Clinical Progress in Renal Cancer

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Clinical Progress in Renal Cancer

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Clinical Progress in Renal Cancer Edited by Tim Eisen Professor Medical Oncology University of Cambridge Dept of Oncology Addenbrooke’s Hospital Cambridge UK

Tim Christmas Consultant Urological Surgeon Department of Urology Royal Marsden Hospital, Charing Cross Hospital London UK

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© 2007 Informa UK Ltd First published in the United Kingdom in 2007 by Informa Healthcare, 4 Park Square, Milton Park, Abingdon, Oxon OX14 4RN. Informa Healthcare is a trading division of Informa UK Ltd. Registered Office, 37/41 Mortimer Street, London W1T 3JH. Registered in England and Wales Number 1072954. Tel.: +44 (0)20 7017 6000 Fax.: +44 (0)20 7017 6699 E-mail: [email protected] Website: www.informahealthcare.com

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior permission of the publisher or in accordance with the provisions of the Copyright, Designs and Patents Act 1988 or under the terms of any licence permitting limited copying issued by the Copyright Licensing Agency, 90 Tottenham Court Road, London W1P 0LP. Although every effort has been made to ensure that all owners of copyright material have been acknowledged in this publication, we would be glad to acknowledge in subsequent reprints or editions any omissions brought to our attention. Although every effort has been made to ensure that drug doses and other information are presented accurately in this publication, the ultimate responsibility rests with the prescribing physician. Neither the publishers nor the authors can be held responsible for errors or for any consequences arising from the use of information contained herein. For detailed prescribing information or instructions on the use of any product or procedure discussed herein, please consult the prescribing information or instructional material issued by the manufacturer. A CIP record for this book is available from the British Library. Library of Congress Cataloging-in-Publication Data Data available on application ISBN 10 1 84184 604 X ISBN 13 978 1 84184 604 0 Distributed in North and South America by Taylor & Francis 6000 Broken Sound Parkway, NW (Suite 300) Boca Raton, FL 33487, USA Within Continental USA Tel: 1(800)272 7737; Fax: 1(800)374 3401 Outside Continental USA Tel: (561)994 0555; Fax: (561)361 6018 E-mail: [email protected] Distributed in the rest of the world by Thomson Publishing Services Cheriton House North Way Andover, Hampshire SP10 5BE, UK Tel.: +44 (0)1264 332424 E-mail: [email protected] Composition by C&M Digitals (P) Ltd, Chennai, India Printed and bound by Replika Press Pvt Ltd

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Contents List of Contributors Colour Plate Section

1. Epidemiology/Aetiology Jinfu Hu, Yang Mao

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2. Molecular genetics and pathogenesis of renal cancer David E Neal, Andreas A Skolarikos

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3. Presentation, staging, and radical nephrectomy Sara Ramsey, Michael Aitchison

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4. The pathological appearance of renal tumours Stewart Fleming

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5. Prognostic factors for outcome in metastatic renal cell carcinoma Paul J Elson

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6. Imaging in renal cancer Steven D Allen, Aslam Sohaib

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7. Interventional radiology in renal cancer David J Breen, Robert D Ward

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8. Management of renal tumours extending to inferior vena cava Bijan Khoubehi, Tim Christmas, Neil Moat 9. Laparoscopic radical nephrectomy and laparoscopic partial nephrectomy for renal cell carcinoma David Hrouda, Mathias Winkler

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10. Surgical treatment of renal cell carcinoma metastatic to the thorax John E Pilling, Peter Goldstraw

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11. Surgery for renal cell cancer bone metastases Stephen R Cannon

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CONTENTS

12. Adjuvant therapy in renal cancer Axel Walther, David Chao, Martin Gore

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13. Current systemic medical therapies for metastatic disease Bernard Escudier, Martin Gore

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14. Novel systemic therapies for metastatic disease James MG Larkin, Tim Eisen

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15. Radiotherapy and supportive care Vincent Khoo, Lynda Pyle

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Index

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Contributors

Michael Aitchison Dept of Urology Gartnavel General Hospital Glasgow UK Steven D Allen Department of Radiology Royal Marsden Hospital London UK David Breen Department of Radiology Southampton General Hospital Southampton UK Stephen R. Cannon Consultant Orthopaedic Surgeon Royal National Orthopaedic Hospital Stanmore Middlesex UK David Chao Consultant Medical Oncologist Department of Academic Oncology Royal Free Hospital London UK Tim Christmas Consultant Urological Surgeon Department of Urology Royal Marsden Hospital Charing Cross Hospital London UK Paul Elson, Cleveland Clinic Foundation Cleveland, OH USA

Tim Eisen Professor Medical Oncology University of Cambridge Department of Oncology Addenbrooke’s Hospital Cambridge UK Bernard Escudier Institut Gustave-Roussy Demoulins Villejuit France Stewart Fleming Professor of Cellular and Molecular Pathology Division of Pathology and neuroscience University of Dundee Ninewells Hospital and Medical School Dundee UK Peter Goldstraw Consultant Thoracic Surgeon Royal Brompton Hospital London UK Martin Gore Professor Urological Unit Royal Marsden Hospital London UK David Hrouda Consultant Urological Surgeon Department of Urology Charing Cross Hospital London UK Jinfu Hu Surveillance and Risk Assessment Division Center for Chronic Disease Prevention and Control Public Health Agency of Canada Ottawa, ON Canada

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CONTRIBUTORS

Vincent Khoo Academic Department of Radiotherapy and Oncology The Institute of Cancer Research and Royal Marsden NHS Foundation Trust Surrey UK Bijan Khoubehi Specialist Registrar Urological Unit Royal Marsden Hospital London UK James MG Larkin Royal Marsden Hospital Sutton UK Yang Mao Surveillance and Risk Assessment Division Center for Chronic Disease Prevention and Control Public Health Agency of Canada Ottawa, ON Canada Neil Moat Consultant Cardiothoracic Surgeon Royal Brompton Hospital London UK David E Neal Professor of Surgical Oncology and Consultant Urological Surgeon Oncology Centre Addenbrooke’s Hospital Cambridge UK John Pilling Specialist Registrar Department of Thoracic Surgery Royal Brompton Hospital London UK

Lynda Pyle Academic Department of Radiotherapy and Oncology The Institute of Cancer Research and Royal Marsden NHS Foundation Trust Surrey UK Aslam Sohaib Department of Radiology Royal Marsden Hospital London UK Sara Ramsey Dept of Urology Gartnavel General Hospital Glasgow UK Andreas A Skolarikos Lecturer in Urology Athens Medical School Sismanoglio Hospital Athens Greece Axel Walther Department of Radiology Specialist Registrar and Clinical Research Fellow Cancer Research UK London UK Robert Ward Department of Radiology Southampton General Hospital Southampton UK Mathias Winkler Specialist Registrar Urology Charing Cross Hospital London UK

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Colour Plates

Figure 4.3 In the uncommon renal cell carcinoma with rhabdoid features there is marked pleomorphism with eosinophilic cytoplasmic inclusions causing eccentric displacement of the nucleus. Figure 4.1 Clear cell carcinoma usually grows as a solid lobulated or bosselated mass, frequently with a surrounding fibrous capsule. The cut surface of the tumour is soft and yellow-white with areas of haemorrhage and necrosis.

Figure 4.2 This typical clear cell carcinoma has an alveolar architecture composed of clear cuboidal cells supported by a rich sinusoidal microvasculature.

Figure 4.4 The Type 2 variant of papillary renal cell carcinoma comprises columnar cells with some pleomorphism but like the type 1 arranged as a single layer of cells supported in a papillary architecture by a fibro-vascular core.

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Figure 4.5 Collecting duct carcinoma has an infiltrating branching tubular morphology eliciting a stromal response from the surrounding kidney.

Figure 4.6 Low grade collecting carcinoma has a spongelike appearance on examination of the cut surface.

Figure 4.8 The epithelial component of mucinous tubular and spindle tumour of the kidney is arranged as microtubules or acini, lined by a bland cuboidal epithelium with intraluminal and stromal mucin.

Figure 4.9 Renal carcinoid has the same morphology as carcinoids elsewhere with cuboidal cells with indistinct borders arranged in variably sized nests.

Figure 4.7 The low grade variant of collecting duct carcinoma has a microcystic morphology, cyst lined by collecting duct carcinoma cells usually as a single layer.

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Figure 8.7 Radical nephrectomy specimen demonstration renal tumour extending into the renal vein and suprahepatic inferior vena cava. The tumour thrombus and kidney are excised en bloc.

Figure 8.8 Radical nephrectomy specimen demonstration renal tumour thrombus extending into the right atrium. The distal part of the thrombus in the atrium is bulbous and is attached to the main tumour via a thin stalk-like tumour thrombus.

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Figure 10.3 (A) An axial cut from a CT of the thorax (lung windows) showing an ovoid left lower lobe lesion. (B) FDG-PET scan of the same patient showing an FDGavid lesion in a similar position in the left lower lobe. (C) Fused images of the CT and FDG-PET showing the left lower lobe lesion seen on CT is the FDG-avid mass seen on FDG-PET.

Figure 10.5 The lung seen via a lateral thoracotomy. A peripheral metastasis has been marked with a suture prior to excision with the diathermy.

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Figure 15.1 An example of conformal radiotherapy treatment fields for a patient suffering a tumour recurrence in the postoperative renal bed site. The target volume (near cylindrical shape) is located centrally and is denoted by the pink outline. Note that each treatment beam has been shaped to the profile of the target volume in the direction of beam delivery, which is then projected onto an outline of the axial skeleton for further illustration of the conformal field shapes.

a

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Figure 15.2 An example of a high-dose co-planar conformal radiotherapy plan to treat a local renal cancer recurrence. (A) The transverse dose distribution through the isocentre of the treatment plan. The isodoses are listed by colour on the right hand side of the diagram. The orientation angles of the three treatment beams are also shown. (B) The sagittal dose distribution. (C). The coronal dose distribution in the same patient as in (A) and (B).

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Epidemiology/Aetiology Jinfu Hu, Yang Mao

INTRODUCTION Kidney cancer is the fifteenth most common cancer in the world,1 accounting for almost 2% of all cancers.2 More than 189 000 new cases are diagnosed annually worldwide, and kidney cancer causes the deaths of more than 91 000 people each year.1 Kidney cancer includes both renal cell cancer (RCC), which arises from cells of the proximal convoluted renal tubule (i.e. cancer of the renal parenchyma), and cancer of the renal pelvis, which arises from the transitional cell epithelium. In adults, 85–90% of kidney cancer cases are RCC.1 In most populations, renal pelvis cancer (RPC) is much less common than RCC. In this chapter, RCC and RPC in adults are addressed separately.

RENAL CELL CANCER Epidemiology The incidence of and mortality from RCC have been consistently increasing worldwide.3–9 The increase in incidence has occurred in both sexes.10–13 In Canada, for example, the agestandardized incidence rates among males and females, respectively, rose from 6.4 and 3.2 per 100 000 population during 1978–1982 to 9.5 and 5.2 per 100 000 during 1993–1997. Over the same time period, the corresponding rates among males and females in Bas-Rhin, France, rose from 9.4 and 4.4 per 100 000 to 15.6 and 7.3, and in Bombay, India, from 1.4 and 0.5 to 2.0 and 1.1 (Figures 1.1 and 1.2). The incidence has increased in all age groups and in both urban and rural populations.8,9 The rapidly increasing incidence of RCC in most populations may be explained in part

by the rising numbers of cancers detected incidentally by new imaging techniques and improvements in diagnosis, and by an increased prevalence of risk factors such as cigarette smoking, obesity, and hypertension.3,7–9, 14,15 The age-specific incidence rate of RCC is relatively low in both sexes under 50 years of age. Most cases occur between the ages of 50 and 75, increasing sharply between the ages of 55 and 75 in both sexes (Figures 1.3 and 1.4). Men are generally affected more frequently than women. The incidence ratio of men to women commonly ranges from 1:1 to 3:1 in most regions.13 Kidney cancer is relatively rare in Asian and African people. The age-standardized incidence rates of RCC are highest in northern, western, and eastern Europe, and in North America, intermediate in southern Europe and Australia, and lowest in Asia (except in Israel), Africa, and Central and South America, where the rates range from 0.4 to 5.0 per 100 000 population.13 In Europe, the incidence is exceptionally high in the Czech Republic and, to a lesser extent, in Bas-Rhin, France (as high as 15–20 per 100 000 among men). Although the incidence is high in black Americans, the incidence is relatively less common in residents of Africa and Asia (except for Israeli Jews). The global variation in incidence is more than 10-fold (Figures 1.5 and 1.6).

Aetiology Tobacco The causal association of active tobacco smoking with kidney cancer has been established by the International Agency for Research on Cancer (IARC).16 Population attributable risks

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Figure 1.1 International trends in age-standardized (to the world population) incidence rates (per 100 000) of renal cell cancer, males, 1978–1997. (Sources: Cancer Incidence in Five Continents. Volumes V–VIII. IARC Sci Publ 1987, 1992, 1997, 2002.10–13)

of RCC caused by cigarette smoking have ranged from 27% to 37% in men and from 10% to 24% in women.17–19 A few studies had limited statistical power in assessing the associations between pipe or cigar smoking and kidney cancer.16 Some studies have reported that cigarette smoking was a risk factor for RCC in men but not in women.20–23 However, numerous studies indicated that cigarette smoking was associated with a statistically significant increase in the risk of RCC17,19,24–28 in both sexes.17,19,27,29,30 The odds ratios (ORs) have ranged between 1.3 and 9.3 in men who smoked.24 A decreased risk of RCC with increased years since quitting smoking was observed in some studies.29,30

Tobacco smoking is clearly implicated in the aetiology of RCC, with a strong dose-dependent increase in risk associated with number of cigarettes smoked per day and a substantial reduction in risk with smoking cessation in both sexes.31 Passive smoking has been linked with various health consequences in humans, including cancer. A large case–control study of RCC provided evidence that exposure to environmental tobacco smoke at home or at work increased the risk of RCC in both sexes.29 Research on genetic factors has explained the role of cigarette smoking in the development of RCC. The genetic effect plays an important role in increasing the risk of RCC,

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EPIDEMIOLOGY/AETIOLOGY

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Figure 1.2 International trends in age-standardized (to the world population) incidence rates (per 100 000) of renal cell cancer, females, 1978–1997. (Sources: Cancer Incidence in Five Continents. Volumes V–VIII. IARC Sci Publ 1987, 1992, 1997, 2002.10–13)

particularly in smokers. N-acetyltransferase 2 (NAT2), which codes for a polymorphic enzyme, is involved in tobacco-carcinogen metabolism.32 A study of gene–environment interactions showed that slow acetylators are at increased risk of RCC and that slow NAT2 genotypes have a strong aetiologic role in the carcinogenic process for RCC resulting from smoking. The effect of smoking is modified by the NAT2 genotype, and slow acetylators are at increased risk of RCC if they also smoke.33 The nitrosamines, specifically N-nitrosodimethylamine, are carcinogens in rodents.34 An experimental animal study reported the presence of

von Hippel–Lindau (VHL) gene mutation in Nnitrosodimethylamine-induced renal epithelial tumours in rats.35

Alcohol The influence of alcohol on kidney cancer risk has not been clearly determined, despite many studies.1 Results on the role of alcohol in the aetiology of RCC are not consistent. Most case– control studies36–40 show no association between alcohol consumption and kidney cancer. Some studies, however, have reported an inverse association between alcohol and RCC in women

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Age-specific rates per 100 000

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China, Shanghai Figure 1.3 Age-specific incidence rates (per 100 000) of renal cell cancer, males aged 20 and over, 1993–1997. (Source: Cancer Incidence in Five Continents. Volume VIII. IARC Sci Publ 2002.13) SEER, Surveillance, epidemiology, and end results.

and in men.29,41,42 Other studies indicated effect modification by sex. A significant inverse association between alcohol consumption and RCC has been observed in women only.21,43–45 Moreover, two cohort studies reported reduced risk of kidney cancer associated with alcohol consumption in postmenopausal women and in women aged 55 or over.46,47 Yet, another cohort study found decreased risk of RCC with alcohol consumption in male smokers.48 Results by type of alcohol have also been inconsistent. Some studies reported that the strongest inverse association with RCC was for wine consumption by women,43,46 while one study found this association in both sexes.42 Other studies showed the strongest inverse association with RCC was for beer consumption by women.45 However, all forms of alcoholic beverages (spirits and beer) were associated with decreased risk of RCC in men.48

One possible mechanism at work here is hormonal, which was suggested as an explanation for the sex-specific associations. Alcohol consumption is influenced by oestrogen metabolism in women. Parker and colleagues hypothesized that reduced risk of RCC in women who drink larger amounts of alcohol could be due to decreased oestrogen metabolism and, thus, decreased formation of reactive quinines.45 Another possible mechanism involves decreased insulin resistance.49,50 Moderate alcohol intake showed a decrease in the level of insulin-like growth factor 1 (IGF-1).51,52 The decreased risk of RCC associated with alcohol intake may be mediated by IGF-1.48

Diet Many studies have been conducted over the past decades to assess the role of diet in the

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China, Shanghai Figure 1.4 Age-specific incidence rates (per 100 000) of renal cell cancer, females aged 20 and over, 1993–1997. (Source: Cancer Incidence in Five Continents. Volume VIII. IARC Sci Publ 2002.13). SEER, Surveillance, epidemiology, and end results.

aetiology of RCC. Findings from epidemiological studies on diet and risk of kidney cancer have been inconclusive. Foods An inverse association between consumption of vegetables and fruit and risk of RCC has been seen in most case–control studies.37,43,44,53–59 The protective effect of vegetables and fruit on cancer risk has been attributed to multiple anticarcinogenic agents found in fruit and vegetables.60–62 Some vegetables and fruit (citrus fruit, in particular) reduce mutations in the VHL gene in RCC.63 An inverse association between RCC and intake of dark-green and cruciferous vegetables was found among females only43,64,65 or not at all.17,44,66 Some researchers have examined the effects of diet in relation to smoking. Total fruit consumption, especially of citrus fruit, had

a stronger protective effect among non-smokers than among smokers.44 A 40–50% reduction in RCC risk was observed in both female never and female ever smokers with high intake of cruciferous/dark-green vegetables, but no association was found among male never or male ever smokers.65 Smoking did not modify the association between consumption of cruciferous/ dark-green vegetables and RCC.64 However, three prospective cohort studies did not find such protective associations,47,67,68 except for the inverse associations between RCC and specific fruit and vegetable subgroups (for example, root vegetables and bananas).47 Elevated risks of RCC have been observed for high intake of meat,17 red meat,54 beef37 and fried meats43,44 in several studies but not in others.58,59,66 One mechanism to explain this increased risk is that some methods of

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AMERICAS USA, SEER, Black USA, SEER, White Canada Columbia, Cali EUROPE Czech Republic France, Bas-Rhin Italy, Varese Province Poland, Warsaw City Finland Switzerland, Geneva Spain, Zaragoza UK, South Thames OCEANIA Australia, NSW New Zealand ASIA Israel, Jews Japan, Miyagi China, Shanghai India, Bombay AFRICA Zimbabwe, Harare: African Uganda, Kyadendo County 0

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Incidence rates per 100 000 Renal parenchyma

Renal pelvis

Figure 1.5 Age-standardized (to the world population) incidence rates (per 100 000) of kidney cancer by selected continental areas, males, 1993–1997. (Source: Cancer Incidence in Five Continents. Volume VIII. IARC Sci Publ 2002.13) SEER, Surveillance, epidemiology, and end results.

cooking red meat (e.g. frying and broiling) result in an increased amount of heterocyclic amines.69 PhIP (one of the heterocyclic aromatic amines) is associated with a significant increase in risk of RCC,54 and it is a carcinogen in animals and possibly in humans.69 However, the effect of consuming red meat was greater than the effect of protein or PhIP, suggesting that other mechanisms could be responsible.54 Meat and fish may contain human carcinogens other than heterocyclic amines.70 Processed meat products have been associated with RCC,65 suggesting that intake of nitrites may be a risk factor for RCC. Nitrosamines can induce RCC,71 however, this was not found in other studies.43,64 One study reported that high consumption of red meat and processed meat appeared to increase RCC risk only among those who

had smoked or among overweight males.65 Increased risk of RCC with increasing intake of dairy products was seen among ever smokers and persons with a body mass index (BMI) of 24.4 kg/m2 or more.64 Nutrients Numerous studies of nutrients have reported that high intake of protein,17,37,39,53,54 fat,37,39, 53,58 and saturated fat37 was associated with increased risk of RCC, but some have not.43,68 Prospective cohort studies indicated that total vitamin E intake was inversely associated with kidney cancer in postmenopausal women46 and with cancer in men.72 An international case–control study also reported increased risk associated with low dietary intake of vitamin E and magnesium.43 Taking vitamin E supplements also reduced the risk of RCC,65 but this finding was not supported by other studies.66,68

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AMERICAS USA, SEER, Black USA, SEER, White Canada Columbia, Cali EUROPE Czech Republic France, Bas-Rhin Italy, Varese Province Poland, Warsaw City Finland Switzerland, Geneva Spain, Zaragoza UK, South Thames OCEANIA Australia, NSW New Zealand ASIA Israel, Jews Japan, Miyagi China, Shanghai India, Bombay AFRICA Zimbabwe, Hararo: African Uganda, Kyadendo County 0

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Figure 1.6 Age-standardized (to the world population) incidence rates (per 100 000) of kidney cancer by selected continental areas, females, 1993–1997. (Source: Cancer Incidence in Five Continents. Volume VIII. IARC Sci Publ 2002.13) SEER, Surveillance, epidemiology, and end results.

Calcium supplementation decreased the risk of RCC, particularly for females.65 Total dietary calcium intake was independently associated with reduced risk of RCC in a cohort study of postmenopausal women,68 but this was not found in other studies.58,66 Chow and colleagues reported that increased dietary calcium was associated with increased risk of RCC, but the effect disappeared after adjusting for caloric intake.66 Some case–control studies showed that high dietary intake of antioxidants was associated with a decrease in RCC risk. Vitamin C44 and carotenoids or beta-carotene37,44,66 were associated with reduced risk of RCC. However, vitamin A did not reduce the risk of RCC.43,44,64

Energy intake Total energy intake was examined in a few studies only, with inconsistent results. A positive association between total energy intake and risk of RCC was observed in some studies43,58,66 but not in others.44,65,68,73 Coffee and tea No association has been found between drinking either tea or coffee and kidney cancer. Although active potential anticarcinogens have been identified in tea leaves and animal experiments suggest protective potential after carcinogen exposure, the epidemiological evidence of a protective role for tea consumption in cancer incidence in humans is weak.74 Many cohort75–77 and case–control studies17,22,78–82 have generally found no association between tea and cancer of the urinary tract or kidney.

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1.0 Canada France, Bas-Rhin UK, South Thames Poland, Warsaw City Spain, Zaragoza Switzerland, Geneva Denmark Japan, Miyagi

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Year Figure 1.7 International trends in age-standardized (to the world population) incidence rates (per 100 000) of renal pelvis cancer, males, 1978–1997. (Sources: Cancer Incidence in Five Continents. Volumes V–VIII. IARC Sci Publ 1987, 1992, 1997, 2002.10–13)

A Norwegian prospective study indicated that there was no association between coffee consumption and kidney cancer.83 The relation of kidney cancer risk with coffee drinking has not been investigated extensively. Overall, epidemiological data on this relation are reassuring.84 Drinking water A few studies have investigated exposure to chlorination by-products in drinking water. A Finnish case–control study based on water supply, quality, and treatment reported a significant excess risk of kidney cancer among men.85 A cohort study in the United States found no excess incidence of kidney cancer when a chlorinated water supply was

compared with a non-chlorinated deep-well water supply.86 In Taiwan, excess mortality from kidney cancer was observed with a significant dose–response relation between arsenic level and drinking water.87 Arsenic ingestion also significantly increased the risk of kidney cancer in Argentina.88 In addition, two ecological studies of drinking water exposed to asbestos found significantly elevated risks for kidney cancer in men but not in women.89,90

Obesity Obesity has been linked to increased risk of RCC. A meta-analysis indicated that 25% of kidney cancer cases in both sexes were

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attributable to excess weight.91 Several studies reported increased RCC risk among obese women, although evidence of the association among men is considered to be weaker.17,92–96 Many studies found a consistently increased risk of RCC with increasing BMI that was equally strong for both sexes,22,42,97–100 including five prospective cohort studies.101–105 Obesity increased the risk of RCC, with a dose–response relation for both sexes,103–105 and this was most pronounced in lifelong non-smokers.104 A high BMI is an independent risk factor for RCC, and this relation is not influenced by energy intake and/or physical activity.105 Numerous potential mechanisms may be responsible for the increased risk of RCC with

obesity, and many may be interrelated. One possible explanation involves oestrogen: obesity may increase RCC risk by elevating the blood level of oestrogen.106,107 Another possibility concerns the fact that obese individuals have raised serum levels of free IGF-1108 and exhibit increased lipid peroxidation.109 These two factors have been related to tumour development. IGF-1 has been shown to stimulate cell proliferation and inhibit apoptosis,110 and lipid peroxidation is likely to be the mechanism responsible, at least in part, for increased risk of RCC.109 As well, in experimental animal studies, lipid peroxidation of the proximal renal tubules is a necessary mechanistic pathway in renal carcinogenesis induced by several different chemicals.

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China, Shanghai Figure 1.9 Age-specific incidence rates (per 100 000) of renal pelvis cancer, males aged 20 and over, 1993–1997. (Source: Cancer Incidence in Five Continents. Volume VIII. IARC Sci Publ 2002.13) SEER, Surveillance, epidemiology and end results.

Physical activity Physical activity may lower the risk of several cancers, but RCC has not been included as one of those.111 A few case–control studies reported an inverse association with RCC for occupational physical activity only112 or recreational physical activity only,113 but others did not.93,94 Five prospective cohort studies also examined physical activity in relation to RCC.73,114–117 One showed an inverse association with occupational physical activity in men only,115 and another two, with leisure-time physical activity in men only73 and in male smokers.117

Reproductive factors and hormones A few studies have examined associations between hormone-related factors and RCC. Some studies reported that women with late age

at menarche and first birth had decreased risk of RCC.94,118 RCC risk was positively associated with number of births in ever-parous women; in particular, the risk increased with number of live births in case–control studies.118–120 A prospective cohort study in postmenopausal women indicated that women who were nulliparous or had experienced more than two live births were at increased risk of kidney cancer compared with women who had one or two live births.46 RCC risk was reduced among long-term oral contraceptive users.118,119 An elevated RCC risk was observed with the use of replacement oestrogens in one case–control study.119 In a cohort study, former users had an increased risk of kidney cancer compared with women who never used oestrogens, but current users did not.46 No such association was found in other studies.68,93,118

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Age USA, SEER, White Poland, Warsaw City

USA, SEER, Black Spain, Zaragoza


China, Shanghai Figure 1.10 Age-specific incidence rates (per 100 000) of renal pelvis cancer, females aged 20 and over, 1993–1997. (Source: Cancer Incidence in Five Continents. Volume VIII. IARC Sci Publ 2002.13) SEER, Surveillance, Epidemiology and end results.

