have been developed. From the clinical point of view, quality-of-life studies are difficult and time consuming, in contrast to more objective measures such as response or survival. Even with apparently 'objective' scales, assessments made by doctors, patients, and their relatives may differ [45]. 31*6*4

31.6.2

Cost utility

Cost benefit

Cost-effectiveness

This form of analysis relates the cost of a treatment to its outcome. Two or more treatments can be compared provided there is a common unit of outcome or effectiveness such as 'life-years gained,' 'pain-free days,' or 'positive cases detected.' Thus, in a cost-effectiveness analysis, a ratio of benefit to cost is derived for each option. The most cost-effective option, therefore, can be defined either as that which maximizes benefits for a fixed cost or as that which minimizes costs for a fixed benefit [43]. It should be noted that this is not necessarily the largest net benefit which represents the optimum choice. In assessing the benefits of a particular treatment, the question arises as to how to deal with costs which occur at different points in time. This is clearly of importance when considering the immediate benefits of a particular treatment versus its long-term risks. Traditionally, benefits have been discounted in a manner similar to that described above for dealing with costs, which has the effect of weighting the short-term benefits. Adopting a zero discount rate, whilst it may be appropriate for areas such as neonatal care, would lead in cancer to an undue preoccupation with late effects in preference to immediate gains and may not, therefore, be appropriate. A number of studies have shown that, in general, radiotherapy is remarkably cost-effective. Thus, Glazebrook was able to show that for external-beam radiotherapy the cost of a year of life gained was C$1992661 (C$19921.82 per day- which he compared to the

This form of analysis, in many ways the most difficult, seeks to determine whether the benefits of using a given therapy outweigh its costs. A monetary value has, therefore, to be assigned to each strategy or treatment, which may amount to deciding how much it costs to save a life or to enable a person to live a pain-free one. Some people have an ethical objection to putting a monetary value on a human life, but such decisions are regularly made in economic planning, even if they are not implicitly stated. In fact, cost-benefit analysis has been regularly used in the analysis of economic and social policy in the public sector for many years. Roberts et al. estimated in 1985 that the NHS could not afford more than £198414000 to save a life [46], and Rees felt that treatment costing less than £19911000 for an improvement in benefit was excellent value, whereas those costing £199110000 probably represented an unfair distribution of resources [47]. Various approaches have been adopted in benefit evaluation. Initial approaches were based upon 'human capital', such as the loss of income incurred by illness. Clearly, this does not take into account benefits for the retired or unemployed. Another approach is to evaluate whether we are willing to pay the stated cost for a particular procedure or service. This is often expressed as a proportion of average income, as an alternative to a straight monetary cost. Thus, in one study, Thompson found that patients with rheumatoid arthritis would be willing to pay 22% of their annual income for a hypothetical cure of the disease.


These considerations are important in brachytherapy. Thus, supposing that brachytherapy for the treatment of breast cancer is as effective as external-beam therapy but is more expensive (as suggested by Jelliffe above), what level of cost is one prepared to pay for improved cosmesis? Such considerations are important and are worthy of further study. The National Radiological Protection Board (NRPB) has attempted to calculate the cost of the health detriment caused by irradiation of the general public by taking into account the frequency of deleterious effects and their respective costs [48]. These costs were estimated from the loss of economic output, the costs of medical treatment for fatal and non-fatal cancers, and the costs for hereditary defects.

31*6*5

Radiation protection

The raison d'etre for the development of afterloading in brachytherapy was the reduction in radiation exposure to the various members of staff- radiotherapists, nurses, and technicians - who were involved in the treatment of patients with active sources, principally radium. As an example, the treatment of patients with cancer of the cervix using the Manchester System [49] involved the insertion of an average of 75 mg radium, which remained in position for approximately 3 days. Prior to the introduction of afterloading systems, approximately 400 patients were treated per annum, totalling approximately 700 insertions carried out, at the Christie Hospital, Manchester. Although, by adherence to all appropriate working procedures, radiation exposure of staff was maintained below the then annual dose limit of

50 mSv, a significant number of people received doses within the range 30-90% of this limit. From an economic perspective, the question arises as to whether the reduction in radiation dosage to staff and visitors justifies the increased costs of afterloading. Fleishman et al. [50] calculated the costs of two schemes for the introduction of LDR afterloading systems: scheme 1 involved the construction of a three twin-bedded, purpose-built, single-storey building, and scheme 2 the construction of two fully protected treatment rooms adjacent to a ward area. The annual cost of the first scheme was £198253000 and of the second £198230000 (Table 31.6). In order to assess the cost benefit of these schemes, reference was made to work by the NRPB, which had attempted to calculate monetary valuations of radiation-induced heath detriment [51], as shown in Table 31.7. These estimates are, of course, highly contentious, involving judgments by the NRPB of the value of public and occupational exposures and other assumptions in estimating the doses received. Using these criteria, Fleishman et al. calculated that the total detriment cost to staff was £198258 000 and to visitors £198234 000, a total of £198292 000, and hence that the costs of introducing afterloading could be justified.

31.7 31.7.1

AREAS FOR FUTURE STUDY Lung cancer

An important development has been the use of intraluminal radiotherapy for the treatment of carcinoma of the bronchus [52]. In order to be able to assess the cost

Table 31.6 Annual costs of two afterloading schemes

Annual capital costs of

(i) equipment (ii) building

26000 22000

26000 13000

Annual service costs of

(i) equipment (ii) building

15000 8000

15000 2000

2000

-6000

-20000

-20000

53000

30000

Net change in operating costs Bed occupancy savings Total net annual cost Data in £1982 taken from Fleishman et al. [50].

Table 31.7 Recommended costs of unit collective dose for members of the public

Principles and Practice of Brachytherapy: Using Afterloading Systems

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