Experimental animal studies support the role of oestrogen-induced carcinogenesis.121 Rats develop significantly more kidney tumours with oestrogen treatment.122 Oestradiol-induced microsatellite DNA alterations are associated with hamster kidney tumorigenesis.123

Medical conditions Hypertension Many studies have confirmed that hypertension is related to risk of RCC. The population attributable risk is estimated to be 20% for hypertension.19 The distinction between the roles played by hypertension and treatment of hypertension in the development of RCC remains unclear because of the high correlation between them. Hypertension increased the risk of RCC in both sexes, according to some case–control studies19,46,97,124,125 but not others.126,127 A history of hypertension was found to be an independent

risk factor for RCC.97 A cohort study in Korean men supports the hypothesis that hypertension is an independent risk factor for kidney cancer mortality.128 Some studies reported that hypertension was clearly associated with RCC risk in women only,129 including a cohort study.130 Yet, another cohort study in the United States indicated that elevated blood pressure independently increased the long-term risk of RCC about three fold in men, with a dose–response relation.101 However, a record linkage study indicated that kidney cancers were more common among hypertensive patients, which was at least partly due to obesity or use of antihypertensive drugs, and not necessarily due to hypertension per se.131 Diabetes mellitus Diabetes has been suggested as a risk factor for RCC, but the evidence is not consistent.124,132,133 Several case–control and cohort studies reported diabetes was

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associated with a 30–70% elevation in RCC risk.124,134,135 Diabetes has been associated with elevated lipid peroxidation.136 However, one recent cohort study found that diabetes does not play a major role in the aetiology of RCC.133 Urinary tract diseases Epidemiological studies have reported data relating urinary tract diseases, such as kidney stones,17,59,124,137,138 kidney infection,17,124,125 and urinary tract infection39,59 with RCC development. A history of urinary tract infection was not restricted to women; most notably, it also affected men with a history of smoking.139 Oophorectomy and hysterectomy Some epidemiological studies have also noted a positive association between a history of oophorectomy or hysterectomy and risk of RCC,118,119,140,141 with about a twofold increase in risk. Nevertheless, another study did not find such an association.93

Drugs Antihypertensive medications Antihypertensive medication (i.e. non-diuretic antihypertensive use) has been reported in relation to kidney cancer risk.138,142 The risk was reduced after adjustment for hypertension.129,142 A prospective cohort study indicated an increased risk of RCC only in women with hypertension who were using hypertension medications alone.130 Results from a continuing cohort study that had previously published findings143–145 indicated that none of the antihypertensives (angiotensin-converting enzyme inhibitors, angiotensin II antagonists, β-blockers and calcium antagonists) was consistently associated with risk of RCC and that it was unlikely that any of these medications play an important role in the aetiology of RCC.133 However, the study did not make available information on confounders such as cigarette smoking, obesity and hypertension. Diuretics Some researchers have reported an increased risk of RCC following diuretic therapy. A review of 12 studies (3 cohort and

9 case–control studies) suggested that longterm use of diuretics might be associated with RCC, more strongly in women than in men.146 However, other study results did not show a positive association,97,127,129 including those of a prospective cohort study.133 Analgesics Results vary on the possible relation between analgesics and RCC. Some case– control studies147–149 and one cohort study150 have shown an elevated risk of RCC associated with chronic use of analgesics (phenacetin, aspirin, paracetamol [acetaminophen]). Regular use of analgesics was identified as a causal factor in the development of RCC (18%) in Los Angeles County, California; there was a statistically significant increasing risk with increasing level of exposure.148 Other studies found no association between long-term use of any type of analgesic and RCC.127, 151,152

Radiation Epidemiological investigators have found that exposure to radiation was associated with RCC. Cancer patients, such as women with cervical cancer or men with testicular cancer, treated with radiotherapy and various types of ionizing radiation appeared to have increased risk of developing RCC.153–155 A case–control study also reported that receiving diagnostic or therapeutic radiation was associated with an increased risk of RCC that was stronger in women than in men.137

Occupational exposures For several decades, epidemiological studies have shown that kidney cancer risk was related to some occupations, although RCC has not generally been considered as an occupational cancer. This occupational association has been reported particularly in chemical and petrochemical industry workers,156–161 metal-related industry workers,162–164 coke-oven workers,162,165 cardboard workers,166,167 laundry and dry-cleaning workers,168–170 171,172 173 health care workers, drivers, and other workers,174 although some studies175–178 found no

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association with these occupations. Numerous case–control and cohort studies have found an association between kidney cancer risk and occupational exposure to specific chemicals: asbestos;162,164,168,179–181 gasoline;156,157,162,182 dinitrotoluene;183 polycyclic aromatic hydrocarbons;184 chlorinated solvents such as trichloroethene,166,185 perchloroethylene,163 and tetrachlorocarbonate;163 cadmium;162,186,187 inorganic lead compounds;187–190 solder fumes;187 and benzene.187 Asbestos Some case–control and cohort studies showed that occupational exposure to asbestos was related to increased risk of RCC.162,168,179–181,191,192 However, other studies did not find any increased risk.157,193–195 The above research includes two meta-analyses of cohort studies of workers predominantly exposed to asbestos that found no association between asbestos exposure and kidney cancer risk194 and no clear association with other cancers except lung cancer and laryngeal cancer.195 In another cohort study, no increased risk of kidney, bladder, or other urinary cancer was found in either sex during the 1964–1997 period.196 Gasoline Exposure to petroleum products, especially gasoline197 and aviation gasoline,182 has been suggested as a risk factor for kidney cancer in men. A significant association was also found between gasoline exposure and RCC among men in an international multicentre study.162 A cohort study in the Nordic countries found that men exposed to gasoline vapours with benzene levels estimated at 0.5–1.0 mg/m3 showed a 30% elevated risk of kidney cancer, as compared with national incidence rates.198 In a Finnish case-referent study, an elevated RCC risk was observed among men, with an exposure–response relation, for gasoline exposure as approximated by the benzene-equivalent concentration.157 Some case–control studies also reported that benzene exposure was associated with RCC risk among both sexes,187 and with a dose– response increased risk of RCC among men for occupational exposure to benzene in

13

petroleum products.193 Other studies, however, found no relation with gasoline or for petroleum workers.176,178,199,200 In addition, a study at a petrochemical research facility from 1970 to 1996 did not find excess risk of kidney cancer.201 Solvents Increased risk of RCC was observed among dry-cleaning workers with exposure to chlorinated solvents in some studies162,168–170 but not in one.202 Occupational and nonoccupational exposure to the solvent trichloroethylene is related to cancer development. Excess incidence of kidney cancer has been found in occupational cohorts exposed to trichloroethylene; however, the possible confounding effects of exposure to other solvents needs to be clarified.203 Polycyclic aromatic hydrocarbons The findings concerning increased RCC risk among coke-oven and petroleum refinery workers have not been entirely consistent. One study reported an elevated risk of kidney cancer mortality among male oil refinery workers.158 A Finnish cohort study of oil refinery workers indicated a significant excess of kidney cancer in male workers, which was highest among men with at least 5 years of employment in oil refineries.161 Case–control studies also reported increased risk of RCC in the oil refinery industry.137,162,204 An elevated mortality of kidney cancer was observed in coke-oven workers.165 Nevertheless, other studies failed to find the association between kidney cancer and polycyclic aromatic hydrocarbons, as estimated by a job exposure matrix.157,187 Diesel and gasoline engine exhaust Occupational case-control and cohort studies have found increased risk of RCC among truck drivers and urban bus drivers.137,205–208 Slight elevations in kidney cancer risk were found in those drivers exposed to the lowest exposure level of engine exhausts.173 An increased risk was seen for workers in various transportation-related occupations.209 These workers might have been exposed to exhaust gas. Constituents of diesel and motor exhaust of particular interest include polycyclic aromatic hydrocarbons.210

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Cadmium Three major sources of cadmium exposure are diet, cigarette smoking, and occupation.210 A significant association between RCC risk and occupational exposure to cadmium was observed in some studies among men162,186,187 and women,187 whereas other case– control and cohort studies have not found any association.137,206,211,212 Lead Occupational cohort and case–control studies have noted significantly elevated risk of kidney cancer among lead smelter workers188,213,214 and welders,172,192,215,216 and some found that lead exposure was significantly associated with RCC.157,187 However, no association was found in other studies.217–219 Lead has been shown to induce renal cancer in animals and nephropathy in humans.219–221 Other occupational exposures A significant increased risk of RCC with exposure to benzidine and vinyl chloride was found in a Canadian case–control study, with a dose– response relation.193 Increased risk of upper urinary tract tumours with exposure to benzidine has also been reported.222 In addition, some researchers observed elevated RCC risk in men associated with long-term occupational exposure to herbicides193,205 and insecticides.205

Genetic susceptibility Two case–control studies reported that having one first-degree relative with kidney cancer was associated with significantly increased (1.6and 2.5-fold, respectively) risks of RCC.124,125 Another population-based study observed an excess of the GSTT1 null genotype in RCC cases as compared with controls (odds ratio [OR] = 1.9, 95% CI = 1.1 to 3.4), and suggested that activity of the GSTT1 enzyme protects against RCC.223 Genetic polymorphisms of the interleukin-4 receptor α gene were associated with the incidence and poor prognosis of sporadic RCC in a Japanese population.224 A population-based familial aggregation analysis using an extensive genealogy database found that the risk of RCC was significantly higher for members of the

extended family of an affected individual, as well as for the nuclear family; germline mutations were significantly involved in sporadic RCC.225 Mutations of the VHL gene occur at high frequency in sporadic cases of RCC.226 Results from the Netherlands cohort study indicated VHL gene mutations were detected in 61% of sporadic clear cell RCC.227

RENAL PELVIC CANCER Epidemiology Cancer of the renal pelvis accounted for up to 13% of kidney cancer cases globally from 1993 to 1997, with incidence rates of generally less than 1 per 100 000 population in both sexes (Figures 2.5 and 2.6).13 The incidence was close to zero in some places in both sexes, such as Bombay, India, and two regions in Africa. For the 1993–1997 period, the highest RPC incidence rates were found in New South Wales, Australia, among women (1.3 per 100 000) (Figure 1.6) and in Denmark among men (1.7 per 100 000).13 From 1978 to 1997, international trends for RPC were inconsistent; incidence decreased in some countries or regions and rose in others (Figures 1.7 and 1.8).10–13 Men were affected by RPC more often than were women.10–13 For both sexes, the tumour was uncommon in persons under 50 years of age, and incidence rates rose sharply with each successive age group after age 60 until age 75 in some regions (Figures 1.9 and 1.10). The inconsistency in RPC trends across continental regions may be explained in part by differences in the misclassification of RCC and RPC in various registries. In addition, varied temporal trends in cigarette smoking and use of phenacetin-containing analgesics may have contributed to the diverse trends, including the decline in RPC in some countries or regions.7

Aetiology The causal role of smoking has been established in the aetiology of RPC. Smoking is strongly related to RPC, causing a three- to

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five- fold increased risk228–232 in both sexes,229–231 with a dose–response relation.229–231 Risk of RPC decreases significantly with increased years of smoking cessation.230 Population attributable risks of RPC due to smoking have been identified as 67% among men and 31% among women.230 Cigarette smoking appears to be the strongest risk factor for RPC, accounting for the majority of cases in most areas of the world.233 High use of phenacetin-containing analgesics has also been implicated in the aetiology of RPC.189 Results from epidemiological studies showed that regular analgesic use raised RPC risk,149,234–236 with a dose–response relation.234,235 The attributable risk for analgesic consumption was 74% among women and 43% among men.234 Some researchers observed that only phenacetin-containing analgesics were unequivocally associated with RPC risk; a weak link with paracetamol was found.234 Either no association236 or no significant association232 was found between use of analgesics (including aspirin, phenacetin, and paracetamol) and RPC.236 A population-based cohort study also indicated that use of analgesics and diuretics was not associated with RPC for either sex.237 Another study reported that history of kidney stones, infection, and injury increased the risk of RPC and that use of antihypertensives and diuretics was related to RPC.138 In addition, occupational exposure to coal, coke, asphalt, and tar products, and working in petrochemical or plastics industries231 and the dry cleaning industry168 showed increased risks of RPC in study subjects.

CONCLUSION Lipid peroxidation has been proposed as an unifying mechanistic pathway by which risk factors such as obesity, hypertension and chemical-induced lipid peroxidation of the proximal tubules could induce renal carcinogenesis. The hypothesis may also explain the role of other RCC risk factors, such as oophorectomy/hysterectomy, parity, smoking, and diabetes, as well as protective factors.109

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The incidence of RCC has been increasing in most populations worldwide. Results from epidemiological studies have provided evidence on risk factors that shows strong causative relations between smoking and obesity and risk of RCC, and have also provided evidence that links hypertension to an elevated risk of RCC. Complex relations between other risk factors and RCC risk need to be further elucidated. Although there have been major advances over the past 20 years in the understanding of the epidemiology and aetiology of RCC, at least 40% of RCC cases have not been explained by the risk factors studied.19 The aetiology of RCC remains incompletely understood. The incidence of RPC is rare, and most regions of the world showed a decline, even in regions with high incidence. The major risk factor identified for cancer of the renal pelvis is cigarette smoking. As well, evidence exists of a relation between analgesic use and RPC.

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Molecular genetics and pathogenesis of renal cancer

2

David E Neal, Andreas A Skolarikos

INTRODUCTION Renal cancer is not a single disease; it comprises several different types of cancer, each with a different histology, a different clinical course, and different genetic changes1 (Table 2.1). For each of these different tumour types, hereditary, familial, and sporadic forms exist. Most of our current knowledge was originally derived from studies on familial forms of the disease, but subsequent studies of sporadic cancers found similar changes2 (Table 2.2). Recent developments in genetics and molecular biology have led to an increasing knowledge of the origin and biology of renal cell carcinoma (RCC), which will be discussed separately for sporadic and inherited forms.

SPORADIC RENAL CELL CARCINOMA Clear cell renal cell carcinoma Chromosome 3 changes; the von Hippel–Lindau tumour suppressor Clear cell RCCs are characterized by nonhomologous chromatid exchange leading to loss of genetic material from the short (p) arm of chromosome 3 and gains of material from the long (q) arm of chromosome 5.3 Loss of heterozygosity (LOH) studies in sporadic RCCs identified three common regions of allelic loss: 3p12-14,4 3p21-22,5 and 3p25-26.6 Loss of 3p and gain of 5q implicate genes within these regions as being involved in clear cell RCC tumorigenesis. Tumour suppressor genes are

likely to be found in areas of chromosomal loss (3p) and oncogenes found in areas of chromosomal gain (5q). The only gene definitively shown to be involved in the development of such tumours is the von Hippel–Lindau gene (VHL), located at 3p25, a documented tumour suppressor.6,7 Renal cell cancers found in VHL follow Knudson’s theory of the two hit model6 of carcinogenesis. The VHL gene is inactivated in patients with VHL and in almost 100% of sporadic clear cell RCCs.7,8 To evaluate whether inactivation of the VHL gene is essential for tumour formation, the patterns and extent of allelic losses on 3p were compared in a set of conventional RCCs with and without VHL mutations. Although the frequency of 3p12-22 LOH was similar in both tumour types, LOH at 3p25-26 was significantly less frequent than LOH at 3p12-22 in tumours without VHL mutation, whereas LOH at 3p25-26 and 3p12-22 was similar in tumours with or without VHL mutation.9–11 These results support the presence of both VHL-dependent and VHL-independent tumorigenic pathways and indicate that inactivation of a tumour suppressor gene at 3p12-22 may play an important role in both these pathways. The inactivation of VHL is accomplished by mutation, deletion, or methylation. Mutations of the VHL gene seen in sporadic RCC differ from those seen in RCC associated with VHL disease. In sporadic RCC, 45% of the mutations are clustered in the second exon, although abnormalities are seen in all three exons. Large deletions are not observed, and 48% of the mutations are micro-deletions or

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Table 2.1

Classification of malignant renal epithelial tumours with their molecular and cytogenetic features

Tumour

Site of origin

Genes

Numerical chromosomal abnormalities

Clear cell RCC

Proximal renal tubule

VHL, BHD, RASSFIA, FHIT

−3p, +5q, −Y, −8p, −9p, −14q

t(3;5)(p;q)

75

Papillary RCC

Proximal renal tubule

c-MET, FH, TFE3,PRCC, RCC 17, BHD

+7, +17, −Y, +12, +16, +20

t(X;1)(p11.2;q21.2) t(X;17)(p11.2;q25.3)

15

Chromophobe RCC

Intercalated cell of renal collecting duct

−1, −2, −6, −10, −13, −17, −21

Unknown

5

Collecting duct RCC

Renal collecting duct

−1q32, −6p, −8p, −21q

Unknown

5

Unknown

Chromosomal translocations

Incidence (%)

Medullary renal carcinoma Unclassified RCC

Table 2.2

Inherited forms of renal cell carcinoma

Syndrome

Gene

Location

Protein

Function

Histology

von Hippel–Lindau (VHL) disease

VHL

3p25

pVHL

Tumour suppressor

Clear cell RCC

Hereditary papillary renal cancer (HPRC)

cMET

7q31

Hepatocyte growth factor receptor (HGF-R)

Oncogene

Type I papillary RCC

Hereditary leiomyomatosis renal cancer (HLRCC)

FH

1q42–43

Fumarate hydratase (FH)

Tumour suppressor

Type II papillary RCC

Birt–Hogg–Dubé syndrome (BHD)

BHD

17p11.2

Folliculin

Tumour suppressor

Chromophobe RCC, oncocytoma

insertions, resulting in frame shifts of the protein-coding sequence.8 The role of the VHL protein in tumorigenesis will be discussed in the section on inherited RCC.

Other candidate genes in the 3p region Apart from the locus in 3p25-26, other loci on 3p chromosome such as 3p12, 3p14.2, 3p21.1, 3p21.3, 3p22, and 3p26.2, may be involved in clear cell RCC development or progression, and tumour suppressor genes at these loci are inactivated in this tumour. Non-papillary renal carcinoma-1 (NRC-1)

and non-papillary renal carcinoma-2 (NRC-2) genes located in 3p12 and 3p14.2 regions, respectively, have also been related to RCC.12,13 Within the NRC-2 region, the tumour suppressive region was further narrowed down to a genomic segment which contains both exons 9 and 10 of the fragile histidine triad gene (FHIT).13 Tumour suppressive activity within the NRC-1 region have also been observed in VHL-defective RCC cell lines, and it was hypothesized that NRC-1 may act either downstream from VHL within the same pathway or acted in a pathway unrelated to VHL.14 Also, a function in apoptosis

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MOLECULAR GENETICS AND PATHOGENESIS OF RENAL CANCER

has been suggested, but the exact role that NRC-1 plays in RCC awaits the identification of further candidate genes in this region. The ‘down-regulated in renal cell carcinoma’ gene (DRR1) has been identified in the chromosomal 3p21.1 region. A reduced expression of this gene in clear cell RCCs, and growth suppression after transfection of DRR1-negative cell lines with wild-type DRR1, supports a role for this gene in RCC development.15 Hypermethylation and subsequent silencing of RASSF1A, a tumour suppressor gene located in 3p21.3 region, has been demonstrated in clear cell carcinomas.16 RASSF1A shows significant homology to the mouse RAS protein Nore1 and to the rat protein Maxp1, both interacting with RAS in a GTPdependent manner.17 The presence of conserved domains in the RASSF1A protein, known to play important roles in several signal transduction pathways, supports a role for RASSF1A in RAS signalling.17 As such, inactivation of the RASSF1A gene may have the same cellular effect as oncogenic RAS mutations.17 Transforming growth factor β (TGF-ß) is a potent inhibitor of epithelial cell growth. By binding to the TGF-ß receptor complex, consisting of type I (TßR-I) and type II (TßR-II) receptors, its biological activity is exerted. The gene for the TßR-II has been mapped to chromosome 3p22. Alterations in TßR-II make epithelial tumours insensitive to the inhibitory effects of TGF-ß and are correlated with malignant progression of the tumour.18 Rescue of wild-type TßR-II activity by gene transfection restored TGF-ß responsiveness and reduced the growth rate in different subtypes of human RCC and in a mouse RCC cell line,19,20 strongly suggesting a role for TßR-II and the TGF-ß regulated pathway in RCC development.18 Further support for such a role was obtained through altered expression of proteins downstream in the TGF-ß signalling pathway, such as SMAD2 and SMAD4.21 Significant elevation of plasma TGF-ß levels have been observed in RCC patients.22

25

Another candidate gene, located on 3p26.2, is the 8-oxoguanine DNA glycosylase gene (OGG1) involved in DNA repair. LOH for this gene was found in about 85% of conventional RCCs and an inactivating mutation was also found in one RCC.23 Based on the frequent loss of chromosome 3 sequences in conventional RCCs, the chromosome 3 candidate genes discussed above are suggested to be specific for this subtype of RCC. However, silencing of the RASSF1A gene by promoter hypermethylation has been detected in papillary RCCs, and genetic alterations in the TßR-II gene have been found in other RCC subtypes.24 In addition, VHL and FHIT locus loss was found in all RCC subtypes, but differed in pattern and prognostic significance.24 Thus, there are overlaps in these tumorigenic pathways between the different RCC subtypes.

Other candidate regions No specific proto-oncogenes from 5q have been found mutated in clear cell RCC.25 With advancing grade and stage, clear cell RCCs exhibit the loss of a variety of stereotypical chromosomal regions, most commonly in 8p, 9p, 14q, 6q, and 17p chromosomes.26 RCC rarely acquires mutations in p53 tumour suppressor gene, suggesting that p53 signalling in this tumour type might be repressed by some other mechanism.27 In RCC cells, p53 undergoes all expected conversions in response to DNA damage but paradoxically does not induce transactivation. This situation can be explained either by lack of some p53 counterpart that is essential for transactivation or by the presence of an inhibitor of transactivation.27 That there is a detectable repression of p53 transactivation in normal kidney cells that is also dominant in cell fusion experiments indicates that RCC cells may use an existing kidney-specific mechanism of p53 attenuation to achieve complete inhibition of the p53 pathway.27 Abnormalities of other known tumour suppressor genes such as RB gene, MCC and APC genes, WT1 gene, and nm23 gene have been implicted in sporadic RCC.28

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Oncogenes and growth factors in sporadic renal cell carcinoma A number of oncogenes have been evaluated in sporadic RCCs. The ras family has been extensively evaluated but does not appear to be critical.29 Conflicting results have been reported concerning the expression of HER-2/neu in renal carcinomas with most investigators showing a low expression.30 Abnormal expression of the myc and fas oncogenes also has been reported in renal carcinomas with significant elevation in 50–90% of sporadic renal cancers.31,32 Other oncogenes, such as abl, fes, fms, myb, src, and raf are apparently not expressed or are expressed infrequently in RCC.32 Activation of several growth factors may be important in the pathogenesis of RCC. Epidermal growth factor (EGF), a potent mitogen, stimulates cultures of RCC cell lines.33 However, most investigators have not detected EGF in tumour tissue from patients with RCC.34 Overexpression of the EGF receptor has been reported by several investigators.34–36 Elevated levels of transforming growth factor α (TGF-α) have been observed in VHL-deficient cancer cells.37 TGF-α acts as growth-stimulating factor and induces the expression of the EGF receptor. Blockage of this receptor by a monoclonal antibody inhibits the growth of RCC cell lines cultured with TGF-α.35 TGF-α acts synergistically with TGF-ß in inducing transformation and, as such, they are both involved in RCC-related pathways.37 Other growth factors may also play a role in the initiation or proliferation of RCC. Truncated fibronectin is secreted by the ACHN RCC cell line and stimulates DNA synthesis in the absence of other growth factors.38 Hepatocyte growth factor appears to stimulate proliferation in some RCC cell lines.39 Other renal carcinoma cell lines appear to secrete an autocrine growth promoter when cultured in the presence of 5-fluorouracil.40 This growth factor potentiated the effects of EGF, TGF-ß, and other mitogens. Sera from patients with end-stage renal disease stimulate proliferation of RCC cell lines, and the uncharacterized growth factor implicated in this proliferation does not appear to be EGF, basic fibroblast

growth factor, or platelet-derived growth factor (PDGF).41

Papillary renal cell carcinoma Papillary renal cell carcinomas (PRCCs) are thought to be of renal proximal tubular origin.42 Two histological subtypes exist, classified as type I and type II.43 The type I histology is less frequent, is associated with c-MET mutations, and is seen in hereditary papillary renal cancer syndrome and occasional sporadic PRCC (with or without MET mutations). The type II form of PRCC does not harbour c-MET mutations and is the type most commonly encountered sporadically.44 A combination of gains of chromosomes 7 and 17 and loss of the Y chromosome have been found in PRCC.45–47 A relative gain of chromosome 3, 3q material, or both has sometimes been found, although not in the setting of detectable VHL gene mutations.45–47 Gains at chromosomes 16 and 20 are also common in PRCC, especially in advanced stages45–47 and chromosomal losses of 1p, 6q, and 9p have also been reported.45,46 A rare subset of PRCC contains losses of the short arm of the X chromosome that are associated with translocations to various chromosomes including T(X;1)(p11;q21), which have repeatedly been encountered.48 Positional cloning of the translocation breakpoint revealed an in-frame fusion of the TFE3 gene on the X chromosome to a novel gene, PRCC, on chromosome 1.48,49 TFE3 is a ubiquitously expressed transcription factor belonging to the family of E-box binding factors.50 Also, PRCC is an ubiquitously expressed nuclear protein characterized by a relatively high proline content, but without homology to any other known protein.49,51 The in-frame fusion results in two fusion genes, TFE3PRCC and PRCCTFE3, which are both expressed in t(X; 1)-positive tumour cells.49 The fusion protein PRCCTFE3 retains all the domains of TFE3 necessary for transcriptional activation. The PRCC protein interacts with MAD2B, a human homologue of the yeast MAD-family protein Mad2, a component of the mitotic spindle checkpoint.52 Mitotic checkpoint

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proteins have been shown to be essential for delaying the onset of anaphase and thus preventing mis-segregation of chromosomes during metaphase.53,54 The MAD2B protein has recently been found to bind indirectly to the anaphase-promoting complex (APC)55 and to act as an inhibitor of Cdh1-mediated activation of APC.53,56 There is evidence suggesting that expression of PRCC/TFE3 leads to impairment of mitotic checkpoint control through interference with MAD2B binding and thus, in a dominant-negative fashion, to PRCC development.24 Cytogenetic studies have revealed variant translocations in which TFE3 is fused to other genes such as RCC17 on chromosome 17, PSF on chromosome 1, and NonO (p54nrb) on the X chromosome (Table 2.3).48,57 As PSF and NonO (p54nrb) both encode pre-mRNA splicing factors, a similar role was suggested for PRCC.58 Although activating mutations of the MET proto-oncogene, which codes for the hepatocyte growth factor receptor, are common in families with hereditary papillary renal cancer, only a few sporadic PRCCs are found to have MET mutations.59 Nevertheless, two- to threefold gains in chromosome 7 or the 7q31 location of the MET proto-oncogene have been noted in sporadic PRCC.47,60 Gains of chromosome 7q harbouring a wild-type MET may be tumorigenic by virtue of increased gene copy number and perhaps increased cellular responsiveness to hepatocyte growth factor. The relative paucity of MET mutations found in sporadic papillary tumours may be explained by the fact that gains of wild-type MET copy number may be sufficient for tumorigenesis.60

Chromophobe renal cell carcinoma Chromophobe RCCs arise from the intercalated cells of the cortical collecting ducts.61 Cytogenetically, the chromophobe RCC shows widespread LOH of chromosomes 1, 2, 6, 10, 13, 17, and 21, and hypodiploidy due to nonrandom multiple chromosome losses.62 The loss of chromosome Y in tumours from male patients has also been noted.42 Allelic changes

27

of 3p have been also described, but these results could be explained by the tendency for the loss of the entire chromosomes of these specific RCCs.63 These multiple losses have made it challenging to define specific genes essential to the development of chromophobe RCC. The p53 tumour suppressor gene has been implicated based on the common finding of chromosome 17 loss, 17p LOH, and the detection of p53 mutations in 30% of these tumours.64 The recently cloned gene for the Birt–Hogg–Dubé (BHD) syndrome may shed light on chromophome RCC, because this neoplasm and its histological variants have been found at increased frequency in patients with this syndrome.65

Collecting duct carcinoma The collecting duct carcinoma is a rare tumour which is derived from the collecting duct epithelia.61 Data concerning the cytogenetic abnormalities of collecting duct carcinoma are scarce. Conflicting findings have been reported, with some studies detecting monosomies and others finding trisomies. Three collecting duct cancers have been characterized cytogenetically. Each cancer was consistently monosomic for chromosomes 1, 6, 14, 15, and 22.66 LOH at 1q32.1-32.2, 6p, 8p, and 21q was subsequently noted in a larger series.66–68 Gains at chromosomes 16 and 20 and losses at 1, 2, 9, 11, and 18 have also been reported.67 Trisomy 17, trisomy or tetrasomy 7, or deletion of chromosome 3p was not observed by cytogenetic analysis, differentiating these tumours from papillary and clear cell carcinoma, respectively.68

INHERITED RENAL CELL CARCINOMA AND THE BIOCHEMICAL PATHWAYS There are four types of inherited epithelial kidney cancer in which the responsible genes have been identified (Table 2.2): VHL clear cell RCC; hereditary papillary renal carcinoma (HPRC, which mainly refers to type 1 papillary renal carcinoma); the BHD syndrome

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Table 2.3 Genes involved in Xp-translocated papillary renal cell carcinoma Resultant fusion genes Translocation t(X;1)(p11.2;q21.2) t(X;1)(p11.2;p34) t(X;17)(p11.2;q25.3)

PRCC-TFE3 PSF-TFE3 RCC17-TFE3

Inversion Inv(X)(p11.2;q12)

NonO-TFE3

(in which chromophobe renal carcinoma and oncocytoma predominate); and hereditary leiomyomatosis renal cell carcinoma (HLRCC, in which type II papillary renal carcinoma and other carcinomas are included).

Von Hippel–Lindau disease: clear cell renal carcinoma In addition to the development of cerebellar haemangioblastomas, retinal cysts and angiomas, phaeochromocytomas, and pancreatic cysts, patients with VHL disease are at significant risk for the development of earlyonset, bilateral, multifocal renal tumours and renal cysts. Genetic linkage analysis of VHL families revealed the VHL gene on the short arm of chromosome 3 at the 3p25 region.69 The VHL gene has been characterized as a tumour suppressor gene.70 In hereditary cancers, patients inherit one defective tumour suppressor gene from one parent in every cell (one ‘hit’) but no tumours occur until their remaining allele becomes mutated or deleted (e.g., somatic loss, a second ‘hit’: the Knudsen hypothesis; Figure 2.1). This two-hit hypothesis is supported by the finding that all patients with VHL syndrome have been found to harbour a germline VHL gene that is either mutant or partially or completely deleted.71 Cells from the clear cell RCCs of VHL patients have also lost their normal unaffected copy of VHL.72 Because patients with familial cancers such as VHL RCC inherit a germline mutation, they only require one hit to inactivate the remaining tumour suppressor gene. Patients with sporadic tumours require two hits, which occurs less frequently.73

VHL disease appears to be a syndrome that demonstrates considerable phenotypic diversity and not all germline VHL mutations are associated with a risk of RCC development. There is a marked genotype–phenotype correlation between VHL gene mutations and manifestations of the different phenotypes. Based on these differences, VHL families have been divided into two major subgroups: VHL types 1 and 2.74,75 The first represents the most common group, and is characterized by a predisposition to develop retinal angiomas, central nervous haemangioblastomas, and conventional RCCs. The second group is subdivided into 2A and 2B. VHL type 2A is the next most common form and is characterized by a predisposition to develop phaeochromocytomas in addition to the manifestations of VHL type 1. The rarest form is VHL type 2B, which is characterized by a predisposition to develop phaeochromocytomas with little or no tendency to develop RCCs.74,75 The genotype may predict the phenotype that will actually develop, and, in some cases this has been demonstrated. Genetic alterations in the VHL gene in type 1 families mostly constitute deletion, nonsense or frameshift mutations; whereas 90% of VHL mutations found in type 2 families are missense mutations.24,75,76 A few mis-sense mutations have been described that specifically lead to VHL type 2A.24 VHL encodes two different protein isoforms. Both isoforms are capable of suppressing renal cell carcinoma growth in vivo and will be referred as pVHL.77,78 pVHL functions as a component of an ubiquitin ligase complex (VBC complex) and its best understood function relates to its ability to target specific proteins for destruction.79 pVHL forms stable complexes that contain other proteins called elongin B, elongin C, Cul2, and Rbx1.80,81 These complexes are capable of directing the covalent attachment of polyubiquitin tails to specific proteins, which serves as a signal for such proteins to be degraded by the proteasome. Several pVHL targets have been identified, including the members of the hypoxia-inducible factor α

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a

c

VHL

b

29

VHL

VHL LOH

Figure 2.1 Two-‘hit’ hypothesis of tumorigenesis in VHL disease. (a) Patients inherit a mutated VHL allele as a first ‘hit’ (black bar). (b) In kidney cells a balanced chromosomal translocation occurs. (c) Loss of heterozygosity (LOH), by losing one paternal allele is the second ‘hit’ of tumorigenesis.

(HIFα) family (HIF-1α, HIF-2α, and HIF3α). HIF-1α and HIF-2α, when bound to a HIF-ß member (such as HIF-1ß, also called ARNT), form a sequence-specific, DNA-binding transcription factor called HIF. Ordinarily, the HIFα members are highly unstable except under low-oxygen conditions. In the presence of oxygen, these proteins become hydroxylated on conserved prolyl residues in a reaction catalysed by members of the EGLN family.82–85 pVHL recognizes the hydroxylated HIF-α species and orchestrates their destruction through ubiquitination86–88 (Figure 2.2). Since the 1990s, evidence has continued to accumulate demonstrating that hypoxia is a common consequence of the rapid growth of many solid tumours, including tumours such as kidney cancer89,90 (Figure 2.3). Studies of renal cell biology also provide evidence that hypoxia is an important regulator of a network of gene expression with the ability to both stimulate and inhibit individual genes and to effect their expression on both posttranscriptional and post-translational levels.89 When there is normoxia, the VHL complex targets HIF and degrades it. In cells that lack pVHL,91 or when oxygen is limiting, the complex

cannot degrade HIF; HIF-1α and 2α are upregulated through the phosphatidylinositol 4,5-bisphosphate-AKT-mammalian target of rapamycin pathway (P13K-AKT-mTOR) and Ras/Raf/MEK/mitogen-activated protein kinase (MAPK) pathway,92 and they then form the transcription factor HIF. HIF is free to accumulate intracellularly and activates the transcription of a cadre of genes that encode proteins essential to cancer cell functions under hypoxic conditions (Table 2.4). Included among these genes are genes that control glucose uptake and metabolism (such as the Glut1 glucose transporter and various glycolytic enzymes), extracellular pH (such as carbonic anhydrase IX), angiogenesis (such as vascular endothelial growth factor [VEGF]), erythropoiesis (such as erythropoietin), and mitogenesis (such as TGF-α and PDGF-B). Signalling occurs through various cell surface receptors, including EGFR, HER2, VEGFR, and type I insulin-like growth factor receptor. These considerations explain the frequent overproduction of HIF, as well as its downstream targets, in RCC.79 pVHL binds to other cellular proteins, some of which may also be polyubiquitinated or in some other way modulated by pVHL.

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Normoxia

Hypoxia

Rbx1

E2

Ub

Elongin B

Elongin C

Cul2

pVHL

OH Ub

HIF-α

O2

Prolyl H hydroxylase

OH

Poll II P300 CBP O2

HIF-α HIF-β

HRE gene

26S proteasomes

Degradation

Hypoxic response

Figure 2.2 The VHL gene targets HIF for destruction. The interaction between HIF and VHL is promoted by oxygendependent prolyl-hydroxylation of HIF.

These proteins include the atypical protein kinase C family members,93 Sp1,94 heteronuclear ribonucleoprotein hnRNP A2,95 specific RNA Pol II subunits (Rpb1 and hsRBP796,97), Jade-1,98 Vdu1/2,99 fibronectin,100 proteins associated with microtubules,101 nuclear factor κB,102,103 and metalloproteinases.104 Although our knowledge of the functions of pVHL is still incomplete,105 studies conducted thus far highlight its role as an inhibitor of HIF, and dysregulation of HIF is likely to contribute to the development of RCC.

Hereditary papillary renal cell carcinoma HPRC is a hereditary cancer syndrome in which affected individuals are at risk for development of bilateral, multifocal type I papillary renal carcinoma.44,106 Genetic linkage analysis in HPRC families identified the proto-oncogene, c-MET, located in chromosome 7q31.1-34 to be responsible for the hereditary form of type I papillary renal carcinoma.107 HPRC-associated MET mutations are activating and the MET functions as a

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classical oncogene. MET belongs to the family of tyrosine kinases, the members of which play important roles in transmitting signals from the cellular surface to the nucleus.108 Most MET mutations have turned out to be mis-sense mutations located within the tyrosine kinase domain. MET mutations do not require concomitant loss of the remaining MET allele, as is true for the VHL gene. Instead, chromosome 7 duplications leading to trisomy 7 have been found to be associated with gain-of-function MET mutations in a majority of HPRC tumours, and genotyping analyses have demonstrated that, indeed, chromosome 7 carrying the mutant MET allele is duplicated in these papillary renal tumours.109,110 MET acts as a transmembrane receptor for the hepatocyte growth factor. Binding of this growth factor induces cellular mitogenesis, morphogenesis and cellular migration, through a growth-stimulating signalling cascade via RAS. It has been suggested that mutations in the cytoplasmic kinase domain of the MET gene might lead to constitutive activation without ligand binding and, thus, to continued activation of the signalling cascade leading to out-of-control cellular proliferation. Transfection studies in combination with biological assays indeed showed that tumorigenicity is related to enzymatic activation of MET.111

Hereditary leiomyomatosis renal cell carcinoma HLRCC is an inherited cancer syndrome in which affected individuals are at risk for the development of cutaneous and uterine leiomyoma and type II papillary renal carcinoma.112 Genome linkage analysis has linked the syndrome to 1q42-44113 and identified mutations in the gene for fumarate hydratase (FH) as the causative abnormality.114,115 These mutations were found to reduce the activity of FH, an enzyme in the tri-carboxylic acid (Krebs) cycle that is involved in energy production and amino acid metabolism. Reduced enzyme activity and associated LOH at 1q42-44 in uterine leiomyomas and renal tumours support the function of FH as a

31

tumour suppressor gene. Types of germline FH mutations in HLRCC included proteintruncating mutations, large and in-frame deletions, and mis-sense mutations.113 Mis-sense FH mutations predisposing to renal cancer had no unusual features, and identical mutations have been found in families without renal cancer, suggesting a role for genetic or environmental factors in renal cancer development in hereditary leiomyomatosis.115 Activation of the hypoxia/angiogenesis pathway may contribute to tumorigenesis in HLRCC. Microvessel density was markedly higher in uterine leiomyomas from HLRCC than in the surrounding myometrium. In HLRCC tumours, there was increased expression of transcripts from the hypoxia-responsive genes VEGF and BNIP3. It is probable that failure of the Krebs cycle in HLRCC tumours causes inappropriate signalling that the cell is in a hypoxic state, leading to angiogenesis and perhaps directly to clonal expansion and tumour growth through some uncharacterized, cell-autonomous effect.116 However, it remains to be elucidated how abnormalities in FH protein expression play a role in HLRCCrelated tumorigenesis.

Birt–Hogg–Dubé syndrome: chromophobe and oncocytic renal carcinoma and oncocytoma The BHD gene (also known as FLCN) has been mapped to chromosome 17p12-q11.2.65 To date, oncocytomas and chromophobe RCC are the most frequently described renal tumours in BHD, but hybrid-oncocytic renal carcinoma, papillary type I, and clear cell RCC have also been reported.117–121 Cytogenetic studies on the clear cell RCCs have revealed that they are identical to sporadic conventional RCCs, with frequent 3p loss and concomitant VHL inactivation and 5q gain.122 Studies on hybrid oncocytic tumours have shown few or no consistently found cytogenetic abnormalities.67 BHD gene alteration is not specific for particular histological types of RCC, unlike abnormalities in VHL (clear cell) or c-met (papillary), and suggests its role is in general

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Hypoxia signal transduction pathway EGF inhibitors: C225, ZD1839, ABXEGF VEGFR inhibitors: SU11248- SU5416 SU6668 PTK-2K BAY43-9006 EGFR inhibitors: PKI 166 OSI 774 ZD 1839 LY294002

Growth factors

Bevacizumab

Tyrosine kinase receptors (EGFR, HER2, VEGFR, IGFR)

PI3K

Ras

FIT

AKT

Raf

Bay43-9006

MTOR

MEK

PD098059 CI-1040

HIF-1α

MAPK

PTEN

Rapamycin CCI779 RAD001 Topoisomerase, Thioredoxin-1 and microtubule inhibitors

NORMOXIA

VBC complex: VHL Elongin B Elongin C Cullin 2 Rbx

HYPOXIA OR LOSS OF VHL

Mutated VHL complex: +

HIF-1α

Degradation via 26S proteasome

Mutated VHL Elongin B Elongin C Cullin 2 Rbx

17-AAG 17-DMAG

HIF-1α +

HIF-1β

Hsp90

VEGF (Angiogenesis) CA IX (pH control) EGFR (tumour growth) TGFα (tumour growth) IGF (tumour growth) Glut-1 (glucose control) CXCR4 (metastasis)

Figure 2.3 Hypoxia-inducible pathway: signalling starts with the interaction of growth factors with several tyrosine kinase cell surface receptors. The phosphatidylinositol 4,5-bisphosphate-AKT-mammalian target of rapamycin pathway (P13K-AKT-MTOR) and the Ras/Raf/MEK/mitogen-activated protein kinase (MAPK) pathway are activated. VHL protein

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Table 2.4

33

Main protein targets of the VHL protein

Target protein

Function

Hypoxia-inducible factors (HIF-1 and HIF-2) Vascular endothelial growth factor (VEGF) Glucose transporter protein (Glut-1) Platelet-derived growth factor (PDGF-β) Transforming growth factor (TGF-α, TGF-β) Intracellular fibronectin Erythropoietin Carbonic anhydrase 9 and 12 Chemokine receptor (CXCR4)

Protein transcription Angiogenesis Glucose transport Angiogenesis, mitogenesis Epithelial proliferation, mitogenesis Epithelial proliferation Erythropoiesis Extracellular pH control Metastasis

renal tumorigenesis.118 There is evidence that it acts as a tumour suppressor gene.120,121 The majority of the mutations detected were predicted to prematurely terminate the BHD protein, named folliculin, and to result in loss of its function.118 Loss of the wild-type BHD allele or somatic frameshift second-hit mutations were confirmed in renal tumours from kindreds with BHD, resulting in bi-allelic inactivation of BHD.118 Mutation analysis of the BHD gene has revealed frameshift or termination mutations in the majority of BHD families.65 There is evidence for possible genotype–phenotype associations. A mutational hotspot, a C insertion/ deletion in exon 11, is frequently mutated in BHD-affected families. Renal tumours developed with a higher frequency in C-insertion carriers than in C-deletion carriers and also more frequently in individuals who inherited a putative splice-site mutation in intron 9. The residual mutant protein produced in patients with the C-insertion mutation might have a dominant-negative effect and interfere with

the wild-type BHD protein function, leading to the development of renal tumours. Alternatively, the residual mutant protein encoded by the C-insertion mutation might predispose kidney cells to form a renal tumour by some as-yet-unknown mechanism.118 The BHD gene product, folliculin, is highly conserved, and reduced BHD expression has been seen in renal tumours from patients with BHD, regardless of the histological type.123 Nevertheless, the protein does not belong to any known protein family, and its function remains to be elucidated.67

Other hereditary renal cancers Germline constitutional chromosome 3 translocations Clear cell RCC segregation has been found in families that show constitutional balanced translocations involving chromosome 3.124 The abnormalities found include: t(3;8)(p14; q24),125 t(3;6)(p13;q25.1),126 t(2;3) (q35;q21),127

Figure 2.3 Continued complexes with elongin B, elongin C, Cullin2, and Rbx1 to form a ubiquitin ligase. In the presence of oxygen, VHL recognizes hydroxylated proline residues on HIF-1α and binds them. Once bound, HIF becomes ubiquinated and tagged for proteosome-dependent protein degradation. In the absence of oxygen or with loss of pVHL function, HIF-1α is allowed to accumulate, ultimately binding to HIF-β and resulting in increased expression of hypoxia-inducible genes. The later encode proteins essential to cancer cell functions under hypoxic conditions, such as glucose transport, angiogenesis, glycolysis, cell growth, migration and pH control. Inhibition of this pathway by small molecules targeted against various steps should at least partly reverse the molecular consequences of VHL loss of function and result in antitumour effects (grey arrows and boxes). EGFR, epidermal growth factor receptor; VEGFR, vascular endothelial growth factor receptor; IGFR, insulin growth factor receptor; MEK, mitogen-activated protein/extracellular signal regulated kinase); HIF, hypoxiainducible factor; FIT, fanesyl transferase inhibitors; VBC, ubiquitin ligase complex; Hsp90, heat shock protein-90; TGF, transforming growth factor; CA IX, carbonic anhydrase IX; CXCR4, chemokine receptor 4; Glut-1: glucose transporter-1.

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t(3;4)(p13;p16),128 t(2;3) (q33;q21),129 t(3;6) (q12; q15)130 and t(1;3) (q32; q13.3).131 These families are characterized by the somatic loss of the derivative chromosomes that, including the short arm of chromosome 3, takes place in the renal tissue. In addition, molecular studies on tumours in these families revealed that some of them carry different VHL mutations in the allele derived from the remaining ‘normal’ chromosome 3. The concurrent observations of loss of 3p derivative chromosomes and somatic VHL mutations have led to the proposition of a three-step model for the carcinogenesis process.3,24,132,133 The first hit would be the occurrence of a germ line chromosome 3 translocation; nondis-junctional loss of the derivative chromosome that carries the 3p segment would represent the second step. Finally, the third step would involve a somatic mutation in the remaining 3p allele of an RCC-related tumour suppressor gene such as VHL. However, since some of the analysed familial tumours did not carry VHL mutations, it seems likely that other tumour suppressor genes located in the 3p arm could also be involved in the development of conventional RCC.

Familial clear cell renal cell carcinoma with no known genetic abnormality Several families with a cluster of clear cell RCCs in which the renal tumours were unrelated to germline VHL mutations, chromosome 3 translocations or MET mutations, have been reported.9,10 These tumours may represent an increased predisposition to develop a first hit in unknown genes within a renal epithelial cell that leads to tumour formation that may be involved upstream or downstream of pathway orchestrated by VHL. It is also possible that these tumours could be related to an unidentified familial exposure.

Renal medullary cancers in sickle cell trait/disease Around 90 cases of renal medullary cancer have been reported, mostly in young black people with sickle cell trait, some with sickle cell disease

or other haemoglobinopathies.134 Most of the patients are men (2:1) and have very advanced disease. The molecular pathology of these tumours has not yet been ascertained.134

THE MOLECULAR PATHOGENESIS OF RENAL CELL CARCINOMA INDICATES NEW APPROACHES AND STRATEGIES FOR TREATMENT (This is discussed further in chapters 13 and 14.) Molecular targeting against RCC has already been studied in several clinical trials (Table 2.5). The VHL pathway can be targeted by blocking the transcription of HIF through inhibition of the mTOR pathway (rapamycin and analogues92,135), inhibition of the ubiquitin/proteasome system (bortezomib136) and inhibition of heat shock protein 90 (geldenamycin and 17-(allylamino)-17-demethoxygeldanamycin137). A number of other agents downregulate HIF via unknown mechanisms, including HDAC inhibitors,138 topoisomerase I inhibitors,139 thioredoxin-1 inhibitors,140 and microtubule disrupters.141 The downstream targets of HIF, such as the VEGFR, the EGFR and the PDGFR, can also be modified in several ways. Sorafenib (BAY 43-9006) is a potent inhibitor of the cellular serine/threonine kinase receptor pathway, and is active against VEGFR and PDGFR, leading to the inhibition of tumour cell proliferation and to anti-angiogenesis.142 Bevacizumab, a neutralizing antibody to VEGF, has been shown to prolong time to progression in patients with metastatic RCC.143 Cetuximab and gefitinib targeted against EGFR have also been studied but they showed no activity against RCC.144,145 Combination agents such as ZD6474 that can inhibit at least two arms of the downstream HIF pathway, VEGFR and EGFR, are currently being evaluated in clinical trials.146 Sunitinib (SU-011248) an orally bioavailable indolinone, works as a signal transduction inhibitor of VEGFR, PDGFR, and the c-kit tyrosine kinase, has shown encouraging results and is presently under

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Table 2.5

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New treatment strategies based on RCC molecular pathogenesis

Category Inhibition of the hypoxia-inducible pathway Rapamycin Rapamycin analogues CCI-779 RAD001 Raf kinase inhibitors (BAY 43-9006) Proteasome inhibitors (bortezomib, PS-341)

Mode of action

Inhibits PI3K-AKT-mTOR signal transduction pathway Inhibits PI3K-AKT-mTOR signal transduction pathway Targets Raf kinase + VEGFR-2 Inhibits 26S proteasome catalytic activity, thus preventing proteolysis

Epidermal growth factor receptor (EGFR) inhibitors Gefitinib, ZD1839 Erlotinib, OSI 774

Inhibits EGFR tyrosine kinase Inhibits EGFR tyrosine kinase

Monoclonal antibody therapy WX-250 Bevacizumab Panitumumab, ABX-EGF MDX-010 Cetuximab (C225), IMC-C225

Antibody that targets VEGF Neutralizing antibody that targets VEGF Antibody that targets EGF receptor (EGFR) Antibody that targets CTLA-4 to block lymphocyte activity Antibody that targets EGFR

Anti-angiogenesis agents Thalidomide Thalidomide analogues (CC5013) Endothelin-1 receptor antagonists (atrasentan, ABT-627) Indolinone (SU-011248) VEGFR + EGFR inhibitors (ZD 6474) VEGFR inhibitors (PTK 787)

evaluation in a phase III trial.147 Thalidomide is also a potent in vivo angiogenesis inhibitor.148 Due to its critical role in RCC biology CA IX (carbonic anhydrase IX) has been exploited as a potential target for immunotherapy.149,150 In addition the c-MET pathway may also be targeted. Studies of the activating point mutations in c-MET found in type I PRCC suggest at least three strategies for therapeutic development: (a) block kinase activation with small molecule inhibitors of ATP binding; (b) block HGF-MET interaction; and (c) block interactions between activated c-MET and downstream intracellular signalling molecules.151

CONCLUSION Many genetic and chromosomal studies characterizing each subtype of kidney tumour have been performed up to date, making RCC one of the best genetically characterized tumours.

Immunomodulatory agent with multiple actions, including VEGF + basic fibroblast growth factor inhibition Immunomodulatory agent with multiple actions, including VEGF + basic fibroblast growth factor inhibition Selective endothelin-1 receptor antagonist Inhibits VEGFR, PDGFR + FLT3 signal transduction, + c-kit tyrosine kinase Targets VEGFR 1,V EGFR Selectively targets VEGFR 1, VEGFR-2 + VEGFR-3 tyrosine kinases

With the availability of advanced molecular tools such as genomics, transcriptomics and proteomics the molecular pathogenesis of kidney tumours has been clarified. This understanding of RCC tumorigenic pathways is leading to better tumour classification and diagnosis, and will certainly result in treatment in the very near future. The role of surgery before or after treatment with these agents in patients with metastatic disease, and their role in the neoadjuvant or adjuvant setting in patients with localized disease will need further clarification.

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and neoplastic human tissues. Mod Pathol 2004; 17: 998–1011. Rodriíguez-Perales S, Meléndez B, Gribble SM et al. Cloning of a new familial t(3; 8) translocation associated with conventional renal cell carcinoma reveals a 5 kb microdeletion and no gene involved in the rearrangement Hum Mol Genet 2004; 13: 983–90. Cohen AJ, Li FP, Berg S et al. Hereditary renal-cell carcinoma associated with a chromosomal translocation. New Engl J Med 1979; 301: 592–5. Kovacs G, Brusa P, De Riese W. Tissue-specific expression of a constitutional 3; 6 translocation: development of multiple bilateral renal-cell carcinomas. Int J Cancer 1989; 43: 422–7. Koolen MI, van der Meyden AP, Bodmer D. A familial case of renal cell carcinoma and a t(2; 3) chromosome translocation. Kidney Int 1998; 53: 273–5. van Kessel A, Wijnhoven H, Bodmer D et al. Renal cell cancer: chromosome 3 translocations as risk factors. J Natl Cancer Inst 1999; 91: 1159–60. Podolski J, Byrski T, Zajaczek S et al. Characterization of a familial RCC-associated t(2; 3)(q33; q21) chromosome translocation. J Hum Genet 2001; 46: 685–93. Eleveld MJ, Bodmer D, Merkx G et al. Molecular analysis of a familial case of renal cell cancer and a t(3; 6)(q12; q15). Genes Chrom Cancer 2001; 31: 23–32. Kanayama H, Lui WO, Takahashi M et al. Association of a novel constitutional translocation t(1q; 3q) with familial renal cell carcinoma. J Med Genet 2001; 38, 165–170. Schmidt L, Li F, Brown RS et al. Mechanism of tumorigenesis of renal carcinomas associated with the constitutional chromosome 3;8 translocation. Cancer J Sci Am 1995; 1: 191. Bodmer D, Eleveld MJ, Ligtenberg MJ et al. An alternative route for multistep tumorigenesis in a novel case of hereditary renal cell cancer and a t(2; 3)(q35; q21) chromosome translocation. Am J Hum Genet 1998; 62: 1475–83. Simpson L, He X, Pins M et al. Renal medullary carcinoma and ABL gene amplification. J Urol 2005 173: 1883–8. Atkins MB, Hidalgo M, Stadler WM et al. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamy-cin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 2004; 22: 909–18. Davis NB, Taber DA, Ansari RH et al. Phase II trial of PS-341 in patients with renal cell cancer: a University of Chicago phase II consortium study. J Clin Oncol 2004; 22: 115–19. Neckers L. Hsp90 inhibitors as novel cancer chemotherapeutic agents. Trends Mol Med 2002; 8: S55–61. Kim MS, Kwon HJ, Lee YM et al. Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes. Nat Med 2001; 7: 437–43.

139. Rapisarda A, Uranchimeg B, Sordet O et al. Topoisomerase I-mediated inhibition of hypoxiainducible factor 1: mechanism and therapeutic implications. Cancer Res 2004; 64: 1475–82. 140. Welsh S, Williams R, Kirkpatrick L et al. Antitumor activity and pharmacodynamic properties of PX478, an inhibitor of hypoxia-inducible factor1alpha. Mol Cancer Ther 2004; 3: 233–44. 141. Mabjeesh NJ, Escuin D, LaVallee TM et al. 2ME2 inhibits tumor growth and angiogenesis by disrupting microtubules and dysregulating HIF. Cancer Cell 2003; 3: 363–75. 142. Ratain MJ, Flaherty KT, Stadler WM et al. Preliminary antitumor activity of BAY 43-9006 in metastatic renal cell carcinoma and other advanced refractory solid tumors in a phase II randomized discontinuation trial (RDT). Proc Am Soc Clin Oncol 2004; 23: 381, abstract 4501. 143. Yang JC, Haworth L, Sherry RM et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003; 349: 427–34. 144. Motzer RJ, Amato R, Todd M et al. Phase II trial of antiepidermal growth factor receptor antibody C225 in patients with advanced renal cell carcinoma. Invest New Drugs 2003; 21: 99–101. 145. Drucker BJ, Schwartz L, Marion S et al. Phase II trial of ZD (Iressa), an EGF inhibitor, in patients with advanced renal cell carcinoma. Proc Am Soc Clin Oncol 2002; 21: 181a, abstract 720. 146. Ciardiello F, Caputo R, Damiano V et al. Antitumor effects of ZD6474, a small molecule vascular endothelial growth factor receptor tyrosine kinase inhibitor, with additional activity against epidermal growth factor receptor tyrosine kinase. Clin Cancer Res 2003; 9: 1546–56. 147. Motzer RJ, Michaelson MD, Redman BG et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 2006; 1; 24(1): 16–24. 148. Bartlett JB, Michael A, Clarke IA et al. Phase I study to determine the safety, tolerability and immunostimulatory activity of thalidomide analogue CC-5013 in patients with metastatic malignant melanoma and other advanced cancers. Br J Cancer 2004; 90: 955–61. 149. Bleumer I, Knuth A, Oosterwijk E et al. A phase II trial of chimeric monoclonal antibody G250 for advanced renal cell carcinoma patients. Br J Cancer 2004; 90: 985–90. 150. Atkins M, Regan M, McDermott D et al. Carbonic anhydrase IX expression predicts outcome of interleukin 2 therapy for renal cancer. Clin Cancer Res 2005; 15: 3601–3. 151. Linehan WM, Vasselli J, Srinivasan R et al. Genetic Basis of Cancer of the Kidney Disease-Specific Approaches to Therapy. Clin Cancer Res 2004; 10: 6282S–6289S.

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3

Sara Ramsey, Michael Aitchison

PRESENTATION Changing patterns in presentation The classic presentation of renal cell carcinoma (RCC) is a triad of symptoms and signs: haematuria, loin pain, and a palpable flank mass. This triad is now often referred to as the ‘too late triad’ and is rarely seen outwith the medical student’s textbook. Even in the 1950s, prior to modern imaging techniques, it was noted that presentation with the classic triad was rare, and associated with advanced disease.1 Studies by Jayson and Saunders in 19982 and Skinner et al in 19713 both from America, have shown that presentation with the classic triad is rare, comprising less than 2% and 10% of symptomatic presentations, respectively. The overall presentation of RCC is changing with increasing numbers of patients diagnosed with asymptomatic, incidentally detected tumours. The figures are now historical, but it was estimated that in the late 1990s over 60% of renal tumours were diagnosed incidentally, compared with around 10% in the early 1970s.2–4 This change has been linked to a significant increase in use of non-invasive imaging such as ultrasound and computed tomography (CT) throughout the population, and a population that is ageing as a whole. However, no figures regarding modes of presentation in the 21st century have been published to confirm this trend. Though incidental diagnosis may lead to an increase in numbers of early-stage tumours, figures from the American SEER (surveillance, epidemiology, and end results) study show an increase

in all stages of renal cancer including metastatic disease.5

Classical presentation Haematuria, whether frank or microscopic, is the most common presenting symptom or sign in patients with RCC.3,6 The mechanism of haematuria is usually ascribed to invasion of the collecting system. However, when frank and microscopic invasion of the collecting system was assessed in one study, 14% of patients had pathological evidence of invasion, yet only half of this group had haematuria as a presenting symptom.7 The mechanism of haematuria in RCC is unclear, particularly in individuals who have a solitary episode. Loin pain may present as either acute or chronic pain. Subcapsular haemorrhage or clot colic may cause acute pain, often mimicking classic ureteric colic. Capsular stretching or local infiltration of surrounding structures may lead to loin pain that is more chronic in nature. Kidneys are usually impalpable, though the lower pole of the right kidney may be palpable in thin, relaxed patients. Patients may be aware of a ‘fullness’ in the abdomen, or the mass may be identified incidentally on clinical examination. The kidney needs to be significantly enlarged before it is palpable, though obviously the patient’s body habitus is an important determinant. The presence of a flank mass is a comparatively rare mode of presentation, and accounted for less than 5% of symptomatic presentation in a recent study.8

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Renal cancer is often referred to as the ‘physician’s tumour’ due to its numerous and varied presenting symptoms in addition to the classic triad. These can be subclassified into symptoms resulting from the local effect of the tumour, symptoms relating to major vessel involvement from tumour thrombus or invasion, symptoms from metastatic disease, and paraneoplastic phenomena.

and brain are among the most frequently encountered metastatic sites and common presenting symptoms related to these are dyspnoea, bone pain, and neurological disturbances, respectively. Cutaneous deposits are also relatively common though the underlying diagnosis may only be made after excision biopsy. Table 3.1 illustrates the frequency of various metastatic sites recorded in one study of patients with metastatic RCC.9

Local effects Local effects from the tumour may include loin pain and haematuria. Local invasion may not only cause pain, but also disruption of the invaded structure. Right-sided tumours may invade or compress the duodenum or biliary tree leading to gastrointestinal symptoms and occasionally jaundice. RCC is unique in its propensity to propagate along the venous system into the inferior vena cava (IVC) and then cranially towards the right atrium. This involvement either by tumour thrombus or by direct invasion of the vessel wall may cause a number of presenting symptoms. These include a left-sided varicocele, or varicocele that persists despite the patient’s recumbency, due to obstruction of the left gonadal vein as it drains into the left renal vein. Rarely, a right-sided varicocele may result from extensive IVC thrombosis obstructing the right gonadal vein. Bilateral lower limb oedema or bilateral deep vein thrombosis may also result from IVC involvement. Tumour thrombus may be identified during routine echocardiography if it has propagated to the right atrium, or due to symptomatic pulmonary emboli.

Distant effects The pattern of metastases in renal cancer is diverse, with a propensity for unusual metastatic sites, and virtually every organ in the body has been recorded as a site of metastasis from RCC. Subsequently, symptomatic presentation of metastatic disease is heterogeneous, and, in addition, patients may be completely asymptomatic despite disseminated RCC. Lung, bone,

Paraneoplastic effects RCC is probably associated with the widest range of paraneoplastic phenomena of any tumour. Paraneoplastic syndromes are constitutional symptoms or derangement of normal biochemistry or haematology which are associated with the presence of a neoplasm, though not caused directly by the primary tumour. They are estimated to occur in 10–40% of patients with RCC.10 Paraneoplastic disorders are more usually associated with metastatic disease, but may be present in patients with localized primary tumours, and tend to resolve after curative resection. They can be subdivided into endocrine and non-endocrine syndromes, depending on the nature of the proteins secreted by the tumour. Endocrine paraneoplastic effects may be due to hypersecretion of a substance normally associated with the kidney such as renin; or due to secretion of an abnormal hormone or hormone-like protein. Syndromes associated with normal kidney secretion include hypertension due to excess renin secretion, and polycythaemia secondary to increased erythropoietin release. Abnormal endocrine secretions include parathormone-related peptide which mimics parathyroid hormone (PTH) leading to hypercalcaemia without bony metastatic involvement.10 Non-endocrine paraneoplastic syndromes include weight loss, fever, night sweats, and fatigue, and may be related to the development of a systemic inflammatory response. It has been suggested that these systemic symptoms are related to interleukin-6 secretion, a proinflammatory cytokine.11 Other non-endocrine

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Table 3.1

Location of metastases

Site of metastasis Lung Soft tissue Bone Liver Central nervous system Skin Other

Single site (%) Multiple sites (%) 72 10 11 5.5 1.4 0 0

77 54 26 26 12 13 7

syndromes include non-metastatic hepatic dysfunction, known as Stauffer syndrome.12 This was first described in 1961 when five cases were recorded with hepatosplenomegaly, grossly abnormal liver function tests, and elevated prothrombin times in the absence of metastatic hepatic involvement. It has been suggested that the underlying cause is hepatic sinusoidal dilatation. This dysfunction is reversible, and biochemical parameters may return to normal after nephrectomy. Anaemia is common despite the endocrine paraneoplastic secretion of erythropoietin. It is estimated that 25–33% of patients with RCC will have a normochromic, normocytic anaemia while only 3% of patients will have polycythaemia.13,14

STAGING The purpose of a cancer-related staging system is to stratify patients into clinically meaningful and distinct categories. These should be devised to allow accurate prognosis of disease, provide information regarding treatment, and allow comparison of outcomes between centres. However, to devise a staging system that fulfils these criteria it is necessary to understand the natural history and biology of the disease. It could be argued that some of the difficulties with staging of renal cancer relate to areas of tumour biology not yet fully understood. The earliest staging system for RCC was devised by Flocks and Kadesky in 195815 and subsequently modified by Robson in 1963.16 This was a simple four-stage system, involving nodal and venous involvement, and the

43

presence of metastatic disease. The tumour node metastases system was devised by Denoix in 1944 and adapted for renal cell cancer in 1978;17 and it is now in its sixth edition following further revision in 2002 (Table 3.2). Its strengths lie in its adaptability, and it offers 72 possible different combinations of each variable. However, it is argued that compressing the variables into four major stages loses some of the prognostic value and areas of controversy still persist.

Areas of controversy/ future modification Discrimination between T1 and T2 tumours is based purely on tumour size, and the cut-off point has undergone numerous revisions. It was lowest in 1987 at 2.5 cm and was raised to 7 cm in the 1997 revision. This breakpoint was chosen arbitrarily as it represented the mean size of tumours in the SEER database. The change was brought about as there was not a significant survival difference between T1 and T2. However, similar criticism has been applied to the current subdivision. A number of authors have examined prognosis and different subdivisions and the general consensus is that the current 7 cm cut-off is too high. However, there is no clear consensus on where the reduced breakpoint should be placed. Various authors have proposed new cut-offs from 3.5 cm to 5.5 cm18,19 though the most common breakpoint suggested is 5 cm, and this may be adopted in future revisions.20,21 A further subdivision of T1 was introduced in 2000 to aid in prognostication and patient selection for nephron-sparing surgery (NSS), with 4 cm chosen as the cut-off between T1a and T1b. This selection has demonstrated a distinct survival advantage for patients with T1a tumours undergoing NSS22 and has recently been validated in patients undergoing radical nephrectomy.23 It could be argued that the current T1a subdivision of 4 cm should be adopted as the T1/T2 breakpoint. No survival difference has been shown between patients with T1b and T2 tumours with the present values,19 and any reduction in

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Table 3.2

TNM Staging System 2002

Tumour Tx T0 T1a T1b T2 T3

T4

Primary tumour cannot be assessed No evidence of primary tumour Tumour less than 4 cm, limited to the kidney Tumour greater than 4 cm, no greater than 7 cm, limited to the kidney Tumour greater than 7 cm in greatest dimension, limited to the kidney Tumour extends into major veins or perinephric fat but not beyond Gerota’s fascia. T3a: Tumour invades perinephric tissues but not beyond Gerota’s fascia T3b: Tumour grossly extends into renal vein(s) or vena cava below diaphragm T3c: Tumour grossly extends into vena cava above diaphragm Tumour invades beyond Gerota’s fascia

Nx N0 N1 N2

Regional lymph nodes cannot be assessed No regional lymph node metastasis Metastasis in a single regional lymph node Metastasis in more than one regional lymph node

Mx M0 M1

Distant metastases cannot be assessed No distant metastases Distant metastases

Nodes

Metastases

the T1/T2 breakpoint may make the T1b classification essentially redundant. Adrenal involvement is more common in upper pole tumours and is estimated to occur in less than 5% of cases.24 Ispilateral adrenal involvement is currently classified as to whether it is involved via direct spread, and classified T3a, or is metastatic deposit and classified M1. However, patients with direct invasion of the adrenal have been shown to have poorer prognosis than other patients with capsular penetration and perinephric fat invasion, also T3a tumours.25 It has been proposed that adrenal extension is reclassified as T4 disease. Subdiaphragmatic IVC involvement was reclassified as T3b in the fifth revision, along with renal vein involvement. Guides for pathologist emphasise that a ‘major’ vein must be involved for T3b RCC to be diagnosed. It is recommended that a major renal vein is defined as containing muscle within the wall but pathologists have complained that classification of a vein as ‘major’ may vary between institutions and pathologists. Nodal disease is known to convey a poorer prognosis even with a favourable T stage and no distant disease. The 5-year survival for patients with nodal invasion is estimated to be

between 7% and 17% even with apparently curative nephrectomy.26 In view of this, it has been suggested that N1/2 nodal disease should be upstaged to stage 4 as the outcome is clearly poorer when compared with patients with perinephric fat or venous involvement in stage 3.

RADICAL NEPHRECTOMY Charles Robson was the founder of the radical nephrectomy with oncological principles for managing RCC. He proposed his staging classification and operative technique in 1963, and published his long-term results in 1969. Robson’s radical nephrectomy used a thoraco-abdominal approach, with the kidney and adrenal removed en bloc within Gerota’s fascia. Robson emphasized the importance of early control of the vessels to prevent dissemination of tumour cells or thrombus into the systemic circulation. He also described a full nodal clearance with dissection extending from the crus of diaphragm to aortic bifurcation. As with all pioneers, Robson’s approach has been modified over the years due to refinements in surgical technique and advances in surgical technology. Laparoscopic radical

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nephrectomy has now become the gold standard for patients with RCC. It is minimally invasive, with reduced pain, shorter hospital stay, and earlier return to work; long-term follow-up has now revealed equal oncological effectiveness when compared with open radical nephrectomy in treating T1/T2 disease.27 Laparoscopic techniques tend to favour removal of the adrenal en bloc with the kidney and new figures may be produced for the rates of involvement of the adrenal if it is routinely excised. The technique of partial nephrectomy, developed at the Cleveland Clinic, Ohio,28 is becoming widespread and is no longer restricted for imperative cases where there is an anatomical or functional single kidney, chronic renal failure, or previous nephrectomy. Cancerspecific survival of 100% at 10 years has been reported for unilateral tumours of less than 4 cm treated with NSS in specialist centres.29 Routine nodal dissection as advised by Robson has fallen out of favour. Distant metastases occur commonly without the presence of regional nodal disease as metastases are propagated through the bloodstream as well as the lymphatics. While nodal dissection is useful for staging and removing all involved tissue is essential for ‘cure’ it is argued that routine nodal dissection overtreats many patients, and may increase operative morbidity. It has been suggested that nodal sampling, where between four and eight nodes are removed, may be adequate to determine nodal status,30 though a more recent study has suggested at least 12 nodes are required to prevent false negative nodal staging.31 However, the presence of micrometastases in nodes that are not enlarged either on imaging or clinically at laparotomy is exceptionally rare;32 and it has also been shown that enlarged nodes on preoperative imaging are commonly reactive rather than metastatic.33 A randomized trial was attempted to compare nodal dissection and nephrectomy with radical nephrectomy alone (EORTC 30881). Preliminary results suggested no significant difference in operative complications between the two groups,34 but no long-term results have been published.

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Handfield-Jone RM, Porritt AE. The Essentials of Modern Surgical Practice, 4th edition. ES Livingstone Ltd, 1951. Jayson M, Saunders H. Increased incidence of serendipitously discovered renal cell carcinoma. Urology 1998; 51(2): 203–5. Skinner DG, Colvin RB, Vermillion CD et al. Diagnosis and management of renal cell carcinoma. Cancer 1971; 28(5): 1165–77. Konnak JW, Grossman HB. Renal cell carcinoma as an incidental finding. J Urol 1985; 134: 1094–6. Hock LM, Lynch J, Balaji KC. Increasing incidence of all stages of kidney cancer in the last 2 decades in the United States: An analysis of surveillance, epidemiology and end results program data. J Urol 2002; 167: 57–60. Ritchie AWS, Chisholm GD. The natural history of renal carcinoma. Semin Oncol 1983; 10(4): 390–400. Uzzo RG, Cherullo EE, Myles J et al. Renal cell carcinoma invading the urinary collecting system: Implications for staging. J Urol 2002; 167: 2392–6. Tsui KH, Shvarts O, Smith RB. Renal cell carcinoma: Prognostic significance of incidentally detected tumours. J Urol 2000; 163: 426–30. Maldazys JD, deKernion JB. Prognostic factors in metastatic renal carcinoma. J Urol 1986; 136: 376–9. Gold PJ, Fefer A, Thompson JA. Paraneoplastic manifestations of renal cell carcinoma. Semin Urol Oncol 1996; 14(4): 216–22. Blay JY, Rossi JF, Wijdenes J et al. Role of interleukin-6 in the paraneoplastic inflammatory syndrome associated with renal-cell carcinoma. Int J Cancer 1997; 72: 424–30. Stauffer MH. Nephrogenic hepatosplenomegaly. Gastroenterology 1961; 40: 694. Chisholm GD, Roy RR. The systemic effects of malignant renal tumours. Br J Urol 1971; 43: 687–700. Marshall FF, Walsh PC. Extrarenal manifestations of renal cell carcinoma. J Urol 1977; 117: 439–40. Flocks RH, Kadesky MC. Malignant neoplasms of the kidney: an analysis of 454 patients followed 5 years or more. J Urol 1958; 79: 196–201. Robson CJ. Radical nephrectomy for renal cell carcinoma. J Urol 1963; 89: 37–41. Harmer M. TNM Classification of Malignant Tumours, 3rd edition. Geneva: International Union Against Cancer, 1978. Wunderlich H, Dreihaupt M, Schlichter A et al. New cut-off point between T1 and T2 renal cell carcinoma – necessary for a better discriminatory power of the TNM classification. Urol Int 2004; 72: 123–8. Ficarra V, Novara G, Galfano A et al. Application of TNM, 2002 version, in localized renal cell carcinoma: is it able to predict different cancer-specific survival probability? Urology 2004; 63(6): 1050–4.

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Zucchi A, Mearini L, Mearini E et al. Stage pT1 renal cell carcinoma: Review of the prognostic significance of size. Urol Int 2003; 70: 47–50. Elmore JM, Kadesky KT, Koeneman KS et al. Reassessment of the 1997 TNM classification system for renal cell carcinoma. Cancer 2003; 98: 2329–34. Hafez KS, Fergany AF, Novick AC. Nephron-sparing surgery for localized renal cell carcinoma: impact of tumour size on patient survival, tumour recurrence and TNM staging. J Urol 1999; 162: 1930–3. Salama ME, Guru K, Stricker H et al. pT1 substaging in renal cell carcinoma: validation of the 2002 TNM staging modification of malignant renal epithelial tumours. J Urol 2005; 173: 1492–5. Sagalowsky AI, Kadesky KT, Ewalt DM et al. Factors influencing adrenal metastasis in renal cell carcinoma. J Urol 1994; 151: 1181–4. Han KR, Bui MT, Pantuck AJ et al. TNM T3a renal cell carcinoma: adrenal gland involvement is not the same as renal fat invasion. J Urol 2003; 169: 899–904. Bassil B, Dosoretz D, Prout GR. Validation of the tumour, nodes and metastasis classification of renal cell carcinoma. J Urol 1985; 134: 450–4. Permpongkosol S, Chan DY, Link RE et al. Longterm survival analysis after laparoscopic radical nephrectomy. J Urol 2005; 174(4pt1): 1222–5.

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Licht MR, Novick AC. Nephron-sparing surgery for renal cancer. J Urol 1993; 148(1): 1–7. Fergany AF, Hafez K, Novick AC. Long-term results of nephron-sparing surgery for localized renal cell carcinoma: 10-year follow-up. J Urol 2000; 163: 442–5. Guinan P, Sobin LH, Algaba F et al. TNM staging of renal cell carcinoma. Workgroup No.3 Union Internationale Contre le Cancer. Cancer 1997; 80(5): 992–3. Terrone C, Guercio S, De Luca S et al. The number of lymph nodes examined and staging accuracy in renal cell carcinoma. BJU Int 2003; 91(1): 37–40. Minervini A, Lilas L, Morelli G et al. Regional lymph node dissection in the treatment of renal cell carcinoma: is it useful in patients with no suspected adenopathy before or during surgery? BJU Int 2001; 88: 169–72. Blom JHM, van Poppel H, Marechal JM et al. Radical nephrectomy with and without lymph node dissection: preliminary results of the EORTC randomized phase III protocol 30881. Eur Urol 1999; 36: 570–5. Studer UE, Scherz S, Scheidegger J et al. Enlargement of regional lymph nodes in renal cell carcinoma is often not due to metastases. J Urol 1990; 144: 243–5.

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The pathological appearance of renal tumours

4

Stewart Fleming

INTRODUCTION Renal malignancy is common and is rapidly increasing in incidence. It accounts for 2.5% of malignancies and is ranked ninth in incidence for men and twelfth for women in the UK. Furthermore, its incidence has almost doubled in the past 20 years. The reasons for this rapid increase in incidence are unclear, but epidemiological evidence has shown correlations with tobacco smoking, obesity, and hypertension. Worldwide it is a significant healthcare problem, particularly in industrialized countries, including eastern Europe, but high incidence rates are also recorded in Uruguay, Argentina, and Brazil. The UK has an annual rate of 11–12/100 000 of population/year and, therefore, a little over 6000 new cases/year. From the 1980s onwards there have been significant advances in our understanding of the genetic abnormalities that lead to the development of renal carcinoma. Emerging from these data is evidence of a strong correlation between the histological appearance of the tumour and the underlying genetic abnormalities. This correlation appeared to extend to risk factors, clinical behaviour, and eventual outcome. These advances in genetics have underpinned the modern classification of renal carcinoma. Conferences to formulate a classification of renal carcinoma were held in Heidelberg, Germany, and Rochester, USA, in 1996.1,2 This classification was based on an understanding of genetic abnormalities but sought to be applicable employing standard histological techniques. In 2004, the most recent World Health Organization (WHO) classification was published,3 not only reflecting our current thinking on the classification

of renal malignancy and its close association with genetic abnormality, but also recognizing a number of new variants that have been described since the publication of the Heidelberg and Rochester classifications. The WHO classification is now to be recommended as the standard for clinical practice and research and is summarised in Table 4.1.

MALIGNANT RENAL EPITHELIAL TUMOURS Clear cell renal cell carcinoma By far the most common renal epithelial tumour encountered in clinical practice is the clear cell renal cell carcinoma (clear cell RCC), accounting for around 75% of all primary malignant renal tumours in adults. Originally its separation as a distinct biological entity, despite a range of morphological appearances, was based on the frequent finding of chromosome 3p loss associated with either mutation or methylation dependent inactivation of the von Hippel–Lindau (VHL) gene.4–6 These tumours are usually solitary (> 95%), located in the cortex and occur with equal frequency in both kidneys. The finding of multicentricity and/or bilaterality together with an early age of onset should raise suspicion of a hereditary cancer syndrome such as von Hippel–Lindau syndrome.7 Clear cell carcinomas usually grow as a solid bosselated mass frequently protruding from the kidney surface while often retaining a surrounding fibrous capsule (Figure 4.1). On sectioning, the interface with the adjacent kidney, in most cases, is seen to be of a pushingtype margin. A more infiltrative border is

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Table 4.1 WHO classification of epithelial tumours of the kidney3 Benign Renal adenoma Metanephric adenoma Nephrogenic adenofibroma Oncocytoma Malignant Renal cell carcinoma clear cell Morphologic variants: Multilocular clear cell renal cell carcinoma Papillary renal cell carcinoma type 1 or 2 Chromophobe renal carcinoma Collecting duct carcinoma Medullary carcinoma of kidney Low-grade collecting duct carcinoma Mucinous tubular and spindle cell carcinoma Primary neuroendocrine tumours of the kidney Carcinoid Neuroendocrine carcinoma Primary neuroectodermal tumour Phaeochromocytoma Mixed epithelial and stromal tumour of kidney Oncocytoid renal tumour associated with neuroblastoma

typical of high-grade or sarcomatoid progression in RCC. These tumours can grow to very large dimensions of up to 15 cm, however, the mean size at presentation is now 6.5 – 7 cm. With modern imaging techniques earlier asymptomatic presentation is more common and tumours under 4 cm are encountered with increasing frequency. The tumour has a yellow/white appearance to the cut surface. Areas of haemorrhage and necrosis are particularly common. The yellow colour is due to a high lipid and glycogen content, which is also responsible for the clear cell appearance on histological examination. The histological appearances give rise to the terminology for this tumour type although morphology can be quite varied. The typical clear cell RCC is composed of clear or granular cells, but shows a range of architectural patterns, the commonest being solid, alveolar, or tubular (Figure 4.2). The cells have a clear cytoplasm with distinct cell membranes, although some histological fields and indeed the bulk of some tumours may be composed of cells with a pale eosinophilic cytoplasm

Figure 4.1 Clear cell carcinoma usually grows as a solid lobulated or bosselated mass, frequently with a surrounding fibrous capsule. The cut surface of the tumour is soft and yellow-white with areas of haemorrhage and necrosis. (See Colour Plate Section).

Figure 4.2 This typical clear cell carcinoma has an alveolar architecture composed of clear cuboidal cells supported by a rich sinusoidal microvasculature. (See Colour Plate Section).

showing fine granularity. In the latter, welldefined cell borders are retained. The nucleus in general is small and round but great variation within tumours and between

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Table 4.2 Grade

Fuhrman nuclear grading of renal carcinoma8 Features

Grade 1 Round uniform nuclei approximately 10 µm in diameter with minute or absent nucleoli Grade 2 Slightly irregular nuclear contours and diameter of approximately 15 µm with nucleoli visible at × 400 Grade 3 Moderately to markedly irregular nuclear contours and diameter of approximately 20 with large nucleoli visible at × 100 Grade 4 Nuclei similar to grade 3 but also multilobular, multiple or bizarre nuclei and heavy clumps of chromatin

cases is encountered. This variation correlates with clinical behaviour, so in this field of histopathology, tumour grading is based entirely on nuclear morphology. After stage, the nuclear grade is the most important prognostic feature of clear cell RCC. There are several grading systems but that of Fuhrman and colleagues is now the most widely used.8 However, there is great subjectivity in its application.9 In practice, the Fuhrman grade is governed by the highestgrade nuclear component regardless of its prevalence. The Fuhrman grading system has four categories (Table 4.2), however, many outcome studies show only three significant survival groups.10 In some studies Fuhrman grades 1 and 2 cannot be separated at end point while in others grades 2 and 3 are indistinguishable. The interpretation of these data is that the difficulty appears to lie in the rigour applied to grading, particular in designation of the upper and lower boundaries of grade 2 by histopathologists. This interobserver variation makes interpretation of the literature somewhat unreliable in this area. Mitoses in general are infrequent although in high-grade tumours they may be readily identified and will be frequently of abnormal morphology. In addition to nuclear grade we now recognise that the most aggressive clear cell RCCs (around 5%) show loss of the epithelial phenotype and transformation to a sarcomatoid variant which shows a spindle cell morphology and an infiltrative growth pattern.11 This sarcomatoid progression of RCC confers a dismal prognosis. The vast majority of clear cell RCCs show loss of regions of the short arm of chromosome 3, and are accompanied by either mutation or methylation-dependent inactivation of the VHL

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gene located on 3p25.4–6 This pattern of genetic loss is typical of an oncosuppressor gene with two hits required for tumour development. Much work has been done on the role of the VHL gene in renal tumorigenesis, and the evidence would now suggest that the mutant form of pVHL fails to regulate hypoxia-inducible factors (HIFs), especially HIF-1α. This in turn leads to upregulation of a number of growth factors including platelet-derived growth factor (PDGF) and transforming growth factor β (TGFβ), as well as up-regulation of the angiogenic factor vascular endothelial growth factor (VEGF). Further genetic abnormalities accumulate at other chromosomal locations as the tumour progresses/metastasizes. There is also recent evidence suggesting involvement of further tumour suppressor genes on 3p, including RASSF1A and NRC-1.12 Although most clear cell RCC are readily classified as such, some relatively recently identified morphological variants of clear cell RCC are worth recognizing, in particular the multilocular cystic RCC, which has a significantly better prognosis and is defined as a separate category in the WHO classification.

Multilocular cystic renal cell carcinoma3,13 This is a tumour composed entirely of cysts with intervening thin fibrous septae. The cyst lining and septae contain either single layers or small aggregates of clear cells identical to those of a clear cell carcinoma. The cells have clear cytoplasm, and are usually cuboidal, but may be flat. They have small dark nuclei lacking pleomorphism and mitotic figures and correspond to Fuhrman grade 1. The septae are fibrous, sometimes with inflammatory infiltrates and calcification is found in about 20% of cases. Tumours of this type rarely, if ever, metastasize. Care is required in distinguishing them from multilocular cystic nephroma.

Renal cell carcinoma with rhabdoid features RCC with rhabdoid features has been demonstrated to have a much more aggressive course

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Figure 4.3 In the uncommon renal cell carcinoma with rhabdoid features there is marked pleomorphism with eosinophilic cytoplasmic inclusions causing eccentric displacement of the nucleus. (See Colour Plate Section)

than conventional clear cell carcinoma.14,15 However, when one corrects for nuclear grade it is debatable whether this is a real difference. The tumour consists of polygonal cells with eosinophilic cytoplasmic inclusion bodies. These inclusions cause eccentric displacement of a vesicular nucleus, showing marked pleomorphism, usually with a prominent single nucleolus and high mitotic activity (Figure 4.3). There is a loss of cohesion with necrosis, and haemorrhage is almost uniformly seen. In a number of cases, more typical clear cell areas are recognized and the immunocytochemical reactivity pattern is similar to that of clear cell carcinoma. These tumours are probably best regarded in a similar way to sarcomatoid renal carcinoma as a progression feature of clear cell cancer rather than as a separate entity in their own right; nevertheless recognition of the existence of this entity with its rhabdoid morphology may assist in pathological diagnosis.

Pigmented renal cell carcinoma Occasionally, clear cell carcinoma shows an unusual morphological appearance with deep black or dark brown pigmentation.16 This is often seen macroscopically during dissection and histologically the cells have intensely

pigmented granular cytoplasm. The tumour cells lack melanosomes and neurosecretory granules, but the pigmented granules frequently stain for lysosomal components. Electron microscopy usually shows degenerate lysosomal bodies. The pigmentation differs from the haemosiderin that is seen frequently in renal carcinomas following haemorrhage. Although this tumour type is not an entity separate from clear cell carcinoma, its recognition is important to distinguish it from other pigmented tumours such as metastatic malignant melanoma, occasional pigmented areas in epitheloid angiomyolipoma and the recently described melanotic perivascular epithelioid clear cell tumour of the kidney.17

Papillary renal cell carcinoma Papillary renal cell carcinoma accounts for about 15% of surgical series and shows several differences from clear cell RCC. Papillary RCC exhibits different epidemiological patterns from clear cell RCC. It may be familial, is more common in men and is the variant of RCC seen in the dialysis population with acquired renal cystic disease. It is also much more commonly multifocal and bilateral. On macroscopic inspection the tumour is well circumscribed, often with a fibrous capsule. It is a red/brown or grey tumour which frequently contains areas of haemorrhage, necrosis and cystic degeneration. Histologically the tumour is composed of a papillary architecture, papillae being lined by a single layer of either a cuboidal or columnar epithelium. At around the time of publication of the Heidelberg and Rochester conferences, Delahunt and Eble18 presented compelling evidence for two subtypes of papillary RCC which could be recognized morphologically and which had a discrete clinical outcome. The type I papillary RCC comprised well-differentiated cuboidal cells with mild nuclear pleomorphism and a low mitotic rate. Type II tumours comprised columnar epithelial cells of higher nuclear grade, often with areas of necrosis and significant mitotic activity (Figure 4.4). The type II tumours had a

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Figure 4.5 Collecting duct carcinoma has an infiltrating branching tubular morphology eliciting a stromal response from the surrounding kidney. (See Colour Plate Section). Figure 4.4 The Type 2 variant of papillary renal cell carcinoma comprises columnar cells with some pleomorphism but like the type 1 arranged as a single layer of cells supported in a papillary architecture by a fibro-vascular core. (See Colour Plate Section).

clinical outcome no different from clear cell carcinoma, whereas the type I papillary renal cell carcinoma appear to have a more benign course. The distinction with respect to the two subtypes of papillary renal cell carcinoma, based on the tumour epithelial morphology, is included in the 2004 WHO classification. The septae of papillae are often indistinct, containing thin-walled blood vessels. Foamy macrophages are frequently found within some septae, a feature which is not seen in other variants of RCC. In areas of haemorrhage and necrosis a neutrophil-rich infiltrate is seen as are cholesterol clefts within the necrotic debris. Not separately identified as a subtype, but a variant which can, on occasion, give difficulty with morphological recognition, is the solid variant of papillary RCC. First described by Renshaw et al,19 it has an apparently more solid or alveolar type of morphology as a consequence of compression of the papillary architecture with the loss of the luminal space. Often more typical papillary areas are seen and, in cases of difficulty, cytoplasmic reactivity for cytokeratin 7 may be helpful. The solid variant does not appear to confer any different prognosis, but may rather lead to misdiagnosis as a clear cell type.

Within kidneys bearing papillary RCC other such tumours or papillary adenomas are frequently found. Careful study of this problem has suggested that up to eight separate renal tumours are identified in the kidney in these cases and has led to a hypothesis of an adenoma-carcinoma sequence in this variant of RCC.20 The multifocal nature of papillary RCC would tend to limit the use of nephron-sparing surgery in this subgroup. There is reasonable evidence to suggest that papillary RCC arises from a papillary adenoma, following the early acquisition of a trisomy of chromosome 7 and mutation of the C-met proto-oncogene carried on the duplicated copy of chromosome 7. However, further genetic alterations may be important in the transition from a benign to malignant phenotype. Familial cases of papillary RCC carcinoma have been shown to harbour germline mutations in the c-met proto-oncogene.

Chromophobe renal cell carcinoma Chromophobe carcinoma, first described in 1985,21 was recognized within the Heidelberg and Rochester classifications, and is believed to arise from intercalated cells in the renal collecting ducts. Both sporadic and familial forms exist. Its two main variants, the chromophobic and eosinophilic forms, are both associated with an excellent prognosis. The importance

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of the recognition of this tumour is the very low rate of progression and metastasis.22 The tumours can achieve a large size although necrosis is uncommon. The cut surface is a rather uniform grey colour and they are well circumscribed. Chromophobe carcinoma cells have irregular often wrinkled or ‘rasinoid’ nuclei, the finding of binucleated tumour cells is common, there is a perinuclear cytoplasmic halo and a low mitotic rate.23 The prognostic impact of nuclear grading has not been validated for chromophobe RCCs but most are grade 2. These tumours are hypodiploid on DNA analysis and show variable pattern of loss of whole chromosomes. The eosinophilic variant of chromophobe carcinoma may present diagnostic difficulty in its distinction from oncocytoma. The cytoplasm on close examination is finely vesicular rather than having the granular appearance of oncytoma. Immunocytochemistry at the moment does not reliably distinguish between these two tumours, although electron microscopy may help by demonstrating cytoplasmic microvesicles in chromophobe carcinoma and cytoplasmic mitochrondria in oncocytoma. To create further diagnostic difficulty, hybrid tumours are recognized and, indeed, are relatively frequently seen in patients with the Birt–Hogg–Dubé syndrome.24

Collecting duct carcinoma This is the most aggressive form of RCC with 90% of patients dying as a consequence of their malignancy. Collecting duct carcinoma is, however, rare, accounting for < 1% of renal malignancies.25 These tumours originate centrally within the medullary zone and elicit a brisk desmoplastic response from the adjacent kidney. The tumour margins are therefore poorly defined. Collecting duct carcinoma has a high nuclear grade, and is characterized by a tubular or tubulopapillary growth pattern in which irregular angulated glands infiltrate the renal parenchyma (Figure 4.5). There is a characteristic nuclear morphology in particular the finding of a single, large, central eosinophilic nucleolus.25,26 There is a propensity for early

metastasis to lymph nodes and distant organs. Collecting duct carcinoma is relatively overrepresented in younger adults and children in comparison with the other subtypes of renal cell carcinoma. In addition to the more typical form of collecting duct carcinoma, renal medullary carcinoma27 is considered to be a variant of collecting duct carcinoma arising in the renal medulla, exclusively associated with sickle cell trait. It is also a high-grade tumour with sheets of poorly differentiated cells, infiltrating tubular elements and a brisk inflammatory response. Sickled red blood cells can be seen within the tumour. The prognosis is very poor.

Low-grade collecting duct carcinoma There has been recent recognition of a lowgrade variant of collecting duct carcinoma.28 This is a rare subtype, often presenting as an asymptomatic primary neoplasm. Although the tumour is of low histological grade and has a better prognosis than the more typical collecting duct carcinoma, it is nevertheless still malignant and potentially fatal. The tumour is better circumscribed than typical collecting duct carcinoma and can often be seen arising within the renal medulla. Grossly, low-grade collecting carcinoma appears microcystic or sponge-like (Figure 4.6) with better defined margins but invasion of the capsule or the renal vein can be seen. Histologically, the tumour has a tubular or microcystic architecture (Figure 4.7), the lining of which is a single layer cuboidal epithelium, often with luminal mucin. The tumour cells have relatively low nuclear grade in terms of pleomorphism and nuclear size, but prominent nucleoli may still be seen. Occasionally, the tumours within these tubules or cysts have a more complex epithelial growth approaching a cribriform architecture. Mitotic figures are infrequent but can occasionally be identified. The tumour shows the same immunocytochemical pattern as typical collecting duct carcinoma with the expression of high-molecular-weight cytokeratin and reactivity for Ulex europeus lectin. At least one case of this tumour has been

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Figure 4.6 Low grade collecting carcinoma has a spongelike appearance on examination of the cut surface. (See Colour Plate Section).

described as part of the hereditary leiomyomatosis complex.29

Renal carcinoma associated with Xp11.2 translocation These carcinomas are defined by a characteristic genetic abnormality involving the TFE3 gene on the short arm of the X chromosome (Xp11.2). There appear to be at least two subtypes, the ASPL-TFE3 type (similar to alveolar soft-part sarcoma) and the PRCC-TFE3 type depending on the nature of the Xp11.2 translocation.30,31 They occur mostly in children or young adults and are often advanced at presentation. There is a range of morphological appearances. The most common appearance is that of a tumour with papillary architecture but composed of clear cells often with voluminous cytoplasm. On occasion, the cells are arranged in a more nested or alveolar architecture and can have granular eosinophilic cytoplasm. The ASPL-TFE3 type has cells with the more abundant cytoplasm, distinct cell borders and vesicular nuclei with prominent nucleoli. The PRCC-TFE3 tumour cells are smaller with a more nested architecture. Morphology alone is unreliable for a definitive diagnosis and must usually be supplemented with genetic confirmation.

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Figure 4.7 The low grade variant of collecting duct carcinoma has a microcystic morphology, cyst lined by collecting duct carcinoma cells usually as a single layer. (See Colour Plate Section).

Renal cell carcinoma associated with neuroblastoma An unusual renal tumour has been identified in patients surviving neuroblastoma.32 Although therapy for neuroblastoma may have contributed to this, the treatment in the various patients with renal carcinoma associated with neuroblastoma has differed and, in at least one case, the renal tumour and the neuroblastoma arose simultaneously. A familial genetic susceptibility may well be involved. There have now been 18 cases of this tumour recorded, with a median age at the time of diagnosis of 13.5 years. Several patients have developed metastases to liver, lymph nodes, bone and adrenal glands. The characteristic morphological appearance is of a tumour with both a solid and a papillary architecture. The tumour cells have abundant foamy and granular cytoplasm with intense eosinophilia. Some clear cell areas may be seen. The tumours have high-grade nuclei with prominent nucleoli; multinucleated and binucleated forms are seen and there is a high mitotic rate. The outcome, as in most other instances of renal malignancy, is strongly associated with stage and probably grade although the latter has proved difficult to apply.

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Figure 4.8 The epithelial component of mucinous tubular and spindle tumour of the kidney is arranged as microtubules or acini, lined by a bland cuboidal epithelium with intraluminal and stromal mucin. (See Colour Plate Section).

are seen but, importantly for distinguishing from sarcomatoid renal carcinoma, the spindle cell areas maintain the low nuclear grade. The spindle cells are often arranged in parallel bundles of cells with eosinophilic cytoplasm and low-grade nuclei. Again, in the spindle cell areas, mitotic activity is infrequent. The stroma contains acidic mucins. The tumour cells are positive for a wide range of cytokeratins including cytokeratin 7 and low- and high-molecular-weight cytokeratins. EMA and CD15 reactivity may be seen, but CD10 reactivity, a marker of proximal tubule, is lacking. These tumours, in keeping with their suggested distal nephron origin, show Ulex europeus reactivity. Compatible with the low-grade morphology, these tumours appear to have a rather indolent course and there is only one recorded case of metastasis. They are therefore best regarded as a low-grade carcinoma of limited metastatic potential.

Mucinous, tubular, and spindle cell carcinoma A tumour with characteristic morphological appearances and an apparently indolent course has been described, using several different names, in a series of papers.33–35 In the WHO classification, the preferred term is mucinous tubular and spindle cell carcinoma, a term which emphasizes the main morphological features. The tumours present across a wide age range, from 17 to 82 years, and appear to have a male to female ratio of 1:4. There may be some association with nephrolithiasis.33 As a consequence of that association many appear to be detected as asymptomatic renal masses during investigation for stone disease. The tumours are well circumscribed, with a grey or light tan appearance and a slight glistening look to the cut surface. Histologically, they are composed of well-formed microtubules in a myxoid stroma with luminal mucin (Figure 4.8). Cuboidal epithelial cells with eosinophilic cytoplasm and indistinct cell borders line the microtubules. Nuclear pleomorphism is mild and mitotic activity is rare. The microtubules are frequently arranged in parallel arrays giving a misleadingly mesenchymal look to the tumour with its mucinous stroma. True spindle cell areas

Neuroepithelial and neuroendocrine tumours of the kidney Although Parham et al36 in their series of 146 cases of primary neuroepithelial tumours of the kidney have argued for a broad and inclusive diagnostic category, the WHO classification recommends separately identifying carcinoid tumours, neuroendocrine carcinoma, primitive neuroectodermal tumours andneuroblastoma.3 Primary carcinoid tumours of the kidney are very rare, with probably less than 50 cases reported in the literature.37 They are well differentiated with neuroendocrine differentiation and morphological features typical of carcinoids in other sites. The tumour cells are arranged in trabeculae or acini. They are supported by a fibrous and vascular stroma. The tumour cells are cuboidal or columnar with granular eosinophilic cytoplasm, round nuclei, with mild nuclear pleomorphism and infrequent mitotic activity (Figure 4.9). The tumour cells may be arranged in packets by intervening fibrous stroma. There is usually a sharp border between the tumour and the adjacent kidney. Renal carcinoids are usually positive for chromogranin with typical basal

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Figure 4.9 Renal carcinoid has the same morphology as carcinoids elsewhere with cuboidal cells with indistinct borders arranged in variably sized nests. (See Colour Plate Section).

granular staining and show diffuse cytoplasmic reactivity for synaptophysin. Tumours at the poorly differentiated end of the neuroendocrine spectrum are categorized as primary neuroendocrine carcinoma of the kidney similar to small cell carcinoma in other organs such as lung.38 These are rare tumours, usually symptomatic on presentation and on dissection show extensive haemorrhage and necrosis with an infiltrative tumour border. The tumours are often large at presentation. Morphologically, the tumours are very similar to small cell carcinoma or poorly differentiated neuroendocrine carcinomas in other sites. The tumour cells are round or fusiform, with poorly defined cell borders, large nuclei showing extensive pleomorphism and stippled chromatin. Nucleoli are not usually seen. The mitotic rate is high, vascular invasion is common and a coexisting urothelial carcinoma is occasionally found. These tumours are variably positive for neuroendocrine markers including chromogranin, synaptophysin and CD56. Small round cell tumours of the primitive neuroectodermal tumour (PNET) or Ewing sarcoma type are found in the kidney. In the past these have frequently been misdiagnosed as adult Wilms’ tumour. They occur in significantly younger patients and are often very large with metastases noted at presentation. Renal PNET comprises monotonous polygonal cells with

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variable amounts of poorly defined cytoplasm. They have hyperchromatic round or ovoid nuclei with finely dispersed chromatin. Mitotic figures are usually frequent. Architecturally, the tumours may form trabeculae or cords and rosettes are frequently seen. Other variant forms resembling clear cell sarcoma of the kidney, epithelioid, malignant peripheral nerve sheath tumours and paraganglioma have all been recorded. The distinction from Wilms’ tumour and, in the clear cell sarcoma of the kidney (CCSK)-like variant, from clear cell sarcoma may be difficult and requires a combination of morphology and immunocytochemistry. Although both Wilms’ tumour and neuroectodermal tumours stain with antibodies to vimentin, cytokeratins, CD56 and CD117, – CD99, which is positive in PNET, and WT1, which is positive in the blastema of Wilms’, may be helpful in differential diagnosis. Karyotyping has only been performed on a limited number of these tumours and the t(11,22) abnormality found in extraskeletal Ewing’s sarcoma has rarely been seen. The use of reverse transcriptase polymerase chain reaction (RT-PCR) for the ES/FLI1 fusion protein has only demonstrated the presence of this abnormal message in about 30% of these tumours.39 The precise genetic relationship, therefore, to PNET, Ewing’s sarcoma and other tumour types remains to be established. These tumours have a poor outcome, with metastases and progression with poor survival being seen in the majority of cases. Neuroblastoma, paraganglioma, and phaeochromocytoma are all described in the kidney, and have morphology and behaviour similar to that of the adrenal or other retroperitoneal sites.

Mixed epithelial and stromal tumour of the kidney This was first described by Pawade et al40 as a cystic hamartoma of the renal pelvis. Although the pelvis is a common site, the tumour can also be found in the renal cortex. It is now considered to be a true biphasic neoplasm, hence the preference now for the term mixed epithelial and stromal tumour.41

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These show a complex histology with a mature, often smooth muscle-like, stroma comprising the bulk of the tumour. However, islands of variably complex epithelium are found within this stroma. These epithelial islands may form cysts, microcysts, or tubules occasionally with broad papillae. The epithelial cells are cuboidal or columnar, lacking pleomorphism and mitotic activity. The tumours appear to behave mostly in a benign manner, but sarcomas have been described arising from the stromal component and I have experience of a case of papillary carcinoma arising within the epithelial component.

Sarcomatoid renal cell carcinoma Previously sarcomatoid renal cell carcinoma was considered a diagnostic entity, however, it is now considered to be a progression factor with any of the above histological variants capable of showing a loss of epithelial differentiation and transformation towards a more mesenchymal or sarcomatoid variant. Sarcomatoid transformed RCC has an extremely poor prognosis.

Renal cell carcinoma, unclassifiable It is recognized that anything up to 5% of renal tumours may not be classifiable by the current WHO criteria. There may be several reasons for this. There are rare variants of RCC tumours that have mixed morphology; and some sarcomatoid renal cell carcinomas are unclassifiable because of an absence, in the histological sections examined, of an identifiable antecedent carcinoma. In these circumstances the tumour is categorized as a renal carcinoma of unclassifiable histological type. Unclassifiable RCC has a poor prognosis reflecting its poorly differentiated phenotype.42,43

BENIGN RENAL EPITHELIAL TUMOURS Papillary adenoma Renal adenomas are tubulo-papillary epithelial proliferations of low nuclear grade, with at most rare mitotic figures and a maximum

tumour diameter of 5 mm. This size is below the resolution of imaging techniques so these are most frequently encountered as an incidental finding in kidneys removed for other pathology, usually papillary RCC. There is a strong association between the papillary subtype of RCC and multifocal and bilateral renal papillary adenomas. This has important implications for surgical management of papillary RCC, in particular the use of nephron-sparing surgery. Renal adenomas have been found to show trisomies of chromosomes 7 and 17 and Y chromosome loss in males, cytogenetic findings which are similar to those observed in papillary RCC. As discussed above it is likely that there is an adenoma-carcinoma sequence within this subgroup of renal tumours and therefore renal adenoma has been defined as a premalignant lesion of the kidney by the WHO Committee on premalignant lesions in the genitourinary tract.20

Metanephric adenoma Metanephric adenoma is an uncommon benign tumour of the kidney which can attain a large size but shows no evidence of infiltration or invasion. Macroscopically it is a wellcircumscribed grey/white tumour usually lacking recognizable areas of haemorrhage or necrosis. The tumour comprises well-differentiated tubules of small diameter, with occasional papillary areas lying within a rather oedematous stroma. Interestingly these tumours also show trisomies of chromosome 7 and 17.44 The relation between renal adenoma, papillary renal carcinoma, and metanephric adenoma remains to be fully investigated.

Renal oncocytoma In clinical practice this is the most important benign renal tumour requiring recognition. Renal oncocytoma has been recognized for more than two decades. In the mid-1980s there were occasional published series of oncocytomas with metastases occurring in a small number of cases.45 It now appears likely that these were cases of chromophobe RCC, an entity which was not described until 1988.

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Table 4.3

TNM staging of renal carcinoma47

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Table 4.4 Summary of histological sampling of renal cell carcinoma50

Primary tumour pT1 pT1a pT1b pT2 pT3 pT3a pT3b pT3c pT4

< 7 cm confined to kidney < 4 cm 4–7 cm > 7 cm confined to kidney Invasion of perinephric tissue, adrenal or vein Adrenal or perinephric fat invaded Invasion of renal vein(s) and/or vena cava below diaphragm Invasion of vena cava above diaphragm Invasion beyond Gerota’s fascia

Lymph nodes NX N0 N1 N2

Nodal status cannot be assessed No nodal involvement One node involved More than one node involved

Metastasis MX M0 M1

Distant metastases cannot be assessed No distant metastases Distant metastases present

Renal oncocytoma is a benign tumour, which if adequately resected will not recur. Oncocytomas have a characteristic naked-eye appearance, being well circumscribed from the adjacent kidney, with a tan colour and often a central stellate ischaemic scar. The tumour is composed of sheets or nests of intensely granular and eosinophilic tumour cells with no mitotic activity, although some nuclear pleomorphism may be seen. The cytoplasmic granularity is the result of accumulation of numerous mitochondria and recent evidence of alteration in mitochondrial DNA has been produced.46

STAGING Staging is the most important prognostic factor in the pathological assessment of RCC. There have been developments in the staging categories for renal cell carcinoma with updating of the TNM classification (Table 4.3).47 The main changes from the earlier TNM classification are the extension of the T1 category to a 7 cm maximum diameter, and in the 2002 version, subdivision of T1 to T1a or T1b with a

Summary of histological sampling of renal carcinoma50 • • • • • • • • • •

One block per cm of primary tumour Two or three blocks of extension into perirenal fat One block per cm of tumour–renal sinus interface One block from renal vein, renal artery, and ureter Blocks from areas of venous or collecting system invasion At least one block from tumour–kidney interface Blocks from all lymph nodes One block from adrenal gland Blocks from any other renal abnormalities One or two blocks from macroscopically normal renal parenchyma

4 cm diameter as the distinguishing criterion. Renal sinus invasion is now categorized along with invasion of perinephric fat (pT3a).48 The nodal status, which remains a diagnostic difficulty for histopathologists in the absence of a full lymph node dissection, is now categorized as either N0 or N1 depending on the absence or presence of identifiable lymph node metastasis. However, in practice many cases require to be classed as Nx. M1 for the presence of distant metastases remains. The 2002 TNM classification has significant implications for the way that a pathologist dissects a nephrectomy specimen and selects blocks for histological examination. Standardized evidence-based protocols have been published for dissection and histological sampling (Table 4.4).49–51 These are based on the identification of maximum tumour size, extension beyond the kidney, invasion of the venous system and the importance of early invasion of the renal sinus fat. These dissection techniques emphasize the good visualization of the renal sinus, the renal vein, and the lateral margins of the tumour.

Necrosis There is now interest in postoperative scoring systems in managing RCC patients. The system most frequently cited is that of Zisman et al.52 This system includes numerical scores for tumour types and most other staging criteria, however, it also scores RCC for the presence or

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absence of necrosis, a histological feature which pathologists should now routinely record. The pathologist now has an important role in the evaluation of RCC especially in the postoperative management through accurate diagnosis, staging, and grading to convey information to the surgical and oncology team.

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soft part sarcoma: a distinctive tumor entity previously included among renal cell carcinomas of children and adolescents. Am J Pathol 2001; 159: 179–92. Medeiros LJ, Palmedo G, Krigman HR, Kovacs G, Beckwith JB. Oncocytoid renal cell carcinoma after neuroblastoma: a report of four cases of a distinct clinicopathologic entity. Am J Surg Pathol 1999; 23: 772–80. Hes O, Hora M, Perez-Montiel DM et al. Spindle and cuboidal renal cell carcinoma, a tumour having frequent association with nephrolithiasis: report of 11 cases including a case with hybrid conventional renal cell carcinoma/spindle and cuboidal renal cell carcinoma components. Histopathology 2002; 41: 549–55. Parwani AV, Husain AN, Epstein JI, Beckwith JB, Argani P. Low-grade myxoid renal epithelial neoplasms with distal nephron differentiation. Hum Pathol 2001; 32: 506–12. Otani M, Shimizu T, Serizawa H, Ebihara Y, Nagashima Y. Low-grade renal cell carcinoma arising from the lower nephron: a case report with immunohistochemical, histochemical and ultrastructural studies. Pathol Int 2001; 51: 954–60. Parham DM, Roloson GJ, Feely M et al. Primary malignant neuroepithelial tumors of the kidney: a clinicopathologic analysis of 146 adult and pediatric cases from the National Wilms’ Tumor Study Group Pathology Center. Am J Surg Pathol 2001; 25: 133–46. Quinchon JF, Aubert S, Biserte J et al. Primary atypical carcinoid of the kidney: a classification is needed. Pathology 2003; 35: 353–5. Kitamura M, Miyanaga T, Hamada M et al. Small cell carcinoma of the kidney: case report. Int J Urol 1997; 4: 422–4. Quezado M, Benjamin DR, Tsokos M. EWS/FLI-1 fusion transcripts in three peripheral primitive neuroectodermal tumors of the kidney. Hum Pathol 1997; 28: 767–71. Pawade J, Soosay GN, Delprado W et al. Cystic hamartoma of the renal pelvis. Am J Surg Pathol 1993; 17: 1169–75.

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41. Adsay NV, Eble JN, Srigley JR et al. Mixed epithelial and stromal tumor of the kidney. Am J Surg Pathol 2000; 24: 958–70. 42. Amin MB, Amin MB, Tamboli P et al. Prognostic impact of histologic subtyping of adult renal epithelial neoplasms: an experience of 405 cases. Am J Surg Pathol 2002; 26: 281–91. 43. Zisman A, Chao DH, Pantuck AJ et al. Unclassified renal cell carcinoma: clinical features and prognostic impact of a new histological subtype. J Urol 2002; 168: 950–5. 44. Granter SR, Fletcher JA, Renshaw AA. Cytologic and cytogenetic analysis of metanephric adenoma of the kidney: a report of two cases. Am J Clin Pathol 1997; 108: 544–9. 45. Lewi HJ, Alexander CA, Fleming S. Renal oncocytoma. Br J Urol 1986; 58: 12–15. 46. Amin MB, Crotty TB, Tickoo SK, Farrow GM. Renal oncocytoma: a reappraisal of morphologic features with clinicopathologic findings in 80 cases. Am J Surg Pathol 1997; 21: 1–12. 47. Sobin LH, Wittekind C. Kidney. TNM Classification of malignant tumours. In: Sobin LH, Wittekind C, eds. New York: Wiley-Liss, 2002: 193–5. 48. Bonsib SM. The renal sinus is the principal invasive pathway: a prospective study of 100 renal cell carcinomas. Am J Surg Pathol 2004; 28: 1594–600. 49. Eble JN. Recommendations for examining and reporting tumor-bearing kidney specimens from adults. Semin Diagn Pathol 1998; 15: 77–82. 50. Fleming S, Griffiths DF. Best Practice No 180. Nephrectomy for renal tumour; dissection guide and dataset. J Clin Pathol 2005; 58: 7–14. 51. Algaba F, Trias I, Scarpelli M et al. Handling and pathology reporting of renal tumor specimens. Eur Urol 2004; 45: 437–43. 52. Zisman A, Pantuck AJ, Wieder J et al. Risk group assessment and clinical outcome algorithm to predict the natural history of patients with surgically resected renal cell carcinoma. J Clin Oncol 2002; 20: 4559–66.

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Prognostic factors for outcome in metastatic renal cell carcinoma

5

Paul J Elson

INTRODUCTION Renal cell carcinoma (RCC) is a heterogeneous disease that has a complex natural history. If detected early, it can be treated surgically, and 5-year survival rates approaching 80–95% can be achieved for patients with organ confined disease (stages T1 T2; N0).1–3 Unfortunately metastatic spread is present in approximately one-third of patients at the time of diagnosis and up to 50% of patients with initially localized disease can be expected to relapse distantly.1,3 Treatment options for these patients are limited and expected 5-year survival is less than 20%.1,3 Metastatic RCC (mRCC) is generally resistant to chemo- and hormonal therapy; and immunotherapy has been the mainstay of systemic therapy since the late 1980s, in particular, regimens based on non-specific cytokines such as interleukin-2 (IL-2) and/or interferon α (IFN-α). Recently however, the importance in RCC of mutations in the VHL gene and the resulting overexpression of the proangiogenic protein vascular endothelial growth factor (VEGF) has been recognized, and much attention has been focused on therapies that target the VEGF–VEGFR signalling pathway. Two small molecules, sorafenib and sunitinib malate, have been found to inhibit multiple tyrosine kinases in this pathway. These agents have been shown to cause objective tumour response or significantly delay time to progression in patients with advanced RCC,4,5 and they have recently received the US Food and Drug Administration’s approval. Despite this advance in treatment, mRCC is not curable. The poor outlook for these patients coupled with RCC’s variable natural history makes

understanding the factors that impact outcome an important consideration in the development, evaluation, and use of new treatment strategies. Tumour stage and nuclear grade are arguably the most important predictors of clinical behavior and outcome in RCC. However, other factors, especially in the metastatic setting, can also have a significant impact. Recognition of known prognostic factors and identification of new ones can be used to help counsel patients, optimize patient care by directing therapies to the patient groups most likely to benefit from them, and in the case of molecular prognostic factors, help develop new targeted treatment strategies. In addition, knowledge of factors that can influence outcome can aid in the design and interpretation of clinical studies. For example, in randomized trials they can be used to stratify patients prior to randomization to ensure balance between the treatment arms and improve treatment comparisons. They can also be used to help ‘fine tune’ sample size calculations. During data analysis, adjustment for known prognostic factors can help distinguish real treatment effects from those that are artifacts of differences in patient/disease characteristics, and help determine the extent to which the natural history of the disease is being altered. A number of patient and disease-related factors are recognized as being of prognostic value in mRCC. With the advent of molecularbased technologies such as reverse transcriptase polymerase chain reaction (RT-PCR), cDNA, and oligonucleotide microarrays, and tissue arrays, a host of new molecular-based candidate prognostic factors are being identified.

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Research on prognostic factors of outcome in mRCC has mainly focused on assessing survival. However, a number of reports have considered objective response as the primary endpoint. The focus of this chapter likewise is on survival since it is well defined and objective; and ultimately it is the endpoint that we want treatment to impact. For completeness, however, a brief summary of factors that have been suggested to be prognostic for response is also included.

SURVIVAL A number of demographic, clinical, pathological, immunological, and genetic factors have been examined to determine their impact on survival. Numerous studies have assessed these factors and the following sections summarize their results based on these broad categories. Over the past two decades a number of welldesigned retrospective studies of prognostic factors for survival in mRCC based primarily on demographic and clinical factors have been conducted.6–21 These studies have generally included fairly large numbers of patients treated in controlled clinical trials, and have generally been statistically analysed using sound methods, including multivariable analysis and in some instances internal/external validation. Table 5.1 summarizes these studies, however, for completeness studies that employed only univariable analysis methods, examined only a limited number of potential predictors, or included both metastatic and non-metastatic patients are also discussed below.

Demographics Most studies have found no association between survival and demographic factors such as age,6–9,11–21 sex,6–9,11–14,16–20 and race.7,12 Exceptions to this are an early study of 101 stage IV patients by Klugo et al22 which suggested that males have a better prognosis than females, the study in table 5.1 by Landonio et al,9 which demonstrated a better prognosis for females in univariable but not multivariable

analysis, and a study by Vaglio et al23 of 51 patients treated with combination IL-2 and IFN-α, which indicated that age (> 60 versus ≤ 60) was an independent predictor of survival.

Clinical factors Performance status and presenting symptoms Performance status (PS) is a subjective measure of overall wellbeing. However, it is perhaps the one factor that has been most consistently found to be an independent predictor of survival. One of the most commonly used PS scales is the Eastern Cooperative Oncology Group (ECOG) score,24 which measures PS on a scale from 0 to 5, 0 being assigned to asymptomatic patients with no restrictions on their activities, and 5 indicating death. Almost all studies summarized in Table 5.1 that assessed PS found it to be an independent predictor of survival,7–13,15–17,20,21 however, it is not a universal finding. The studies by Mekhail et al14 and Leibovich et al19 for example did not find it to be associated with outcome once other factors were adjusted for. Patients with mRCC often present with a history of recent weight loss or other constitutional symptoms such as fatigue, early satiety or decreased appetite, musculoskeletal pain, or respiratory symptoms. Taken together these paraneoplastic symptoms can also be considered a measure of general health. Constitutional symptoms and PS are correlated, however, several studies have identified them as independent prognostic factors,6–8,19 even after adjusting for PS. Other studies, however, such as those by Mani et al,12 Palmer et al,13 and Negrier et al20 have found no such association. A possible explanation for this discrepancy is that the studies by Mani and Palmer were restricted to patients with good ECOG PS (0 or 1) and in all three studies relatively few patients presented with recent weight loss (11–15%). In contrast, the studies that found it prognostic included patients with poorer PS (ECOG 2 and greater) and had a greater proportion of patients with weight loss or other symptoms (29–72%).

N

158

610

295

156

463

106

84

Neves6

Elson7

Fossa8

Landonio9

Motzer10

Ljungberg11

Mani12

1983–1991

1982–1999

1982–1996

1978–1993

Immuno

Chemotherapy Hormones Radiotherapy Supportive care

Immuno-based

Chemotherapy Hormones Immuno

Chemotherapy Immuno-based

Yes

No

No

Yes

N/A

Yes

No

Prior systemic therapy

0–1

0–4

0–2

0–4

0–3

0–3

N/A

ECOG PS

ECOG PS > 1 > 1 metastatic site Elevated ESRd Serum calcium > ULNe Renal vein invasion ECOG PS 1 Bone metastasis Sarcomatoid histology

Recent weight loss ≥ 10% > 1 metastatic site Nuclear grade > 2 Increased ECOG PSb Recent weight loss MFI ≤ 12 months; > 1 metastatic sitec Prior chemotherapy ECOG PS > 1 Recent weight loss > 10% MFI ≤ 12 months Elevated ESRd ECOG PS > 2 MFI < 24 months > 2 metastatic sites No prior nephrectomy ECOG PS > 1 MFI < 12 months Haemoglobin < LLNe LDH > 1.5 × ULNe Corrected calciumf >10 mg/dL

PROGNOSTIC FACTORS FOR OUTCOME IN METASTATIC RENAL CELL CARCINOMA

(Continued)

Sex, age, and race MFI Recent weight loss Prior nephrectomy, radiotherapy and chemotherapy Lung, liver, lymph node metastasis Local recurrence

Prior nephrectomy and radiotherapy Location and no. of metastatic sites Serum alkaline phosphatase and albumin Age and sex Tumour size Nuclear grade DNA ploidy Serum albumin

Sex and age

Sex and age Prior nephrectomy Metastatic sites

Sex and age Size of the primary Tumour side Sex, age and race Prior nephrectomy and radiotherapy

Factors examined but not found to influence survival in univariable and/or multivariable analysis

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1975–1990

Chemotherapy Hormones

N/A

Treatment(s)a

Factors associated with poor survival in multivariable analysis

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1975–1984

1970–1980

Treatment period

Patient population

Multivariable analyses of clinical and tumour-related prognostic factors

Reference

Table 5.1

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63

N

327

353

255

109

73

425

173

Palmer13

Mekhail14

Fyfe15

Citterio16

Canobbio17

Atzpodien18

Leibovich19

1989–2000

1988–1998

1988–1992

1988–not specified

Immuno-based

Immuno-based

Immuno

Chemotherapy Radiotherapy Immuno Supportive care

Immuno

No

Yes

Yes

No

Yes

No

Yes


0–2

0–1

0–2

0–3

0–4

0–1

0–1

ECOG PS

MFI < 3 years Bone metastasis ≥ 3 metastatic sites LDH > 220 U/L CRP > 11 mg/L Neutrophil ≥ 6500/µL Constitutional symptomsk Regional lymph nodes Location of metastasesl Sarcomatoid component; TSH > 2 mIU/L

ECOG PS > 0 > 1 metastatic site

ECOG PS > 1; Haemoglobin ≤ 10 g/dL

ECOG PS > 0 No prior nephrectomy Short MFId

MSKCC scoreh Prior radiotherapy >1 metastatic sitei Histologyj

ECOG PS 1 MFI ≤ 24 months > 1 metastatic siteg

(Continued)

Sex and age ECOG PS T stage Tumour size Nuclear grade Paraneoplastic syndromem

Sex and age Recent weight loss Prior nephrectomy, radiotherapy and chemotherapy Age and sex Tumour side Nuclear grade Prior nephrectomy Neutrophil count Serum albumin, creatinine, and alkaline phosphatase Age Prior chemotherapy Number of metastatic sites Disease limited to lung Sex and age MFI Stage Nuclear grade Metastatic sites Serum creatinine, ferritin, albumin, calcium, LDH, alkaline phosphatase, and triglycerides Sex and age Prior nephrectomy and chemotherapy MFI Sex and age ESR Haemoglobin

Factors examined but not found to influence survi in univariable and/or multivariable analysis

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N/A

Chemotherapy Immuno-based

Immuno

Treatment(s)a


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1987–2002

1986–1990

Treatment period

Patient population

64

Reference

Table 5.1 Continued



153

Stadler21 Chemotherapy

Immuno-based

Treatment(s)a

Yes

N/A


0–2

0–2

ECOG PS ECOG PS ≥ 1 MFI ≤ 12 months > 1 metastatic site Liver, bone, mediastinal metastases Haemoglobin < LLNe; ESR ≥ 100 mm/h or CRP ≥ 50 mg/L Neutrophils ≥ 7500/µL Alkaline phosphatase > 100 U/L ECOG PS > 1 No prior nephrectomy ≥ 3 metastatic sites; Corrected calcium > 10 mg/dL Alkaline phosphatase > ULNe Albumin < 4 g/dL


Age Prior treatment with immunotherapy Histology Nuclear grade Haemoglobin LDH

Sex and age Recent weight loss Stage Prior nephrectomy Lymphocyte count Platelet count

Factors examined but not found to influence survival in univariable and/or multivariable analysis

b

a

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1997–2001

1992–1998

Treatment period

Patient population

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Immuno – immunotherapy only, generally IFN-α and/or IL-2; immuno-based – immunotherapy ± chemotherapy, generally vinblastine or 5-fluorouracil Analysed as an ordinal variable, 0 vs. 1 vs. 2 vs. 3. c Based on lung, hepatic, brain, and ‘other’. d Analysed as a continuous measure. e ULN (LLN) – upper (lower) limit of the laboratory’s reference range. f Total calcium–0.707[albumin–3.4]. g Based on lung, bone, and ‘other’. h Memorial Sloan–Kettering Cancer Center score based on PS, MFI, haemoglobin, LDH, and corrected calcium10 (see ‘Motzer’ table entry). i Based on lung, liver, and retroperitoneal nodes. j In a subset of patients after adjustment for other identified prognostic factors. k Rash, sweats, weight loss, early satiety or decreased appetite, other gastrointestinal disturbances, musculoskeletal pain, respiratory symptoms. l Multiple sites and single sites other than lung or bone. m Hypercalcaemia (> 10 mg/dL), polycythaemia (haematocrit> 54%), anaemia (haematocrit < 40%), abnormal liver function test (AST or ALT > 50 U/L, alkaline phosphatase > 105 U/L). ECOG PS, Eastern Cooperative Oncology Group Performance Status; MFI, metastasis free interval; LDH, Lactate dehydrogenase; ESR, erythrocyte sedimentation rate.

Negrier

782

N

20

Reference

Table 5.1 Continued



65

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Other paraneoplastic symptoms, such as anaemia, fever, hypercalcaemia, liver dysfunction, neutrophilia, and thrombocytosis can also be present at presentation, and a number of investigators have assessed the impact of related (pretreatment) haematological and laboratory parameters, and serum markers of inflammation, especially erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and IL-6, which in addition to being a proinflammatory cytokine also has immunoregulatory functions.25 The most consistent finding in these studies is an association between elevated inflammatory markers and poor survival.8,11,18,20,26,27 Ljungberg et al,26 for example assessed ESR, CRP, ferritin, haptoglobin, orosomucid, and α1-antitrypsin in 170 unselected RCC patients. All six acute phase reactants were highly correlated with each other (correlation coefficients (r) ranged from 0.40 to 0.81, p < 0.001 in all cases) and grade, and in univariable analysis with survival. In multivariable analysis, however, only ESR (using a cut-point of 54 mm/h) was seen to have independent prognostic value once stage and nuclear grade were adjusted for. Hoffmann et al27 on the other hand found both CRP (cut-point of 8 mg/L) and ESR (cut-point 70 mm/h) to be independent predictors of survival in a study of 99 mRCC patients treated with immunotherapy with or without chemotherapy. Similarly Negrier et al20 found elevated ESR (≥ 100 mm/h) or CRP (≥ 50 mg/L) to be an independent predictor of poor outcome in a large database study of 782 mRCC patients. In contrast, Atzpodien et al18 found CRP but not ESR to be of prognostic value in an analysis of 425 mRCC patients treated with immunotherapy-based regimens. Other investigators assessing only ESR have similarly found it to be an independent predictor of survival.8,11 Blay et al25 assessed serum levels of IL-6 and CRP in 138 mRCC patients treated with IL-2 with or without IFN-α and found the two markers to be significantly correlated (r = 0.63, p < 0.0001); and both were associated with survival in univariable analysis. Negrier et al28 likewise found elevated serum levels of IL-6 to be associated with

poor outcome in a subset of 138 patients from a 425-patient randomized trial of IL-2, IFN-α, or the combination (CRECY trial).29 Stadler et al,30 on the other hand did not find it to be an independent predictor of outcome. Anaemia, hypercalcaemia, neutrophilia, hypoalbuminaemia, elevated alkaline phosphatase, and elevated lactate dehydrogenase (LDH) have been assessed by a number of investigators, but results have been mixed. Studies by Motzer et al,10 Mekhail et al,14 Citterio et al,16 and Negrier et al20 all found patients who were anaemic pretreatment (generally defined as haemoglobin below the lower limit of the laboratory’s reference range) to have a 25–75% increased risk of death compared to patients with normal haemoglobin levels. Stadler et al21 and Wittke et al31 on the other hand found no association between haemoglobin levels and outcome. Similarly, Motzer et al,10 Ljungberg et al,11 Mekhail et al,14 and Stadler et al21 found elevated serum calcium (defined as a corrected calcium > 10 mg/dL or simply calcium levels above the upper limit of the laboratory’s range) to be an independent predictor of poor survival, whereas Citterio et al16 found no such association. Motzer et al10 and Mekhail et al14 also identified elevated serum levels of LDH (using a cut-point of 1.5 × the upper limit of the laboratory’s reference range) to be an independent predictor of poor outcome, but failed to find an association between survival and serum alkaline phosphatase or albumin. Atzpodien et al18 and Wittke et al31 likewise found elevated LDH levels (≥ 220 –240U/L) to be associated with poor survival, and Citterio et al16 and Ljungberg et al11 found no prognostic value in serum alkaline phosphatase or albumin levels, respectively. In contrast, Stadler et al21 identified both alkaline phosphatase and albumin, but not LDH as independent prognostic indicators. Citterio et al16 and Hoffman et al27 also found no prognostic value in LDH. However, Negrier et al,20 like Stadler found elevated alkaline phosphatase levels to be associated with poor survival. Using predefined cut-points of 6.0–7.5 K/µl Donskov et al,32

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Atzpodien et al,18 and Negrier et al20 all found pretreatment neutrophil count to be an independent predictor of survival, whereas Mekhail et al14 and Hoffman et al27 found neutrophil count to be unrelated to outcome in multivariable analysis although it was related in univariable analysis. Likewise Misbah et al33 identified platelets > 400 K/µL as an independent predictor of poor survival in a database study of 700 previously untreated patients while Negrier et al20 found no such association in multivariable analysis, although it was prognostic in univariable analysis. In addition to these presenting symptoms a number of other haematological and biochemical markers have also been assessed to a very limited extent and found to be associated (thyroid stimulating hormone19 and urinary albumin23) or not associated with survival (serum creatinine,14,16 lymphocyte count,20 triglyceride levels,16 γ-glutamate transferase,34 β2 microglobulin,35 and β-human chorionic gonadotrophin36).

Disease-related factors Aggressiveness of the disease, as measured by the metastasis-free interval (MFI), which is defined as the interval between diagnosis and the development or treatment of metastatic disease, and the extent of disease or tumour burden, as measured by the number of metastatic sites have been extensively studied. As can be seen from Table 5.1, most investigators who assessed these features have found them to be independent predictors of survival. Cut-points for assessing MFI have varied (most investigators used 12 months,7,8,10,14,20 but some used 24,9,13 36,18 or no cut-point15), however these studies have consistently demonstrated a 43–95% increased risk of death for patients with a short MFI. The value of MFI as an independent predictor, however, is not a universal finding and the studies by Mani et al,12 Citterio et al,16 and Canobbio et al17 did not find it to be of prognostic value once other factors were adjusted for. Similarly although most investigators have found the number of metastatic sites involved at the time of systemic treatment to be inversely associated with survival, there is no

67

consensus on how to count them. Most investigators have used an overall count,6,9,11,17,18,20,21 however, some investigators have restricted the count to specific sites. Elson et al,7 for example, based the count on the presence or absence of lung, liver, brain, and ‘other’ metastases, Palmer et al13 used lung, bone, and ‘other’ metastases as the basis, and Mekhail et al14 used lung, liver, and retroperitoneal nodal metastases. In addition, investigators have used both one6,7,11,13,14,17,20 or two9,18,21 metastatic sites as a cut-off for determining prognosis. Although these investigators have all identified the number of metastatic sites as an independent predictor of survival, the estimated increased risk of death due to more extensive disease ranged from 24 to 286%. This wide range of effect is likely due in part to the variable definitions used, and in part to the fact that these studies include patients treated over a 30-year time period, and that imaging procedures have advanced considerably during that time making it easier to detect metastatic deposits. As with MFI, some investigators have found no prognostic value in either the number or location of metastatic sites.8,10,12,15,16 In addition to MFI and disease extent, several investigators have examined tumour size,6,11,19 stage,16,19,20 and location of the primary (right versus left kidney),6,14 however, none of these factors appear to impact survival once other factors are accounted for.

Prior treatment There is little evidence to suggest that prior radiotherapy7,10,12,13 or systemic therapy12,13,15,17,21 impact on survival in mRCC once other factors have been adjusted for. However in the study by Mekhail et al14 prior radiotherapy was found to be an independent prognostic factor even after adjusting for factors such as ECOG PS, MFI, number of metastatic sites, haemoglobin, LDH, and serum calcium. Similarly Elson et al7 found prior chemotherapy to remain an independent predictor after adjusting for EGOC PS, MFI, number of metastatic sites, and weight loss. Although adjunctive cytoreductive nephrectomy appears to improve outcome in prospective randomized

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trials37 and the studies by Landonio et al19 and Stadler et al21 also found a history of nephrectomy to be associated with improved survival, most of the studies in Table 5.17,8,10,12–14,17,20 found no association between survival and nephrectomy. It should be noted, however, that nephrectomy and MFI are highly correlated, and it is MFI that was generally included in the final model in these studies. In addition these studies did not assess the timing of the nephrectomy, only whether or not it was performed at some point in time during the patient’s treatment.

Pathology A number of investigators have assessed pathological features such as nuclear grade, histology, and DNA ploidy as potential prognostic factors. In unselected series of all stages of RCC tumour, nuclear grade is frequently identified as an independent predictor of survival (see for example Zisman et al,38 Frank et al,39 and Patard et al40). Once RCC metastasizes, however, there is little evidence that grade impacts on survival after other important factors are taken into account.11,14,16,19,21 Although in the study by Neves et al,6 patients with poor differentiated or undifferentiated tumours had significantly worse survival than patients with well or moderately well differentiated tumours, even after adjusting for weight loss and number of metastatic sites. A large multicentre study of over 4000 RCC patients, approximately 25% of who had metastatic disease, by Patard et al40 demonstrated a clear trend in outcome based on histological subtype defined according to the International Union Against Cancer (IUCC) and the American Joint Committee on Cancer (AJCC) recommendations41 in a univariable analysis. Considering all patients, patients with clear cell tumours had an estimated 5-year survival of 64% compared to 70% for patients with papillary tumours and 84% for patients with chromophobe tumours, p < 0.001. However, restricting attention to mRCC, survival was similar for patients with clear cell and papillary tumours (p = 0.60; no mRCC patients had chromophobe tumours). In

addition, once adjustment was made for TNM stage, nuclear grade, and ECOG PS histological subtype was no longer prognostic in the combined data set. Stadler et al21 likewise found no association between survival and histology. In contrast Mani et al12 and Leibovich et al19 both identified the presence of sarcomatoid features to be an independent predictor of poor outcome and Mekhail et al14 identified non-clear cell histologies (mostly papillary) as a negative predictor. These latter studies should be viewed cautiously, however, because they included relatively small numbers of patients with sarcomatoid features (6% and 12%, respectively) or non-clear cell histologies (13%). Results from studies of DNA ploidy have been mixed. Several studies have reported that patients with aneuploid tumours have a poor prognosis,42,43 whereas others have found no association between ploidy and outcome,11,44–46 or that aneuploidy is positively associated with survival.47 A possible explanation for these contradictory findings is that RCC tumours are heterogeneous and therefore the likelihood of defining a tumour as diploid or aneuploid is highly dependent on the number of samples assessed.42,43

Immunological factors IL-6 and IL-10 have a number of immunological functions that can enhance or impair the immune response to RCC and several investigators have assessed their prognostic value. The impact of serum levels of IL-6 is described above in the discussion of markers of inflammation, and therefore only IL-10 is discussed here. IL-10 is an immunosuppressive cytokine that inhibits the growth of T lymphocytes48 and has been shown to downregulate major histocompatibility complex (MHC) class I and II molecules on antigen-presenting cells, thereby leading to impaired antigen presentation.31 Wittke et al31 found serum IL-10 levels greater than 1 pg/mL to be an independent predictor of poor survival after correcting for the effects of elevated ESR, LDH, and anaemia. In contrast Negrier et al28 did not find an association between detectable IL-10

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levels and outcome in their study of a subset of patients treated on the CRECY trial. Several investigators have studied the impact on survival of the absolute or relative numbers of various lymphocyte subsets. Hernberg et al,49 for example found an increasing CD4+/CD8+ ratio during treatment with vinblastine plus IFN-α to be correlated with improved survival. Donskov et al32 on the other hand found no association between survival and the number of natural killer cells (NK) or T-cell subsets including CD4+ and CD8+ T cells at baseline or following 8 weeks of therapy with IL-2±histamine.

Genetic factors Cytogenetics Although not extensively studied, several investigators have examined the relationship between chromosomal abnormalities and survival in RCC. In small series of unselected patients Wu et al50 and Moch et al51 suggest that indicators of genetic instability may be of prognostic value. Wu, for example, found that loss of the long arm of chromosome 14 was associated with poor survival in a study of 30 non-papillary RCCs. Moch, on the other hand, found loss of chromosome 9p, but not 14q, to be associated with poor outcome in a study of 41 non-mRCC patients. Moch also found that patients with a total of three or more chromosomal deletions had a poorer prognosis than patients with fewer than three deletions.

Gene expression The advent of gene expression and tissue microarray technologies has enabled rapid molecular and protein expression profiling of tissue samples, thereby allowing investigators to screen large numbers of potential genetic prognostic factors. Increasing attention is being paid to these methodologies, and markers associated with cell cycle regulation, tumour proliferation and growth, cellular adhesion, and angiogenesis are being assessed. To date, however, relatively few studies have focused specifically on mRCC.

69

One example of an investigation that has targeted mRCC is a study by Vasselli et al52 of 58 patients that used a general cDNA microarray and both supervised and unsupervised analysis methods to identify prognostic subgroups of patients based on global expression patterns in the primary tumours. Using this approach two groups of patients that differed significantly with respect to survival (18.2 months versus 5.9 months, p < 0.05) could be identified based on the expression patterns of 45 genes. In addition, vascular adhesion molecule 1 (VCAM-1) was identified as the most highly predictive marker in the set, with patients expressing high levels having significantly better survival than patients with low expression levels. This result is somewhat different from an earlier study by Hoffman et al27 that selectively looked at serum levels of soluble forms of VCAM-1, intercellular adhesion molecule 1 (ICAM-1) and E-selectin. In that study the soluble form of ICAM-1 but not VCAM-1 was identified as an independent predictor of survival. Recently Burczynski et al53 assessed global expression patterns using peripheral blood mononuclear cells, rather than primary tumour samples, from 45 patients treated on a clinical trial of the mTor inhibitor, CCI-779. Using an oligonucleotide array with over 12 000 sequences and both supervised and unsupervised analysis methods four prognostic subgroups of patients could be identified. In another recent study, Kim et al54 used a tissue array comprised of samples from 150 mRCC patients with clear cell tumours who underwent nephrectomy prior to treatment with immunotherapy, to focus attention on eight genes that had previously been reported in the literature as being associated with the development and progression of cancer, Ki67, p53, phosphatase and tensin homolog (PTEN), epithelial cell adhesion molecule (EpCAM), gelsolin, vimentin, and the hypoxia-inducible genes, carbonic anhydrase IX (CAIX) and CAXII. Adjusting for the effects of T stage, nuclear grade, and ECOG PS, CAIX, p53, PTEN, and vimentin were all seen to be independent prognostic factors for survival, with high expression levels of CAIX and PTEN, and

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low levels of p53 and vimentin being associated with improved outcome. Atkins et al55 likewise found CAIX expression to be an independent predictor of survival in a study of 66 mRCC patients treated on IL-2 based trials conducted by the Cytokine Working Group between 1990 and 2001.

RESPONSE Although objective response has not been studied as extensively as survival, a number of clinical, histological, immunological, and genetic factors that may impact on patients’ response to therapy have been identified. Most of these studies have been conducted since the advent of immunotherapy, and have therefore focused on response to cytokinebased therapy, in particular IL-2 and/or IFNα based therapies. An early report by Fyfe et al15 of 255 patients treated with high-dose IL-2 indicated that patients who were ECOG PS 0 were almost twice as likely to achieve an objective response (17%) compared to PS 1 patients (9%). Factors that did not correlate with response included sites of metastatic disease, prior nephrectomy, MFI, and history of prior chemotherapy. Lissoni et al56 also observed a significant correlation between response and PS, and no association with prior nephrectomy in a study of 48 patients treated with subcutaneous IL-2. In contrast to Fyfe, however, MFI and the number of metastatic sites were also found to be independent predictors of outcome. A study by Gez et al57 of 62 patients treated with combination IL-2, IFN-α, 5-fluorouracil, and vinblastine likewise found good PS, but also prior nephrectomy and lack of bone metastases, to be associated with response. Negrier et al29 on the other hand did not find an association between response and PS, prior nephrectomy, or MFI in the CRECY trial; the only independent predictors identified were the number of sites of metastatic disease (1 versus ≥ 2) and treatment (combination versus monotherapy). Other factors examined but not found to be associated with response were, gender, age, individual sites of metastatic disease (i.e. lung, bone, liver,

other), prior treatment with chemotherapy or radiotherapy, and weight loss. More recently, a meta-analysis of 80 published studies of IL-2 based therapies in mRCC identified PS 0, prior nephrectomy, male gender, and age (> 55, approximately) as being positively correlated with response. Sites of metastatic disease were not associated with outcome; other factors were not examined.58 In contrast to all of these studies, Fossa et al59 found no association between the likelihood of response and any pretreatment factor, including age, gender, PS, or sites of metastatic disease in a study of 57 mRCC patients treated with IFN-α with or without vinblastine. The importance of histology as a prognostic factor has been assessed in several studies. Upton et al60 for example, identified several characteristics of clear cell RCC that were associated with response to low-or high-dose IL2 in a study of 146 patients with clear cell tumours and 17 patients with non-clear cell histologies, and was able to define three prognostic subgroups. Patients with clear cell tumours that contained no granular or papillary features had the best response (39%, 14/36). In contrast, 19% (15/77) of patients with tumours that had some granular ( < 50%) but no papillary features responded, as did only 4% (2/50) of patients with papillary and/or ≥ 50% granular features, or non-clear cell histology. The impact of nuclear grade and necrosis was also examined, but neither factor was found to be associated with response. Similar results were observed by Motzer et al61 in that among 43 mRCC patients with non-clear cell tumours (primarily collecting duct) treated with IFN-α and/or IL-2, only two patients (5%) achieved objective responses. Fossa et al59 also assessed the impact of several histological features, including cell type, grade, morphology, the presence or absence of necrosis, ploidy and S-phase fraction, but did not find any associations with response. Several investigators have also examined immunological factors and markers of inflammation. For example, Donskov et al62 reported that patients who achieved a response to IL-2 and IFN-α, with or without histamine (n = 4)

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had statistically significantly higher baseline levels of intratumoral CD8 cytotoxic T cell, CD4 helper T cell, and CD57 NK cell subsets than patients whose best response was stable disease or progression (n = 19), p < 0.03 in all cases. Blay et al25 reported a positive association between response and lack of detectable pretreatment serum IL-6 levels and/or CRP levels ≤ 50 mg/L; and Bain et al63 observed a positive association between response to IL-2 and human leucocyte antigen (HLA) A32 expression in a study of 79 patients. In contrast, Negrier et al28 found no association between response and baseline serum IL-6 levels (or IL10 and VEGF levels) in a subset of 138 patients treated in the CRECY trial, and Mattijssen et al64 found no association between response and HLA class I or II antigen expression in a study of 31 patients treated with IFN-α and IFN-γ. As mentioned in the discussion of survival, attention is increasingly being focused on genetics-based prognostic factors. Bui et al65 for example assessed the impact of CAIX expression on survival and response to IL-2 based therapy, and reported that among 86 treated patients, those with high expression levels (staining in > 85% of cells) were almost twice as likely to have achieved an objective response (27%) than patients with low expression levels (14%). Similar results were reported by Atkins et al.55 In that study, which was enriched to include a significant number of patients who responded to IL-2, 78% (21/27) of patients who achieved a complete or partial response had high expression levels compared to non-responders (51%, 20/39), p = 0.04. Recently Pantuck et al66 used gene expression profiling to identify differences in expression patterns between patients achieving a complete response to IL-2 and those who did not respond. Global differences in a number of genes were identified, and a customized tissue array of 109 patients was used to assess several genes further, CAIX, CAXII, PTEN, vimentin, gelsolin, EpCAM, p53, and Ki67. In multivariable analysis, high expression levels of CAIX were again seen to an important predictor of response, as was PTEN overexpression.

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CONCLUSIONS Clinical factors that are easily obtained as part of the normal patient work-up have been extensively evaluated as potential prognostic factors in advanced RCC. PS is the most important of these identified to date. Although it is subjective, it never the less has consistently, albeit not universally, been shown to have excellent discriminatory power in numerous studies with respect to both survival and response. With the exception of PS most studies that have evaluated clinical factors have examined different groups of them, used varying definitions, and/or treated different patient populations, and therefore, it is difficult to fully assess their value as independent prognostic indicators. To address this issue, at least with respect to survival, a comprehensive database of approximately 4000 previously untreated patients who were entered into controlled clinical trials has been developed by an international consortium of researchers. The goal of this effort is to define a single, validated prognostic model for survival in mRCC that is based on clinical factors.67,68 In addition to ‘classical’ prognostic factors, new molecular-based technologies are helping to better define the biology of RCC and identify new predictors. As discussed above, a number of immunological, genetic, and molecular factors are correlated with outcome. Their value as independent prognostic factors needs to be confirmed, however, by examining them uniformly in relatively homogeneous groups of patients and in conjunction with the classical predictors.

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18. Atzpodien J, Royston, P, Wandert T et al. Metastatic renal carcinoma comprehensive prognostic system. Br J Cancer 2003; 88: 348–53. 19. Leibovich BC, Han K, Bui MHT et al. Scoring algorithm to predict survival after nephrectomy and immunotherapy in patients with metastatic renal cell carcinoma: a stratification tool for prospective clinical trials. Cancer 2003; 98: 2566–75. 20. Negrier S, Escudier B, Gomez F et al. Prognostic factors of survival and rapid progression in 782 patients with metastatic renal carcinomas treated by cytokines: a report from the Groupe Francais d’Immunotherapie. Ann Oncol 2002; 13: 1460–8. 21. Stadler WM, Huo D, George C et al. Prognostic factors for survival with gemcitabine plus 5-fluorouracil based regimens for metastatic renal cancer. J Urol 2003; 170: 1141–5. 22. Klugo R, Detmers M, Stiles R et al. Aggressive versus conservative management of stage IV renal cell carcinoma. J Urol 1977; 118: 244–6. 23. Vaglio A, Buzio L, Cravedi P et al. Prognostic significance of albuminuria in patients with renal cell cancer. J Urol 2003; 170: 1135–7. 24. Oken MM, Creech RH, Tormey DC et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5: 649–55. 25. Blay JY, Negrier S, Combaret V et al. Serum level of interleukin-6 as a prognosis factor in metastatic renal cell carcinoma. Cancer Res 1992; 52: 3317–22. 26. Ljungberg B, Grankvist K, Rasmuson T. Serum acute phase reactants and prognosis in renal cell carcinoma. Cancer 1995; 76: 1435–9. 27. Hoffmann R, Franzke A, Buer J et al. Prognostic impact of in vivo soluble cell adhesion molecules in metastatic renal cell carcinoma. Br J Cancer 1999; 79: 1742–5. 28. Negrier S, Perol D, Menetrier-Caux C et al. Interleukin-6, interleukin-10, and vascular endothelial growth factor in metastatic renal cell carcinoma: prognostic value of interleukin-6. J Clin Oncol 2004; 22: 2371–8. 29. Negrier S, Escudier B, Lasset C et al. Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. N Engl J Med 1998; 338: 1272–8. 30. Stadler WM, Richards JM, Vogelzang NJ. Serum interleukin-6 levels in metastatic renal cell cancer: correlation with survival but not an independent prognostic indicator. J Natl Cancer Inst 1992; 84: 1835–6. 31. Wittke F, Hoffmann R, Buer J et al. Interleukin 10 (IL-10): an immunosuppressive factor and independent predictor in patients with metastatic renal cell carcinoma. Br J Cancer 1999; 79: 1182–4. 32. Donskov F, Hokland M, Marcussen N et al. Monocytes and neutrophils as ‘bad guys’ for the outcome of interleukin-2 with and without histamine in metastatic renal cell carcinoma – results from a randomized phase II trial. Br J Cancer 2006; 94: 218–26.

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33. Misbah SA, Shaheen PE, Elson PJ et al. Thrombocytosis as a prognostic factor for survival in patients with metastatic renal cell carcinoma. J Clin Oncol 2005; 23: 420S. 34. Lopez-Hanninen E, Kirchner H, Atzpodien J. Interleukin-2 based home therapy of metastatic renal cell carcinoma: risks and benefits in 215 consecutive single institution patients. J Urol 1996; 155: 19–25. 35. Rasmuson T, Grankvist K, Ljungberg B. Serum β2microglobulin and prognosis of patients with renal cell carcinoma. Acta Oncol 1996; 35: 479–82. 36. Hotakainen K, Ljungberg B, Haglund C et al. Expression of the free β-subunit of human chorionic gonadotropin in renal cell carcinoma: prognostic study on tissue and serum. Int J Cancer 2003; 104: 631–5. 37. Flanigan RC, Mickisch G, Sylvester R et al. Cytoreductive nephrectomy in patients with metastatic renal cell cancer: a combined analysis. J Urol 2004; 171: 1071–6. 38. Zisman A, Pantuck AJ, Dorey F et al. Improved prognostication of renal cell carcinoma using an integrated staging system. J Clin Oncol 2001; 19: 1649–57. 39. Frank I, Blute ML, Cheville JC et al. An outcome prediction model for patients with clear cell carcinoma treated with radical nephrectomy based on tumor stage, size, grade, and necrosis: the SSIGN score. J Urol 2002; 168: 2395–400. 40. Patard JJ, Leray E, Rioux-Leclercq N et al. Prognostic value of histologic subtypes in renal cell carcinoma: a multicenter experience. J Clin Oncol 2005; 23: 2763–71. 41. Storkel S, Eble JN, Adlakha K et al. Classification of renal cell carcinoma. Workshop no 1. union internationale cntre le cancer (UICC) and the American joint committee on cancer (AJCC). Cancer 1997; 80: 987–9. 42. Ljungberg B, Mehle C, Stenling R et al. Heterogeneity in renal cell carcinoma and its impact on prognosis – a flow cytometric study. Br J Cancer 1996; 74: 123–7. 43. Ruiz-Cerda JL, Hernandez M, Sempere A et al. Intratumoral heterogeneity of DNA content in renal cell carcinoma and its prognostic significance. Cancer 1999; 86: 664–71. 44. Nakano E, Kondoh M, Okatani K et al. Flow cytometric analysis of nuclear DNA content in renal cell carcinoma correlated with histologic and clinical features. Cancer 1993; 72: 1319–23. 45. Lanigan D, McLean PA, Murphy DM et al. Ploidy and prognosis in renal carcinoma. Br J Urol 1993; 71: 21–4. 46. van Bezooijen RL, Goey H, Stoter G et al. Prognostic markers for survival in patients with metastatic renal cell carcinoma treated with interleukin-2. Cancer Immunol Immuother 1996; 43: 293–8. 47. Eskelinen M, Lipponen P, Nordling S. Prognostic evaluation of DNA flow cytometry and histomorphological criteria in renal cell carcinoma. Anticancer Res 1995; 15: 2279–84.

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48. Taga K, Mostowski H, Tosato G. Human interleukin10 can directly inhibit T-cell growth. Blood 1993; 81: 2964–71. 49. Hernberg M, Muhonen T, Pyrhonen S. Can the CD4+/CD8+ ratio predict the outcome of interferon-α therapy for renal cell carcinoma? Ann Oncol 1997; 8: 71–7. 50. Wu SQ, Hafez GR, Xing W et al. The correlation between the loss of chromosome 14q with histologic tumor grade, pathologic stage, and outcome of patients with nonpapillary renal cell carcinoma. Cancer 1996; 77: 1154–60. 51. Moch H, Presti JC, Sauter G et al. Genetic aberrations detected by comparative genomic hybridization are associated with clinical outcome in renal cell carcinoma. Cancer Res 1996; 56: 27–30. 52. Vasselli JR, Shih JH, Iyengar SR et al. Predicting survival in patients with metastatic kidney cancer by gene-expression profiling in the primary tumor. Proc Natl Acad Sci USA 2003; 100: 6958–63. 53. Burczynski ME, Twine NC, Dukart G et al. Transcriptional profiles in peripheral blood mononuclear cells prognostic of clinical outcome in patients with advanced renal cell carcinoma. Clin Cancer Res 2005; 11: 1181–9. 54. Kim HL, Seligson D, Liu X et al. Using tumor markers to predict the survival of patients with metastatic renal cell carcinoma. J Urol 2005; 173: 1496–501. 55. Atkins M, Regan M, McDermott D et al. Carbonic anhydrase IX expression predicts outcome of interleukin 2 therapy for renal cancer. Clin Cancer Res 2005; 11: 3714–21. 56. Lissoni P, Barni S, Ardizzoia A et al. Prognostic factors of the clinical response to subcutaneous immunotherapy with interleukin-2 alone in patients with metastatic renal cell carcinoma. Oncology 1994; 51: 59–62. 57. Gez E, Rubinov R, Gaitini D et al. Interleukin-2, interferon-α, 5-fluorouracil, and vinblastine in the treatment of metastatic renal cell carcinoma. Cancer 2002; 95: 1644–9. 58. Elias L, Hunt WC. A literature analysis of prognostic factors for response and quality of response of patients with renal cell carcinoma to interleukin-2based therapy. Oncology 2001; 61: 91–101. 59. Fossa SD, Nesland JM, Melvik JE et al. Prediction of objective response to recombinant interferon-alpha with or without vinblastine in metastatic renal cell carcinoma. Acta Oncol 1990; 29: 303–6. 60. Upton MP, Parker RA, Youmans A et al. Histologic predictors of renal cell carcinoma response to interleukin2 based therapy. J Immunother 2005; 28: 488–95. 61. Motzer RJ, Bacik J, Mariani T et al. Treatment outcome and survival associated with metastatic renal cell carcinoma of non-clear cell histology. J Clin Oncol 2002; 20: 2376–81. 62. Donskov F, Bennedsgaard KM, von der Maase H et al. Intratumoral and peripheral blood lymphocyte subsets in patients with metastatic renal cell carcinoma

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undergoing interleukin-2 based immunotherapy: association to objective response and survival. Br J Cancer 2002; 87: 194–201. 63. Bain C, Merrouche Y, Puisieux I et al. Correlation between clinical response to interleukin-2 and HLA phenotypes in patients with metastatic renal cell carcinoma. Br J Cancer 1997; 75: 283–6. 64. Mattijssen V, Van Moorselaar J, De Mulder PH et al. Human leukocyte antigen expression in renal cell carcinoma lesions does not predict the response to interferon therapy. J Immunother 1992; 12: 64–9. 65. Bui MHT, Seligson D, Han K et al. Carbonic anhydrase IX is an independent predictor of survival in advanced renal cell carcinoma: implications for

prognosis and therapy. Clin Cancer Res 2003; 9: 802–11. 66. Pantuck AJ, Fang Z, Liu X et al. Gene expression and tissue microarray analysis of interleukin-2 complete responders in patients with metastatic renal cell carcinoma. J Clin Oncol 2005; 23: 386S. 67. Bukowski RM, Negrier S, Elson P. Prognostic factors in patients with advanced renal cell carcinoma: development of an international kidney cancer working group. Clinical Cancer Res 2004; 10: 6310S–14S. 68. Elson PJ, Manola JB, Mazumdar M et al. Prognostic factors for survival in patients with renal cell carcinoma: a study from the Kidney Cancer Association’s International Kidney Cancer Working Group (IKCWG). J Clin Oncol 2005; 23: 386S.

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Imaging in renal cancer

6

Steven D Allen, S Aslam Sohaib

INTRODUCTION Diagnostic imaging is playing an increasing role in the management of patients with renal cancer. The increased use of imaging over the past few decades has resulted in an increased detection of renal tumours, often incidentally.1 Furthermore, diagnostic imaging techniques continue to evolve with improvement in existing imaging techniques and development of new methods of imaging patients with cancer. This potentially allows for more refined assessment of patient with renal cancer, in tandem with development in surgical techniques as well new medical and radio-therapeutic treatment options. This chapter reviews the expanding diagnostic imaging tools and their implications in the management of renal cancer.

ULTRASOUND Ultrasound provides a simple, quick, easy and cheap method for the assessment of the kidneys. One of the main effects of ultrasound in renal cancer is that the ultrasound machines have become cheaper and more widely available. Therefore there has been a steady increase in the amount of abdominal ultrasounds performed which has resulted in the increased detection of small renal tumours at an earlier stage. This has clear benefits in terms of not only surgical management but also survival rate.2 Advances in ultrasound equipment and software have improved the quality of the greyscale images, with newer techniques such as harmonic tissue imaging, compound imaging, and various Doppler ultrasound techniques all improving the sensitivity of both lesion

detection and characterization.3 Harmonic tissue imaging is a unique signal processing technique which directly addresses fundamental ultrasound limitations such as depth penetration and resolution. It utilizes harmonic signals, which are normal ultrasound waves generated within the patient, when tissue is interrogated by ultrasound at high frequency. These additional waves, although not as strong as the main wave, are not as prone to degradation and have a complementary effect. This leads to an improved signal-to-noise and an overall enhanced signal which contributes significantly to the image and improves contrast resolution. This technique is particularly well suited to imaging obese patients or to imaging deep retroperitoneal structures such as the kidneys.4 Spatial compounding is a technique that allows acquisition of overlapping scans of an object from different angles due to electronic steering of the ultrasound beam. This produces ‘real-time’ images of higher resolution and fewer artefacts.5 Doppler ultrasound techniques use the Doppler effect to show blood flow by detecting the change in frequency of ultrasound waves in relation to moving structures such as blood. Colour flow Doppler imaging supplements grey-scale imaging by confirming the presence of blood flow and its direction. The speed of flow and its direction with respect to the ultrasound transducer will thus influence the exact colour obtained from the blood vessel.6 Spectral Doppler provides a spectral analysis of the Doppler ultrasound and can be used in the assessment of renal perfusion. With power Doppler ultrasound, there is no directional blood flow information and the signal is related to the amount of flow. Power

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Doppler provides a greatly increased sensitivity to the presence of flow, such as in demonstrating cortical renal perfusion.7 Ultrasound probes and machine have also become smaller enabling intraoperative sonography. Intraoperative ultrasound may be used in locating small tumours (< 4 cm) or deeply located tumours not visible to the surgeon.8 They may also identify small synchronous tumours in patients with hereditary cancer such as von Hippel–Lindau disease.9 Ultrasound has also been used as a screening tool in the detection of renal cell carcinoma. Detection rate in the populations screened (over 40 years of age) has been typically low, around 0.1%.10 In a Japanese abdominal ultrasound screening study malignant neoplasms and renal cancer was detected in 0.33% and 0.09% of cases, respectively.11 However, a recent study screening an older age group (over 50 years), has shown a higher detection rate of solid renal masses of 0.32%.12 The costeffectiveness of screening for renal cancer remains to be determined. From studies to date it is likely that early detection for renal cancer will form part of a screening programme for other pathology with the abdomen.

COMPUTED TOMOGRAPHY Since the introduction of computed tomography (CT) nearly 30 years ago,13 major technical developments have occurred with regard to the speed of the examination and image reconstruction. Major development include spiral (helical) CT in the late 1980s and the introduction of multislice CT in the late 1990s. In spiral CT, the incorporation of slip ring technology enables the x-ray tube to rotate in one direction indefinitely. Therefore while the x-ray tube is rotating, the table supporting the patient also moves continuously so that a volume of tissue rather than individual slices are scanned. Scans of the abdomen can be acquired in approximately 30 seconds rather than in several minutes, as in CT examinations prior to spiral CT. In spiral CT only a single row of detectors are used, however in multislice CT (also known as multi-detector

row CT) multiple rows of detectors are used (i.e. 8, 16, 32 or even 64). Therefore on a 32detector CT the abdomen can be imaged in less than 1 second! Manufacturers are developing multislice CT with a flat panel detector of 128 or more detectors.14 In addition to being able to scan faster on multislice CT, the multidetector capability allows images to be acquired using thinner slices. On single slice scanners, slice thickness was of the order of 7–10 mm, however on multidetector CT it is possible to acquire images with sub-millimetre slice thickness. Slices are more typically acquired at 1–5 mm thickness depending on the indication for imaging. This has led to an explosion of data; in some studies of the kidneys as many as 1000 slices may be acquired which provide a volume dataset for analysis (Table 6.1). Multislice CT has resulted in a transformation from a trans-axial crosssectional technique into a true three-dimensional (3D) imaging modality that allows viewing of examinations in arbitrary planes as well as 3D rendering techniques. There are four main post-processing techniques: multiplanar reformation (MPR), maximum intensity projection (MIP), shaded surface display (SSD), and volume rendering (VR).15–17 In MPR the images can be reconstructed into multiple arbitrary planes that can be determined by the viewer. The reconstruction plane can even be curved allowing curved planar reformation. MPR is useful for displaying tubular structures such as renal vessels. MIP images are obtained by projecting the highest attenuation voxels through a scan volume onto an image plane. This results in the entire volume being collapsed with only the highest attenuation structures being visible. This allows visualization of structures that do not lie in a single plane. MIP images are useful for displaying the renal vessels, aorta, inferior vena cava (IVC), or other vascular structures. A limitation of the technique is that vessels adjacent to bony structures may be obscured and calcification in vessels may not be visualized. SSD images reconstruct a model of the surface that forms the outline of an object (organ). It allows surface information to be

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IMAGING IN RENAL CANCER

Table 6.1

Multislice CT: advantages and disadvantages

Superior

Advantages • Faster acquisition compared with spiral scanner (hence better for uncooperative, breathless, and trauma patients) • A larger area can be covered during a single acquisition • Fewer movement artefacts • Multiplanar reformats • Improved vascular imaging • Potential for faster throughput of patients

L

Posterior Right Posterior/Right

Anterior Left Anterior/Left D

Disadvantages S

• Increased capital cost • Increased costs for replacement tubes and data storage • More time required to analyse data • Increased radiological workload • Potential for higher radiation dose

visualized by selecting a voxel threshold. This technique produces 2D images of the surface of the kidney and or tumour with effective 3D perception as a result of the shading. Disadvantages of this technique are that it can be affected by noise and artefacts, and vascular calcification may be obscured. VR reconstructs a 3D model from a 2D image set. The technique can simultaneously display and distinguish a wide variety of anatomical structures of various grey-scales, by modifying opacity levels, or colours in a single volume dataset. VR images can be manipulated interactively to present the best viewing point so that some structures are excluded (made transparent), and others are opaque. It allows different techniques of 3D visualization such as external visualization of the kidney, or a fly-through technique for an endoscopic type visualization18 (Figure 6.1). This technique forms the basis of CT angiography (CTA) and CT venography (CTV) as well as CT urography (CTU)19 (Figure 6.2). In renal cancer the significance of MPR and 3D imaging is that it allows for better assessment of the disease especially with respect to surgical planning and staging.17 For example the relation of the tumour to surrounding structures such as the under surface of the liver or the adrenal gland is best appreciated

P R

Inferior

L A

Voxar 3D

Figure 6.1 Renal cell carcinoma (stage T1). A volume rendered colour image showing a right midpole tumour (arrow). The relation of the tumour to the adjacent duodenum (D) and liver (L), are clearly visualized.

Superior

Right

Left

Inferior

Voxar 3D

Figure 6.2 A coronal reformatted CT urogram image demonstrating normal pelvicalyceal opacification. A right renal lower pole simple cyst is demonstrated (arrow).

on a coronally rendered image. In a series of 60 cases of patients undergoing multislice CT examinations with MPRs performed preoperatively, the most valuable information was

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definition of the relation of tumour to the collecting system, depiction of anatomical variants and rendering of the renal vasculature. Of 77 multiple renal arteries found at surgery, 64 were detected by CT volume rendered images. Of 69 renal veins identified at surgery, 64 were detected by CT. CT was as accurate as traditional angiography in identification of the arteries but superior in demonstrating venous anatomy and anatomical variations.16

MAGNETIC RESONANCE IMAGING The role of magnetic resonance imaging (MRI) is often complementary to that of CT in the assessment of renal disease. MRI has several advantages over CT in lesion characterization and disease staging in part due to its greater contrast resolution, although the traditional advantage of direct multiplanar imaging on MRI is no longer present with the advent of multislice CT. MRI is of particular use in patients who are unable to receive iodinated intravenous contrast, due to allergies or renal failure. As no ionizing radiation is utilized, the role of MRI is likely to continue to extend. Technical developments have not only improved the imaging capabilities of MRI with faster imaging but also MRI systems are more user friendly and versatile, and the scanners are more comfortable and less claustrophobic for patients. This has resulted in increased patient throughput and MR examinations have therefore become more cost-effective.20 For clinical imaging the magnetic field strength has gradually increased over the years and most clinical imaging units now operate at 1.5 Tesla (T) (earth magnetic field strength is 30–70 µT). A few clinical imaging systems at higher field strengths, e.g. 3 T are coming on to the market for body imaging. The role of the 3 T system in renal or oncological imaging remains to be defined. In neuroradiological practice these systems are being used for functional and spectroscopic imaging studies.21 Coils, which receive the signal used to reconstruct the MR images, have continued to improve. Optimization of coils has led to improved detection of the MR signal. For example, phased array coils placed over the

kidneys use an array of small coils working together allowing high sensitivity for coverage of a large volume, with fewer artefacts.22 With continued improvement in the software and hardware technology in MR systems, imaging acquisition has become faster and new sequences are continually being developed. Examples include MR angiography, urography,23 and 3D imaging techniques (Figure 6.3). Until recently, MR angiographic and venographic techniques used to rely on the effect of moving blood on the magnetic resonance signal to produce angiographic images. However, such techniques have a number of limitations and more recently 3D contrast enhanced MR angiography acquires images in a single breath-hold.24 Such arteriographic images can be used in the assessment of renal artery stenosis, planning transplant surgery and may also be used to gain information prior to partial nephrectomy for renal cancer.25 Delayed images from an MR angiographic sequence provides venographic images allowing the assessment of tumour thrombus within the IVC.26 Dynamic contrast enhanced MRI may be used to measure regional blood volume, capillary permeability, and volume of extracellular space.27 Dynamic contrast enhanced techniques have been used to assess tumour grade and type, and treatment efficacy. Malignant lesions have been shown to be more vascular because of increased production of angiogenic factors.28 These techniques may also be used to test the efficacy of newer antiangiogenic agents. Comparative studies before and after treatment should actually be able to quantify tumour perfusion and assess disease response in these terms. Much of this work has been done in other cancers, e.g. breast, brain, and liver tumours,29,30 though a recent study examining tumour perfusion in renal cancer also demonstrated promising results in MRI assessment of tumour response to therapy.31 Open magnet systems are available and are used for claustrophobic patients. These usually operate at lower field strengths (< 0.5 T) but newer open systems at higher field strengths are being developed. This combined with real time interactive imaging sequences and the

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Figure 6.3 A series of MR images in a patient with a large left upper pole renal cell carcinoma. (A) An axial T2weighted image demonstrating the large left upper pole tumour (arrow). (B) A coronal T2-weighted image demonstrating the large left upper pole tumour (arrow). (C) Curved coronal reformatted image from a contrast enhanced 3D MR acquisition shows extension of tumour (arrow) into an expanded left renal vein. (D) Delayed MIP images from the 3D contrast enhanced MR sequences show an MR urogram demonstrating the relation of the tumour to the upper pole calyx of the collecting system (arrow).

open access on these systems has led to an increasing interest in interventional MRI techniques such as MR-guided biopsies of lesions seen only on MRI and thermal ablation of tumours.32,33 Other modifications, such as MRI safe anaesthetic and monitoring equipment and surgical instruments, have allowed an imaging suite to function as a MR-compatible operating theatre.

POSITRON EMISSION TOMOGRAPHY A recent development in radionuclide imaging is that of positron emission tomography (PET). This technique uses radioisotopes that emit

positrons for imaging. In cancer patients, F-182-fluoro-2-deoxyglucose (FDG) has become the most commonly used radiopharmaceutical for clinical PET. FDG is transported into cancer cells like glucose. It accumulates within the cell in proportion to the cell’s rate of glycolysis. Much of the clinical utility is based on the fact that diseased tissue has a different rate of glucose utilization to normal tissue; in particular tumours often exhibit high metabolic rates. Much of the initial work on PET is based on PET-only scanners which provided planar views of the body with limited anatomical details. This limitation has been overcome with the combined PET-CT scanners. This allows the PET and CT images to be fused

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Figure 6.4 PET-CT study in a patient with recurrent renal cell carcinoma. (A) An axial CT image showing a subcutaneous soft tissue nodule within the posterior abdominal wall (arrow). (B) FDG-PET image at the same level abnormal uptake in the region of the subcutaneous nodule (arrow) in keeping with recurrent disease. Note the normal uptake in the right kidney.

giving both the functional and anatomical detail. The latest PET-CT machines utilize multislice CT technology and thus offer the advantages of multislice CT in addition to the PET information.34 PET-MRI scanners have also been described, thus combining the spatial and soft tissue details of MRI with the functional information of PET. However, there has been no work to date in patients with renal cancer.35 The eventual role in renal cancer of PET-CT is yet to be defined, however the co-registration of these techniques uniquely allows simultaneous functional and anatomical data acquisition, and has shown promising results in other malignant diseases.36 PET-CT is not yet a proved role in detection or characterization of RCC though it is likely to have a developing role initially in the evaluation of recurrent and metastatic disease (Figure 6.4).

DETECTION AND CHARACTERIZATION OF RENAL TUMOURS Renal tumours are often detected incidentally on imaging usually on ultrasound or CT with up to 83% of asymptomatic tumours detected on ultrasound, diagnosed at a smaller size than in symptomatic patients.37 In suspected RCC the first line of investigation is probably best performed with CT as staging information is

Figure 6.5. An axial contrast-enhanced CT image demonstrating a left renal mass lesion with a central area of low attenuation in keeping with a scar (arrow). Although this appearance is not specific, it is typical of an oncocytoma.

also obtained. If a lesion is clearly solid it has traditionally been thought most likely to represent a RCC. More recently however there has been increasing evidence that not all solid lesions are RCC and some features might suggest alternative diagnoses such as a central scar in oncocytomas38 (Figure 6.5). If the features are atypical on imaging then an image-guided biopsy should be performed prior to surgery.

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Where the lesion remains indeterminate on CT further characterization may be performed with ultrasound or MRI. Despite the advances in ultrasound technology the main role for ultrasound has remained in distinguishing between solid or cystic renal lesions. Cystic renal lesions are classified using the Bosniak system according to CT features39 (Table 6.2), though certain aspects of this classification can be augmented by ultrasound findings. Category 2 cysts may contain up to two thin septa, or a small amount of calcification in an otherwise thin-walled anechoic lesion, and can be well characterized on ultrasound where CT findings are equivocal. Certain category 3 cysts can be further characterized such as hyperattenuating non-enhancing cysts, which are suspicious for hypovascular tumours, but are commonly completely anechoic and benign on ultrasound. Also certain RCCs with massive necrosis can appear pseudocystic and indistinguishable from complex (category 3) cysts. Ultrasound may characterize intracystic fluid content as heterogeneous, and further define a thickened, irregular wall hence augmenting the CT features.37 Doppler ultrasound can aid in the assessment of renal lesions. A recent study by Jinzaki et al evaluated power Doppler combined with greyscale findings and yielded promising results.40 Of 64 small renal tumours evaluated, they found that all RCCs had either a complete peripheral vascular distribution or some penetrating vessels in addition. However, these findings were not specific and benign angiomyolipomas (AML) tended to have intratumoural and penetrating vessels.40 The use of ultrasound contrast agents is still under evaluation, but these agents may be of use in the assessment of small lesions that are suspicious for RCC. It allows significant cortical enhancement after intravenous administration, on both standard grey-scale and colour Doppler imaging.41 At maximal enhancement, small lesions appear as rounded cortical defects surrounded by significantly enhanced normal parenchyma and blood vessels on early imaging. No large series has yet evaluated this technique in RCC but it has had excellent results in other tumours. This technique may

Table 6.2

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The Bosniak cyst classification CT findings

Category 1

Category 2

Category 3 Category 4

Benign simple cysts: hairline thin walls; no septa, calcifications, solid components; no enhancement Benign cystic lesions: thin walls; hairline thin septa; fine calcification in wall/septa; minimal enhancement; hyperdense non-enhancing cysts also included (< 3 cm) Indeterminate masses: thick irregular walls or septa that show enhancement Malignant cystic masses: thick irregular walls or septa that show enhancement, with enhancing soft tissue components

Adapted from Bosniak MA. The current radiological approach to renal cysts. Radiology 1986; 158: 1–10.39

have a role in the assessment of indeterminate liver lesions that are suspicious for metastases.42 MRI may be used alternatively to CT or ultrasound in the assessment of an indeterminate lesion. Similar morphological and contrast enhancement features are evaluated on MRI as with CT or ultrasound. However the greater contrast sensitivity of MRI to different tissue types aided with enhancement following intravenous gadolinium, make MRI invaluable in characterizing lesions. Furthermore certain specific MRI techniques may also be helpful in defined clinical situations. For example chemical shift imaging allows detection of a small amount of intracellular fat as signal loss in the out-of-phase images. This may help to predict tumour cell type, as clear cell RCC is histologically characterized by cytoplasmic fatty granules.43 It also allows distinction of a RCC from an AML which shows dramatic signal loss in the out-of-phase sequence.44 Imaging is also used in characterizing lesions suitable for partial nephrectomy. A number of imaging findings are vital in the preoperative evaluation of these patients, and include the position of the kidney, the tumour size and precise location with respect to the renal surface, collecting system and the vessels. The most suitable lesion for nephron-sparing surgery is small (< 4 cm), polar, cortical and distant from the renal hilum and collecting system. This information can be obtained with CT,17 or MR.45

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STAGING Staging in renal cancer is usually performed with CT. Ultrasound has only a very limited role in tumour staging, as abdominal bowel gas will often limit the evaluation. CT is excellent at assessing tumours confined to the renal capsule. It is currently superior in the assessment of small RCC (< 2 cm), and is the preferred modality in assessing ultrasonically detected suspicious small lesions and unlike MRI will detect lesion calcification. Another feature of RCC seen typically in tumours confined within the renal capsule is the pseudocapsule. This, however, is best assessed by MRI, and is identified as a hypointense rim surrounding the tumour on T2-weighted images. This is a significant advantage over CT which does not demonstrate this structure. An intact pseudocapsule has been shown to be an excellent predictor of lack of perinephric fat invasion, and very useful in staging for nephron-sparing surgery.46

Tumour Staging perinephric invasion (T3a disease) is a common source of staging error. An enhancing perinephric mass is a highly specific finding, but many patients with perinephric invasion may not have this feature on CT or MRI. Other less specific findings of capsular invasion include an indistinct tumour margin, and thickening or stranding of the perinephric tissues. However, these findings are non-specific and can be due to perirenal haemorrhage, vascular engorgement, or inflammation due to other causes such as previous stone disease, and are in fact present in half of patients with T1 or T2 disease.17 If the thickening is contiguous with the tumour then this specificity may be higher.47 MPRs are likely to improve this accuracy significantly, though to date no studies have actually confirmed this. Venous extension of tumour (Stage T3b-c disease) can be assessed with ultrasound, CT, or MRI. Sonography is highly accurate at assessing tumour thrombus within the IVC if the examination is technically adequate. Although visualization of the entire IVC is often not achieved,

specificity in assessing the intra and suprahepatic portions along with the right atrium can be as high 100%.48 Transoesophageal or transthoracic echocardiography may be helpful if tumour thrombus is suspected to extend into the right atrium. Colour Doppler assessment improves overall accuracy in assessing tumour extent.49 On an enhanced CT the presence of a persistent low-attenuation filling defect within the renal vein or IVC is a sensitive and specific sign of thrombus. Thrombus within the collateral veins and abrupt change in renal vein calibre are useful signs, but enlargement alone of the renal vein is not reliable. This can be due to a hypervascular RCC causing venous engorgement or just be a normal variant.50 Equally, tumour thrombus may not necessarily cause venous enlargement. In distinguishing tumoural thrombus from plain thrombus, direct extension from the tumour and heterogeneous enhancement are useful features. Venous invasion can be more difficult to diagnose on the right side as the vein is shorter. Sagittal and coronal reformatted images allow determination of the upper extent of IVC thrombus, which is of great importance in surgical planning. MRI is extremely useful in assessing venous invasion, particularly in delineating the extent of IVC thrombus, which is best determined in the sagittal and especially the coronal plane. Superior extent, in particular the relation to the hepatic veins, diaphragm, and right atrium, can be evaluated. Tumoral invasion of the IVC wall can sometimes be predicted by MRI. Tumour extending through the wall allows a definitive diagnosis, but altered wall thickness and signal and particularly altered vessel wall enhancement may also be features.51

Nodes The presence of lymph node disease is a poor prognostic factor. On both CT and MRI the diagnosis of lymph node involvement is based on size criteria, which has well known limitations. CT and MRI are unable to identify metastases in normal sized lymph nodes and

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both are unable to distinguish enlarged nodes due to reactive change from enlargement due to metastases. However metastatic tumour is invariably present in nodes larger than 2 cm.52 Microscopic lymph node invasion is uncommon, occurring in less than 5% of patients.53 Overall accuracy of CT staging of lymph nodes has been reported as 83–88%.52 MRI has better soft tissue contrast resolution than CT and intravenous contrast medium is not required to distinguish lymph nodes from vessels. Lymph node staging of MRI is at least comparable with that of CT.54 MR lymphography with lymph node specific contrast media (ultrasmall iron oxide particles, USPIO) may improve the diagnostic sensitivity and accuracy in assessing lymph node metastases,55,56 however, there have been no studies to date in patients with renal cancer.

Metastases In the assessment of metastatic disease a combination of CT/MRI of the body, brain, and a radionuclide bone scan is utilized as clinically indicated. Distant metastases occur most commonly due to haematogenous spread and are often multifocal in site, though they occur most frequently in the lungs, especially in patients with locally advanced disease. Other favoured sites include bone, liver, contralateral kidney, adrenal, and brain.57 Accurate CT staging of the lungs is vital as a solitary metastasis may be amenable to resection, and may confer a survival benefit.58 Pulmonary metastases are usually multiple soft tissue density lesions classically described as ‘cannon ball’ metastases on a chest radiograph, however, lesions may be smaller and of varying size. Other patterns in the chest include lymphangitis carcinomatosa and rarely endobronchial metastases. The advent of multidetector CT is likely to increase the detection of small pulmonary metastases. Bone metastases are typically lytic and expansile, and occur mainly in the axial skeleton, though may affect the diaphyses of the long bones. Plain radiography and 99mtechnetium MDP bone scintigraphy are usually used to

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identify bone metastases in patients with advanced disease. However, bone scintigraphy is poor at identifying lytic metastases. In this regard MRI may be more sensitive than bone scintigraphy.59 Until now the practical use of MRI for whole body imaging, in the detection of metastases, had been limited by cost, acquisition time and convenience. However, recent developments in MRI with fast image acquisition and the implementation of dedicated software, whole body imaging has become practical. Whole body MRI may have a role in the assessment of metastatic disease in particular bone disease. Our experience is that it is more sensitive than bone scintigraphy while maintaining specificity in the detection of bone metastases.60,61 Liver metastases are typically hypodense on CT, but renal cancer is one of the few malignancies that can produce hypervascular liver metastases. These enhance very rapidly following intravenous contrast, and are most conspicuous on unenhanced and arterial phase studies. MRI is useful in evaluating the liver when a lesion is equivocal on CT or ultrasound. Contrast enhanced ultrasound is also of use in this regard, with liver metastases showing reduced enhancement in the portal venous phase compared to normal surrounding liver.42 In other tumours such as lung cancer and lymphoma, PET is increasingly being used in the assessment of metastatic disease. The role of PET in assessment for metastases in advanced renal cancer is unclear. Some renal cancers can have variable uptake of FDG, though in the largest study to date, CT was superior in diagnosing lung and retroperitoneal nodal metastases, and the combination of CT and a bone scan were at least comparable in diagnosing bone metastases.62

SUMMARY Many imaging techniques are available in the management of renal cancer patients. An understanding of these imaging techniques will help to maximize the information needed for the care of the patient. For most purposes

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multislice CT will provide the bulk of the information needed but this can be supplemented with ultrasound, MRI, or PET imaging.

17.

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33. Anzai Y, Lufkin R, DeSalles A et al. Preliminary experience with MR-guided thermal ablation of brain tumors. AJNR Am J Neuroradiol 1995; 16(1): 39–48. 34. Townsend DW, Carney JP, Yap JT, Hall NC. PET/CT today and tomorrow. J Nucl Med 2004; 45 Suppl 1: 4S–14S. 35. Seemann MD. Whole-body PET/MRI: the future in oncological imaging. Technol Cancer Res Treat 2005; 4(5): 577–82. 36. Even-Sapir E, Metser U, Flusser G et al. Assessment of malignant skeletal disease: initial experience with 18F-fluoride PET/CT and comparison between 18Ffluoride PET and 18F-fluoride PET/CT. J Nucl Med 2004; 45(2): 272–8. 37. Helenon O, Correas JM, Balleyguier C, Ghouadni M, Cornud F. Ultrasound of renal tumors. Eur Radiol 2001; 11(10): 1890–901. 38. Heidenreich A, Ravery V. Preoperative imaging in renal cell cancer. World J Urol 2004; 22(5): 307–15. 39. Bosniak MA. The current radiological approach to renal cysts. Radiology 1986; 158(1): 1–10. 40. Jinzaki M, Ohkuma K, Tanimoto A et al. Small solid renal lesions: usefulness of power Doppler US. Radiology 1998; 209(2): 543–50. 41. Correas J, Helenon O, Moreau JF. Contrastenhanced ultrasonography of native and transplanted kidney diseases. Eur Radiol 1999; 9 Suppl 3: S394–400. 42. Brannigan M, Burns PN, Wilson SR. Blood flow patterns in focal liver lesions at microbubbleenhanced US. Radiographics 2004; 24(4): 921–35. 43. Forman HP, Middleton WD, Melson GL, McClennan BL. Hyperechoic renal cell carcinomas: increase in detection at US. Radiology 1993; 188(2): 431–4. 44. Israel GM, Hindman N, Hecht E, Krinsky G. The use of opposed-phase chemical shift MRI in the diagnosis of renal angiomyolipomas. AJR Am J Roentgenol 2005; 184(6): 1868–72. 45. Pretorius ES, Siegelman ES, Ramchandani P, Cangiano T, Banner MP. Renal neoplasms amenable to partial nephrectomy: MR imaging. Radiology 1999; 212(1): 28–34. 46. Roy C, Sr., El Ghali S, Buy X et al. Significance of the pseudocapsule on MRI of renal neoplasms and its potential application for local staging: a retrospective study. AJR Am J Roentgenol 2005; 184(1): 113–20. 47. Reznek RH, Webb JAW. Renal tumours. In: Husband JE, Reznek RH, eds. Imaging in Oncology. Abingdon: Taylor and Francis, 2004: 273–305. 48. Kallman DA, King BF, Hattery RR et al. Renal vein and inferior vena cava tumor thrombus in renal cell carcinoma: CT, US, MRI and venacavography. J Comput Assist Tomogr 1992; 16(2): 240–7. 49. Habboub HK, Abu-Yousef MM, Williams RD, See WA, Schweiger GD. Accuracy of color Doppler sonography in assessing venous thrombus extension in renal

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Interventional radiology in renal cancer David J Breen, Robert D Ward

INTRODUCTION The past few decades have seen the role of interventional radiology in the management of renal cancer continue to evolve. Initially it was restricted primarily to the diagnosis and characterization of renal tumours by arteriography with reports in the literature as early as 1954.1 In 1969 transcatheter embolization of renal neoplasms was first suggested.2 With the clinical application of ultrasound in the 1970s and computed tomography (CT) in the 1980s came the ability to diagnose, further characterize, and percutaneously biopsy renal tumours using image guidance. These two modalities, together with magnetic resonance imaging (MRI), continued to develop rapidly and today their use has become widespread. The increased use of imaging has resulted in increasing numbers of small, ‘subclinical’ renal cell carcinomas (RCCs) being detected incidentally at imaging for alternative symptomatology. Diminishing tumour size at the time of detection along with a realization that resection of smaller volume disease leads to significantly improved 5-year survival3–5 has led to a gradual clinical stage migration. This has recently been acknowledged by the UICC (Union Internationale Contre le Cancer, TNM atlas, fourth edition 1997) whereby T1 disease now includes tumours up to 7 cm in diameter, and increasingly tumours smaller than 4 cm are staged as T1a, further reflecting improved outcome. These tumours, by virtue of their size and the fact that they often occur in elderly patients with significant comorbidities, lend themselves to minimally invasive

treatment techniques such as image-guided ablation (IGA). In more advanced disease interventional radiology can offer techniques such as embolization, either as adjuncts to surgery, or in palliation and the future may well see targeted therapy delivered directly to renal tumours enabling higher local concentrations of treatment agent with decreased systemic side effects. Technological advances in fluoroscopy have greatly improved image quality and developments in catheter and guidewire design have allowed safer and deeper vessel cannulation. IGA has recently come of age and radiofrequency ablation (RFA) is now an increasingly commonplace image-guided interventional tool.

THE ROLE OF PERCUTANEOUS BIOPSY Image-guided percutaneous fine needle aspiration biopsy and core biopsy are central to the diagnosis of many solid organ tumours, particularly as few exhibit features that are diagnostic on imaging criteria alone and therefore corroborative information in the form of cytology or histology is essential prior to the commencement of any proposed treatment in these situations. This, however, is not the case for renal masses where imaging studies have been repeatedly shown to be more accurate than biopsy. Dechet et al6 performed 18-gauge biopsies on 106 tumours at the time of radical or partial nephrectomy and compared the results of these biopsies with those from whole tissue specimens. They showed that intraoperative core

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biopsy when compared against resected histology yielded a sensitivity of 81%, specificity of 67%, and negative predictive value of only 71% for malignancy. The same study also looked at previous reports in the literature and found wide variations in reported sensitivities ranging from 62% to 100% and specificities ranging from 0% to 100%. Another study showed that non-diagnostic samples were produced in 15 of 73 biopsies (21%).7 CT, however, has been shown to be the most accurate diagnostic tool to use before resection.8 Modern multislice technology with thin collimation, rapid contrast injection and three phase imaging9 allows for the detection of nearly all renal masses8 of which approximately 85% will be malignant.10 Even very small masses can be detected with 95% of renal masses 8–15 mm in diameter visible on CT.11 A recent study by Tuncali et al12 however, raised concern over the sole use of CT for the diagnosis of renal malignancy. Twenty-seven patients were referred by urologists for MRguided cryotherapy of a suspected renal tumour detected on CT or MRI. Ten (37%) of these patients, however, turned out to have benign renal masses, three masses were proved benign by biopsy, three by imaging and four by a combination of biopsy and imaging. Rather than serving to downgrade the role of crosssectional imaging in the diagnosis of renal tumours this study clearly demonstrates that diagnosis of a renal tumour is not just dependent on the detection of an enhancing solid mass. More critical and detailed interrogation of the lesion is required, particularly with regard to its internal structure, enhancement characteristics, and fat content, taken together with the age of the patient and clinical presentation. If necessary, follow-up imaging may be required. With meticulous attention to imaging technique and lesion interpretation a correct diagnosis can be made in the overwhelming majority of cases and potential mimickers of RCC can usually be excluded. Biopsy of renal tumours has however been shown to be useful in several circumstances such as differentiating RCC from renal lymphoma, metastases, and abscess13 or providing a histological diagnosis in patients with a renal

mass who are not surgical candidates.14 The technique is similar to obtaining a core biopsy from any other solid organ. The patient is appropriately consented and a check is made to ensure normal blood clotting. At our institution the vast majority are performed under ultrasound guidance. The patient is positioned appropriately to allow best access to the lesion, usually by being placed in the lateral, oblique, or prone position. The lesion is thoroughly examined in several planes and note is made of any cystic or likely necrotic components that if biopsied would be unlikely to yield a positive result. Ideally the planned needle trajectory should be such that the biopsy is taken tangentially through the outer rim of the lesion thereby avoiding any possible necrotic centre. Local anaesthetic is infiltrated into the skin at the planned skin entry site and into the abdominal wall. Care is taken not to inject any air bubbles as this can cause the lesion to be obscured. We prefer to use a 16-G or 18-guage cutting core biopsy needle. Under realtime ultrasound guidance, and preferably with suspended respiration, the biopsy needle is inserted so that the tip of the needle just penetrates the lesion. The device is then ‘fired’. Usually two cores are obtained and placed in formalin. At the end of the procedure the patient is rescanned to check for any obvious signs of post biopsy haemorrhage and is closely observed for 4 hours. Clinically significant complications are unusual, the commonest being haemorrhage of which the vast majority can be treated conservatively.15 Ralls et al16 found definite CT evidence of haemorrhage after 91% of biopsies with 1% deemed clinically significant requiring therapeutic embolization. It would seem therefore that virtually all patients undergoing renal biopsy develop some degree of haematoma. Most other studies report lower incidences of post-biopsy bleeding although this is likely to underestimate the true incidence because post-procedural imaging is not always routine.17 Tumour seeding along the biopsy needle tract is rare and limited to a handful of case reports.18–21 Smith22 estimated the incidence of needle tract seeding to be approximately 1 in 20 000 patients. Both

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INTERVENTIONAL RADIOLOGY IN RENAL CANCER

pseudoaneurysm and arteriovenous fistula formation are well-recognized complications of percutaneous renal biopsy.17,23 Typically, they are clinically silent but may manifest as retroperitoneal haemorrhage requiring arterial embolization.17

EMBOLIZATION IN RENAL CANCER Transarterial embolization (TAE) of renal tumours was first described by Almgard et al in 1973 for palliation in metastatic disease and as adjunctive therapy prior to surgical nephrectomy.24 Since then the role of embolization of renal tumours has been controversial and over the past 30 or so years has gone in and out of favour with radiologists and urologists. In 1983 a postal survey of UK urologists found that 60% of respondents practised embolizationnephrectomy25 while in 1992 a similar survey found that less than 0.2% performed the procedure in the routine management of RCC.26 The same survey, however, found that 35% of urologists thought it a useful technique in the palliation of RCC although this figure had nearly halved since 1983. In a review of published series between 1973 and 1997 Kalman and Varenhorst27 found that 78% of renal embolization patients underwent global renal embolization prior to nephrectomy in order to reduce tumour vascularity and size and thereby allow for easier and safer subsequent surgery. There is little good evidence in the form of a randomized controlled trial to support the use of preoperative embolization. Christensen et al28 compared patients who underwent preoperative embolization with those who had previously had nephrectomy alone. Although the surgeon felt that preoperative embolization facilitated nephrectomy, comparison between differences in blood loss and operating time in the two groups did not reach statistical significance. In addition, there was no difference in survival between the two groups. Bakal et al29 compared operative blood transfusion requirements in 93 consecutive patients who underwent nephrectomy for renal cell carcinoma of which 24 underwent embolization prior to nephrectomy. Even though the embolized tumours were significantly

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larger than the non-embolized tumours, patients who underwent complete embolization received significantly smaller mean blood transfusion volumes than control patients. Zielinski et al30 looked at 118 patients who underwent preoperative embolization and compared them to a matched group of 116 patients who underwent nephrectomy alone. Preoperative embolization was found in this study to be an important factor influencing survival. Patients who had undergone preoperative embolization experienced 5- and 10year survival rates of 62% and 47% compared with 35% and 23%, respectively, in the nonembolized group. Wallace et al31 reported that following embolization the kidney became oedematous with a maximal peak at 48–72 hours after embolization. This created a more obvious plane between the tumour and the renal bed thereby facilitating dissection. Greater than 72 hours after embolization a collateral circulation developed making nephrectomy more difficult. In a later study, however, this plane was not identified in any of 28 patients who had undergone preoperative embolization32 although surgical technique differed between the two papers.

Embolization for palliation There is a more accepted place for embolization in the modulation of symptoms from advanced RCC although in Kalman and Varenhorst’s review of the literature this accounted for only 19% of patients undergoing embolization27 Such palliation includes control of haematuria, pain, polycythaemia, hypercalcaemia, hypertension, congestive cardiac failure and pain (Figure 7.1). Munro et al33 reported on 25 patients who did not undergo surgery due to either unresectable disease, being unfit for surgery or through patient choice. All patients had the entire tumour-bearing kidney embolized and following this 17 of 25 (68%) reported no further problems from their primary tumour. Nurmi et al34 found that of 14 patients with heavy haematuria, 11 were successfully palliated as were 3 of 6 patients with severe loin pain. Onishi et al35 looked at 54 patients with disseminated disease and poor performance status;

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Figure 7.1 (A) Large hypervascular tumour at lower pole of right kidney (arrow). Note the deficient perfusion at the necrotic centre of the tumour. (B) Following embolization of the entire kidney and in particular the hypertrophic lower pole artery feeding the tumour. There is typical retained tumour staining (arrow) and contrast stasis within the draining veins. (Images courtesy of Dr A Odurny.)

24 patients underwent embolization and they were compared to 30 patients who refused embolization. In the TAE group all showed enlarged areas of tumour necrosis on post-TAE CT compared with pre-TAE studies. In addition the tumour was smaller in 50% of TAE patients and 75% reported resolution of tumour-related symptoms such as haematuria and loin pain. Interestingly there was a statistically significant improvement in survival in the TAE group compared with the no TAE group although other studies have reported no survival benefit in this situation.31,36 Repeat embolizations may be required to control symptoms although due to increasingly chaotic tumour revascularization with supply often from lumbar and mesenteric vessels this becomes more and more difficult with each embolization (Figure 7.2).

Embolization of osseous metastases Approximately 40% of RCC patients will at some point develop bony metastases. In addition,

RCC is the fourth commonest metastatic tumour to affect the spine and the commonest tumour to present as a neurological deficit secondary to an unknown primary malignancy.37 Malignant infiltration of the spine produces bony destruction and mechanical instability leading to pain, radiculopathy, and spinal cord compression requiring surgical decompression and stabilization when radiotherapy fails. Most metastatic renal tumours are hypervascular which poses special problems to the surgeon due to unpredictable and potentially lifethreatening intraoperative bleeding. Sundaresan et al38 looked at 30 patients undergoing surgery for spinal metastases from renal cancer. Excessive blood loss, defined as intraoperative blood loss greater than 10 units with associated hypotension occurred in 11 patients, of which 9 had not undergone preoperative embolization. Olerud et al39 evaluated perioperative blood loss in 21 similar patients of which 11 underwent preoperative embolization and found that for a posterior approach to the spine

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Figure 7.2 Same patient as in Figure 7.1. There is prominent tumour revascularization via lumbar and retroperitoneal vessels (arrows). (Image courtesy of Dr C N Hacking.)

average blood loss in the embolized group was 33% of the blood loss in the non-embolized group. One patient in the non-embolized group died post operatively due to uncontrolled bleeding having lost 15 L of blood peroperatively. Manke et al40 found that mean intraoperative blood loss in patients who had undergone preoperative embolization was 1500 mL (range 300–8000 mL) compared with 5000 mL (range 1440–15 000 mL) in a control group who had not undergone preoperative embolization. It is for this reason that most orthopaedic surgeons take the view that embolization of spinal metastases is essential prior to surgical decompression and spinal fixation in these patients. The embolization procedure itself is a technically demanding one often requiring the use of microcatheters to cannulate small tumour feeders. Initially an aortogram is performed to identify vascular anatomy and any obvious tumour supply, usually evident by a characteristic tumour blush. Selective bilateral catheterization of segmental intercostal (for thoracic lesions) or lumbar arteries (for lumbar lesions)

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two levels above and below the lesion is then performed. In the case of cervical lesions, catheterization of vertebral, thyrocervical, and costocervical arteries is carried out. Meticulous attention is paid to digital subtraction angiograms of tumour feeding vessels, looking for spinal cord supply from radicular arteries which fortunately appear as characteristic hairpin loops. At our institution we routinely use tris-acryl gelatin microspheres (Embospheres; Biosphere Medical, Rockland, MA, USA) as the embolic agent while the use of polyvinyl alcohol (PVA) particles (Boston Scientific, Target Vascular, Fremont, CA, USA), absolute alcohol and Gelfoam (Pharmacia and Upjohn, Kalamazoo, MI, USA) has also been described.38–40 To avoid non-target embolization of intercostal or lumbar arteries, the artery distal to the origins of tumour feeders is occluded with platinum microcoils (Figure 7.3). Complete embolization of all vertebral lesions is not always possible with complete embolization success rates varying from 50% to 86% in the published literature.40 This can be due to inability to successfully cannulate all tumour feeders, an unstable catheter position or when embolization has to be aborted due to the presence of spinal feeders arising from the tumour supply. In the latter instance a more cautious approach is warranted due to the risk of causing permanent paralysis especially since surgery for spinal metastatic disease does not affect survival.41 Most series report no major complications associated with embolization although transient neurological defects have been described.38 Neurological symptoms can even occur during the initial angiogram before any embolization is performed.40 In one series 8.5% of patients experienced severe complications including permanent paraplegia, quadriparesis that gradually resolved, and aortic dissection.42 Embolization without subsequent surgery for compressive spinal metastases has also been described43,44 with reported improvements in pain and neurological function although repeat embolizations may be required for recurrent symptoms.43 Embolization is also employed elsewhere in the skeleton in renal metastatic disease, most commonly in the femur and humerus. Indications are similar

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Figure 7.3 (A) Sagittal MR image demonstrating altered signal due to tumour infiltration of the vertebral body at D5 with cord impingement (white arrow). (B) Cannulation of posterior right intercostal vessel at D5 level demonstrates tumoural blush in the D5 vertebral body. (C) Deeper cannualtion of intercostal vessel and laying of a protective coil to prevent non-target chest wall embolization. (D) Post embolization appearances with reduction in tumoural vascularity and contrast stasis. (Images courtesy of Dr C N Hacking.)

to those in spinal disease namely relief of pain and the reduction of blood loss during subsequent orthopaedic surgery.45,46

IMAGE-GUIDED ABLATION Whereas until recently surgery – either open or laparoscopic – was the only viable treatment option, increasingly, in certain groups of patients IGA is playing a significant role in the management of early disease. IGA has been with us for a few decades. In essence it is the targeted use of thermal energy – either cold or hot – to destroy living, perfused tissue. Cryotherapy has been a practical tool for the longest period but has only very recently been developed into a narrow-gauge probe which can be used percutaneously. Interstitial laser

photocoagulation matured in the 1980s but has not caught on due to the need to place multiple bare fibres to create even modestly sized lesions. High intensity focused ultrasound (HIFU) and microwave are still evolving clinical tools but it is radiofrequency ablation (RFA) which has disseminated rapidly due to its ability to create a 3–5 cm sphere of ablated tissue within a practical timeframe. Monopolar RFA is the application of high frequency (460–500 kHz), alternating current to a targeted tissue by means of an exposed antenna which induces a sphere of thermal injury around the uninsulated probe tip. Large dispersive grounding pads are attached to the patient’s thighs and the concentration of current flux around the much smaller probe tip induces coagulative necrosis at temperatures

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Generator

Ground pads Figure 7.4 Circuit arrangement for routine monopolar radiofrequency ablation. Large dispersive grounding pads are attached to the patient’s thighs and current flux density induces thermal injury around the probe tip.

of between 55°C and 110°C (Figure 7.4). Coagulative necrosis can occur at temperatures as low as 46°C but only if maintained for 60 minutes. Small increments in temperature above this markedly reduce the time necessary to induce cell death while at temperatures between 60°C and 100°C near-instantaneous cell death occurs.47 Temperatures in excess of 105°C can be counterproductive due to the induction of tissue boiling, vaporization and carbonization, all of which impair optimal heat transmission from the probe tip to the more peripheral parts of the lesion.48 The goal therefore is to maintain a temperature of between 60°C and 100°C throughout the entire target volume. Several RFA probes are currently available. The RITA (RITA Medical Systems, Mountainview, CA, USA) and LeVeen (Boston Scientific Corp, San Jose, CA, USA) systems consists of a 14 or 15-gauge electrode with multiple retractable tines that can be extended into the target lesion at 1 cm increments to suit the desired treatment volume. The Tyco-Radionics system (Tyco-Radionics, Burlington, MA, USA) consists of either a single 17-gauge needle or a cluster of three needles in a triangular configuration, either system employing electrode cooling and pulsed energy delivery to increase ablation volume (Figure 7.5). More recently treatment volumes and the time taken have been reduced by the use of multiple ‘switched’ probes in configurations determined by the target tumour.

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Indications Currently, there are no absolute indications for the use of RFA in the treatment of renal tumours, and the first line treatment for patients with renal tumours remains partial or radical nephrectomy. There is, however, a group of patients in which RFA appears well suited. This includes patients in whom an open operation poses considerable risk due to significant comorbidities, patients who refuse surgery, those with marginal renal reserve where preservation of normal functioning tissue is paramount and patients at risk of developing further tumours in the future, e.g. in Von Hippel–Lindau disease. Dependent on accruing experience the indications may well broaden to include a large proportion of small-volume disease.

Factors influencing success Since the first report of RFA of a renal tumour in 1997,49 numerous workers have published results of series, with the largest by Matsumoto et al of 109 patients.50 Almost all focus on two main factors that appear to be important predictors of success, that is lesion size and position. At present one of the main limitations of RFA in the treatment of renal tumours is the maximum size of the ablation volume possible and therefore the maximum lesion size that can be confidently treated during a practicable treatment session. It appears that, with current technology, tumours less than or equal to 4 cm can be successfully ablated during one RF session with most series quoting figures at or very close to 100% regardless of lesion location51–55 (Figure 7.6). Larger lesions can still be treated but by using several overlapping ablation spheres such that even 5 cm lesions can be considered for RFA.52 Certainly with increasing lesion size the chances of incomplete ablation and the need for further treatment sessions increases (Figure 7.7). The scope of IGA may increase further with the use of adjunctive pre-embolization which aims to diminish tumour perfusion and thereby increase the efficacy of thermal ablation. This has been observed experimentally in studies

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Figure 7.5 (A) An expandable, multitined radiofrequency (RF) probe (in this case from RITA Medical Systems, CA, USA). (B) A ‘cluster’ monopolar RF probe (from Tyco, MA, USA).

on swine kidneys where tumour perfusion reduction with either renal artery balloon occlusion or selective tumour embolization with particles prior to RFA results in a 60% increase in the maximum diameter of ablation56 (Figure 7.8). There have been no case reports of patients developing metastatic disease following incomplete tumour ablation at the first sitting and although complete one session tumour destruction is desirable, a repeat ablation appears to carry the same low risk as the initial ablation. The second important determinant of success is lesion location. Exophytic tumours which are partly surrounded by fat appear more easily treated than central tumours (usually taken as those with less than 50% of their volume lying outside the renal outline). Fat appears to serve as an effective heat and current insulator allowing more effective ablation and therefore more reliable tumour necrosis. In contrast centrally located tumours although in contact with some sinus fat are also situated close to large vessels. It is believed that these can act as ‘heat sinks’ conducting heat away from the treatment zone and may reduce the temperature achieved, and thereby the chances of a successful ablation. Gervais et al57 reported 100% ablation of all exophytic tumours but this dropped to 78% for central tumours and 61% for ‘mixed’ tumours with both exophytic and central components. In this study all tumours less than 4 cm were completely ablated regardless of location and therefore it appears that tumour situation is particularly important for lesions greater than or equal to 4 cm. Some workers have posited

active cooling of the pelvicalyceal system via a retrograde ureteric catheter so that more thorough ablation can be applied at the deep aspects of such tumours while reducing the chance of thermal injury to the collecting system.58 This approach will require further study.

Effect on surrounding normal kidney A considerable advantage of RFA over surgical treatment is the ability to destroy renal cancers completely while inflicting minimal damage on the surrounding renal parenchyma. This is particularly important given the patient population for which it is currently employed where patients often have limited renal reserve. Matlaga et al59 performed RFA in 10 patients immediately prior to nephrectomy. The nephrectomy specimens were examined and in the eight tumours that were completely ablated the mean treatment margin was 6.75 mm (range 2–13 mm) suggesting that damage to functioning nephrons and therefore overall renal function is minimal and, importantly, tissue destruction was complete with no skip areas.

Technique At our institution patients are selected for RFA following discussion with urologists, oncologists, and radiologists at a multidisciplinary meeting. Imaging assessment is by CT of the chest, abdomen, and pelvis to fully stage the disease. Ultrasound examination is also carried out to assess the feasibility of performing

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Figure 7.6 (A) Typical 3 cm right interpolar renal tumour, ideally suited for RF ablation (arrow). (B) One week following ablation the tumour devascularization is clearly apparent on this post-contrast CT study. (C) Six months after RFA there is gradual involution of the treated lesion further demonstrated at 1 year (D) and 2 years (E).

RFA using ultrasound guidance alone and the patient is also assessed by an anaesthetist. The vast majority of renal RFAs are performed percutaneously with the patient in a prone or prone-oblique position using either conscious sedation or under general anaesthetic for larger lesions or where adjunctive manoeuvres may be required. Using a sterile field and under image guidance a Trucut biopsy of the target lesion is first performed. The RF probe is then inserted into the lesion in the same

manner as a biopsy needle using either CT, ultrasound guidance or often both modalities for optimal image guidance. Due to the close proximity of bowel, usually colon or small bowel, it is sometimes necessary to increase the distance between the tumour and bowel in order to prevent thermal injury to the gut and possible perforation. When repositioning of the patient fails to displace bowel, ‘hydro-dissection’ is performed (Figure 7.9). Using CT guidance an 18-gauge sheathed

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Figure 7.7 (A) 4 cm left interpolar renal tumour (arrow). (B) One week following ablation there is a persistent crescent of enhancing tumour (arrow) indicating subtotal treatment. (C) Following re-treatment the entire tumour has been ablated. (D) Slow involution of treated mass at 1 year.

needle is inserted into the retroperitoneal plane between kidney and bowel and 5% dextrose is infused in order to displace heat sensitive organs such as the colon. These manoeuvres have considerably expanded the safe applicability of IGA to small, solid renal tumours around the whole kidney.

poor determinant of treatment adequacy as the dead tumour cells often appear structurally intact. Periprocedural determination of treatment completion remains the subject of a number of studies which are looking at immediate post-treatment contrast-enhanced ultrasound and ‘T1-thermometry’ with MR among other techniques.

Monitoring during treatment Clearly IGA is a non-extirpative therapy which leaves the ablated tumour in situ. Determination of treatment efficacy remains an issue for image-guided tumour ablation. The ablation process causes vaporization and bubble formation and significantly impairs lesion appreciation by ultrasound at the time of the procedure. In most series to date treatment efficacy has been determined by the absence of contrast enhancement on post-procedural imaging studies. In our experience the zone of tissue death is often better defined approximately 1 week after the procedure and we therefore perform an outpatient contrast-enhanced CT or MR study at about that time. Importantly, postprocedural biopsy has been found to be a very

Follow-up Clearly an in situ therapy such as RFA lacks extirpative histology not only to formalize the diagnosis of cancer but also to confirm that intact surgical margins have been achieved. RFA therefore places a considerable onus on radiological imaging to report the adequacy of treatment and to detect any local recurrence or metastatic disease. For the present RFA followup is by means of contrast-enhanced CT or MRI. Lack of enhancement in a previously enhancing tumour, the absence of growth over time, and gradual tumour involution has been taken to indicate tumour eradication. This has been borne out by our experience of almost 100 treated tumours in which cases of local recurrence and subtotal treatments have always

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Figure 7.8 (A) CT of a 6.5 cm left interpolar renal tumour (white arrow). (B) Tumour neovascularity is appreciated in relation to the large left interpolar tumour (arrow). (C) Following embolization there is complete tumour devascularization (arrows). (D) A larger RF lesion encompassing the entire lesion is achieved following embolization (arrow).

been appreciated on the early post-procedural imaging. Using MRI, lesions that have been treated with RFA demonstrate slightly variable appearances that evolve over time. Immediately post-RFA the ablation zone can be hypo-, iso-, or hyperintense on unenhanced T1 images, and on T2 images it is usually hypointense although with a faintly bright surrounding rim. Following contrast administration a thin rim of enhancement is noted around the ablation zone and corresponds with a reactive inflammatory response noted on extirpative histology. This marginal inflammatory response resolves gradually over time becoming barely detectable at 3 months and should not be mistaken for residual tumour. At 3 months post-RFA the ablation zone remains hypointense on T2 imaging and 67% of tumours will be hyperintense on T1 GRE images.60 Using CT a successfully treated tumour will be of uniformly low density on unenhanced images. For up to 3 months after RFA a thin rim of enhancement may be seen

around the ablated lesion on enhanced images and an ablation ‘halo’ is often noted in the perinephric fat. Under follow-up of over 5 years we have found that lesions may either completely resolve with a bare cortical scar or reduce to a small ‘nubbin’ of non-enhancing tissue.

Long-term results As yet, 5-year results for RFA of renal tumours are still accruing and therefore the oncological efficacy of this procedure is yet to be ratified, however, results so far are promising. Gervais et al57 followed up 85 patients with mean duration of 2.3 years (3.5 months to 6 years) and in the 80 patients without pre-existing metastases or contralateral tumours none developed new metastases. A single case of local progression was seen just over 1 year after RFA and this was, in retrospect, present on an earlier scan and therefore related to poor appreciation of an initial subtotal treatment. Matsumoto

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Figure 7.9 (A) CT of right interpolar renal tumour in prone-oblique position (arrow). Note the close application of the adjacent gas-filled colon. (B) A cannulated needle inserted into the anterior pararenal space and the colon displaced by instillation of approximately 300 mL of 5% dextrose (arrow). (C) The expandable probe is placed in the tumour and the tumour can now be safely treated following colonic displacement (opposed white arrows).

et al50 reported on results on 109 renal tumours and found that 107 (98%) underwent successful initial ablation. One patient developed a local recurrence that was successfully ablated and with follow-up of up to 3 years, no further recurrences were detected. Hwang et al55 found that 23/24 tumours continued to show evidence of complete ablation at median follow up of 385 days (range 342–691) with one centrally located tumour exhibiting contrast enhancement at 1 year. Varkarakis et al51 reported ‘local’ recurrences in 3/46 patients who were initially thought to have undergone successful RFA with mean

follow-up of 27.5 months. These were detected at 24, 25, and 31 months after treatment and were in patients with central tumours greater than or equal to 3 cm. Post-procedural radiological assessment is critical and it remains open to debate as to whether this represented ‘under-reading’ of initial subtotal treatments. In our own experience of 105 renal tumours in 97 patients (Breen DJ et al, submitted for publication) we found that 83 out of 105 tumours (79%) were completely treated at a single sitting. Twelve of the remaining tumours were successfully re-treated and a clinical decision was made not to re-treat a further 7 (full

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details in publication). All tumours less than 3.5 cm in size were successfully ablated in a single treatment. Our mid to long-term case follow-up has also demonstrated steady involution of treated lesions to date, and with a mean follow-up of 16.7 months (range 1–76 months), no revascularization of treated tumours has been noted. A recent study by Michaels et al,61 suggested that residual viable tumour was present in all 20 resected small volume renal tumours on the basis of haematoxylin and eosin staining and in four of five of the most recent tumours, on nicotinamide adenine dinucleotide (NADH) diaphorase staining. There has been some criticism of the adequacy of the radiofrequency treatment cycles used by these authors where the mean treatment time was 9.1 minutes. In addition, haematoxylin and eosin staining has been repeatedly criticized as an inadequate determinant of thermally induced cell death.

RFA in other situations The role of RFA in renal cancer extends into the management of more advanced disease, including symptom palliation. Wood et al62 performed RFA of a 7 cm renal tumour in a solitary kidney in a patient with disseminated RCC to try to relieve gross haematuria. Embolization had been attempted but had not been successful, however, 24 hours following RFA haematuria ceased and did not recur for 8 months. McLaughlin et al63 successfully ablated a 7 cm renal bed recurrence 4 years following nephrectomy. Due to its size three geographically separate ablations were performed; 16 months following the procedure the mass had reduced in size with no evidence of enhancement to suggest subtotal treatment and the patient had become asymptomatic. Distant metastases have also been treated with RFA. Zagoria et al64 ablated two pulmonary metastatic nodules in a patient who refused further chemotherapy and surgery; 16 months following this there was no sign of recurrence. Although uncommon, some patients appear to gain survival benefit following eradication of distant metastases. This is most often seen

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in patients undergoing metastasectomy for a small number of lung metastases.65 RFA of lung metastases has been widely reported for metastases from colorectal cancer but in renal cancer experience is limited which is in part due to the extremely poor prognosis when the disease is at this stage. Certainly, for the present, experience of RFA of lung metastases is limited to those patients who are non-operative candidates.66 The presence of bone metastases is the commonest cause of cancer-related pain.67 In renal cancer where standard oncological treatment of bony metastases is relatively ineffective the role of RFA is gathering pace. A recent multicentre trial involving the treatment of 62 patients with painful bony metastases, 14 of which were due to RCC, showed that 95% of patients experienced a clinically significant drop in pain with resulting decreases in opioid usage. In addition this study showed that pain continued to improve over the 6-month period of follow-up in most patients.68 Percutaneous vertebroplasty whereby methyl methacrylate is injected into a vertebral body lesion under image guidance has been shown to reduce pain and provide stabilization due to consolidation of weight-bearing bone.69 Other methods of ablating bony deposits include ethanol injection, laser-induced interstitial thermotherapy, and cryoablation. Together with RFA these device-based ablation tools can be combined with the use of methyl methacrylate (‘bone cement’) for stabilization of metastatic bone disease at significant risk of fracture.70

REFERENCES 1. Lofgren FO. Renal tumour not demonstrable by urography but shown by renal angiography. Acta Radiol 1954; 42: 300–4. 2. Lalli AF, Peterson N, Bookstein JJ. Roentgen-guided infarctions of kidneys and lungs. A potential therapeutic technic. Radiology 1969; 93: 434–5. 3. Thompson IM, Peek M. Improvement in survival of patients with renal cell carcinoma – the role of the serendipitously detected tumor. J Urol 1988; 140: 487–90. 4. Sweeney JP, Thornhill JA, Graiger R, McDermott TE, Butler MR. Incidentally detected renal cell carcinoma: pathological features, survival trends and implications for treatment. Br J Urol 1996; 78: 351–3.

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5. Rodriguez-Rubio FI, Diez-Caballero F, MartinMarquina A, Abad JI, Berian JM. Incidentally detected renal cell carcinoma. Br J Urol 1996; 78: 29–32. 6. Dechet CB, Sebo T, Farrow G, Blute ML et al. Prospective analysis of intraoperative frozen needle biopsy of solid renal masses in adults. J Urol 1999; 162: 1282–4. 7. Lechevallier E, Andre M, Barriol D et al. Fine-needle percutaneous biopsy of renal masses with helical CT guidance. Radiology 2000; 216: 506–10. 8. Zagoria RJ. Imaging of small renal masses: a medical success story. AJR Am J Roentgenol 2000; 175: 945–55. 9. Israel GM, Bosniak MA. How I do it: evaluating renal masses. Radiology 2005; 236: 441–50. 10. Davis CJ Jr. Pathology of renal neoplasms. Semin Roentgenol 1987; 22: 233–40. 11. Szolar DH, Kammerhuber F, Altziebler S et al. Multiphasic helical CT of the kidney: increased conspicuity for detection and characterization of small (< 3 cm) renal masses. Radiology 1997; 202: 211–17. 12. Tuncali K, van Sonnenberg E, Shankar S et al. Evaluation of patients referred for percutaneous ablation of renal tumors: importance of a preprocedural diagnosis. AJR Am J Roentgenol 2004; 183: 575–82. 13. Bosniak MA. The small (less than or equal to 3.0 cm) renal parenchymal tumor: detection, diagnosis, and controversies. Radiology 1991; 179: 307–17. 14. Rybicki FJ, Shu KM, Cibas ES et al. Percutaneous biopsy of renal masses: sensitivity and negative predictive value stratified by clinical setting and size of masses. AJR Am J Roentgenol 2003; 180: 1281–7. 15. Wood BJ, Khan MA, McGovern F et al. Imaging guided biopsy of renal masses: indications, accuracy and impact on clinical management. J Urol 1999; 161: 1470–4. 16. Ralls PW, Barakos JA, Kaptein EM et al. Renal biopsy-related hemorrhage: frequency and comparison of CT and sonography. J Comput Assist Tomogr 1987; 11: 1031–4. 17. Caoili EM, Bude RO, Higgins EJ, Hoff DL, Nghiem HV. Evaluation of sonographically guided percutaneous core biopsy of renal masses. AJR Am J Roentgenol 2002; 179: 373–8. 18. Goethuys H, Van Poppel H, Oyen R, Baert L. The case against fine-needle aspiration cytology for small solid kidney tumors. Eur Urol 1996; 29: 284–7. 19. Kiser GC, Totonchy M, Barry JM. Needle tract seeding after percutaneous renal adenocarcinoma aspiration. J Urol 1986; 136: 1292–3. 20. Wehle MJ, Grabstald H. Contraindications to needle aspiration of a solid renal mass: tumor dissemination by renal needle aspiration. J Urol 1986; 136: 446–8. 21. Ferrucci JT, Wittenberg J, Margolies MN, Carey RW. Malignant seeding of the tract after thin-needle aspiration biopsy. Radiology 1979; 130: 345–6. 22. Smith EH. The hazards of fine-needle aspiration biopsy. Ultrasound Med Biol 1984; 10: 629–34.

23. Silberzweig JE, Tey S, Winston JA, Mitty HA. Percutaneous renal biopsy complicated by renal capsular artery pseudoaneurysm. Am J Kidney Dis 1998; 31: 533–5. 24. Almgard LE, Fernstrom I, Haverling M, Ljungqvist A. Treatment of renal adenocarcinoma by embolic occlusion of the renal circulation. Br J Urol 1973; 45: 474–9. 25. Ritchie AW, Chisholm GD. Management of renal carcinoma – a questionnaire survey. Br J Urol 1983; 55: 591–4. 26. Lanigan D, Jurriaans E, Hammonds JC, Wells IP, Choa RG. The current status of embolization in renal cell carcinoma – a survey of local and national practice. Clin Radiol 1992; 46: 176–8. 27. Kalman D, Varenhorst E. The role of arterial embolization in renal cell carcinoma. Scand J Urol Nephrol 1999; 33: 162–70. 28. Christensen K, Dyreborg U, Andersen JF, Nissen HM. The value of transvascular embolization in the treatment of renal carcinoma. J Urol 1985; 133: 191–3. 29. Bakal CW, Cynamon J, Lakritz PS, Sprayregen S. Value of preoperative renal artery embolization in reducing blood transfusion requirements during nephrectomy for renal cell carcinoma. J Vasc Interv Radiol 1993; 4: 727–31. 30. Zielinski H, Szmigielski S, Petrovich Z. Comparison of preoperative embolization followed by radical nephrectomy with radical nephrectomy alone for renal cell carcinoma. Am J Clin Oncol 2000; 23: 6–12. 31. Wallace S, Chuang VP, Swanson D et al. Embolization of renal carcinoma. Radiology 1981; 138: 563–70. 32. Teasdale C, Kirk D, Jeans WD et al. Arterial embolisation in renal carcinoma: a useful procedure? Br J Urol 1982; 54: 616–19. 33. Munro NP, Woodhams S, Nawrocki JD, Fletcher MS, Thomas PJ. The role of transarterial embolization in the treatment of renal cell carcinoma. BJU Int 2003; 92: 240–4. 34. Nurmi M, Satokari K, Puntala P. Renal artery embolization in the palliative treatment of renal adenocarcinoma. Scand J Urol Nephrol 1987; 21: 93–6. 35. Onishi T, Oishi Y, Suzuki Y, Asano K. Prognostic evaluation of transcatheter arterial embolization for unresectable renal cell carcinoma with distant metastasis. BJU Int 2001; 87: 312–15. 36. Flanigan RC. The failure of infarction and/or nephrectomy in stage IV renal cell cancer to influence survival or metastatic regression. Urol Clin North Am 1987; 14: 757–62. 37. Schaberg J, Gainor BJ. A profile of metastatic carcinoma of the spine. Spine 1985; 10: 19–20. 38. Sundaresan N, Choi IS, Hughes JE, Sachdev VP, Berenstein A. Treatment of spinal metastases from kidney cancer by presurgical embolization and resection. J Neurosurg 1990; 73: 548–54. 39. Olerud C, Jonsson H Jr, Lofberg AM, Lorelius LE, Sjostrom L. Embolization of spinal metastases reduces peroperative blood loss. 21 patients operated

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Management of renal tumours extending to inferior vena cava

8

Bijan Khoubehi, Tim Christmas, Neil Moat

INTRODUCTION Renal cell carcinoma (RCC) has the ability to grow intraluminally within the renal venous system. The extent of growth can vary from extension just into the renal vein to extension into the inferior vena cava (IVC). The tumour thrombus within the IVC can extend as far as the right atrium. This intracaval extension of tumour thrombus is rather unique, because in the majority, it just extends along the cava without involvement of the wall. It is an intriguing aspect of RCC that in patients with IVC extension, there may be no local invasion or metastatic disease. Vena caval tumour thrombus extension in an RCC is a relatively uncommon event occurring in 4–15% of all patients with RCC.1–5 Within this group, 2–16% will have tumours extending into the right atrium.1,2,5 Although such intravascular growth implies a heightened biological behaviour of the tumour, the presence of tumour thrombus associated with RCC has not been shown to have any bearing on distant spread and survival when treated surgically,1,4,5 but when present and if not treated, these patients have low survival rates.6 Tumour thrombus associated with RCC is no longer considered to have a detrimental impact on survival in patients who are surgical candidates. Radical nephrectomy with vena cavotomy and resection of the caval thrombus provides effective treatment and long-term survival rates as high as 68% at 5 years.4,6

CLASSIFICATION OF THROMBUS EXTENSION INTO THE INFERIOR VENA CAVA Subclassification of RCC with IVC thrombus is helpful in planning treatment. Various classification systems have been proposed; in all of these systems, the superior margin of the tumour in the IVC is the basis for classification. In the TNM classification, the venous invasion is divided into two groups: tumours that grossly extend into renal vein(s) or IVC below the diaphragm (T3b), and tumours that grossly extend into vena cava above diaphragm (T3c).7 Some of the other proposed classification systems are summarized below. Pritchett et al identified three groups, namely subhepatic thrombus (level I), thrombus extending into the intrahepatic or retrohepatic IVC below the diaphragm (level II), and supradiaphragmatic thrombus (level III).8 Wilkinson et al classified IVC thrombus as type 1 – renal vein involvement; type 2 – suprarenal IVC below the diaphragm; and type 3 – supradiaphragmatic.9 Libertino redefined this classification into two major groups, namely infradiaphragmatic and supradiaphragmatic.10 The supradiaphragmatic group was divided into intracardiac and intrapericardial, while all infradiaphragmatic thrombi could be above or below the hepatic veins. Stief et al stratified extension into the inferior vena cava into two types depending on the need for circulatory arrest.11 Type 1 included intracaval protrusions with an

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infrahepatic cranial margin. These patients do not require circulatory arrest. Type 2 is divided into 2a and 2b. Type 2a thrombi have suprahepatic but infradiaphragmatic extension or supradiaphragmatic extension of a free-floating thrombus. Circulatory arrest in these patients is not usually required. Type 2b involves the suprahepatic IVC, hepatic veins, or right atrium and these patients are at high risk for thrombotic embolism or have a large suprahepatic thrombus. Circulatory arrest is usually necessary in these situations. In 1988 Belis et al suggested a simple classification of IVC thrombus into two levels with two surgical approaches based on preoperative magnetic resonance imaging (MRI): 1 – below the major hepatic veins requiring transabdominal excision, and 2 – at or above the major hepatic veins with the need for cardiopulmonary bypass, deep hypothermia, and circulatory arrest.12 The classification most widely used is that proposed by the Mayo Foundation who proposed four groups based on the level of extension of tumour thrombus. The levels of classification were extension to the renal vein (level I), infrahepatic IVC (level II), intrahepatic IVC (level III, this was defined as any thrombus in the retrohepatic and suprahepatic portion of the IVC, not extending into the atrium) and extension to atrium (level IV).2 Some authors have further subdivided the level III thrombus in the IVC depending on the need for dissection and exposure of the major hepatic veins as well as the degree of vascular control of the IVC required to extract this thrombus: IIIa (intrahepatic) – thrombus extending into the retrohepatic inferior vena cava but below the major hepatic veins; IIIb (hepatic) – thrombus extending into the retrohepatic IVC, reaching the ostia of the major hepatic veins and perhaps extending into them, causing the Budd–Chiari syndrome; IIIc (suprahepatic infradiaphragmatic) – thrombus extending into the retrohepatic IVC above the major hepatic veins but below the diaphragm; and IIId (suprahepatic, supradiaphragmatic and infra-atrial) – thrombus extending into the supradiaphragmatic intrapericardial IVC but not into the right heart.13

IMAGING MODALITIES FOR STAGING The diagnosis of IVC invasion and the level of tumour extension in RCC are important determinants when planning the surgical approach; hence, accurate preoperative determination of the superior level of tumour extension is essential.1,8,14–17 If present, certain clinical manifestations such as recurrent pulmonary emboli, lower extremity oedema, renal or hepatic dysfunction, malabsorption, varicocele and engorgement of abdominal wall veins may indicate complete occlusion of the vena cava by tumour thrombus.10 However, these signs are seldom detected because most often the tumour thrombus is non-obstructive or sufficient collaterals have developed.4,10,18,19 For this reason, the diagnosis of IVC extension is mainly based on radiological examinations.5,14,10,20–22 Contrast inferior venacavography (CVC) had been the traditional diagnostic modality for delineating thrombus level, with a reported sensitivity of 100%23–25 (Figure 8.1). However, CVC is an invasive study with the attendant need for intravenous contrast administration. Since the advent of computed tomography (CT) and MRI, there has been a shift away from use of CVC. CT scan may be necessary to assess the local extent of tumour, and presence or absence of metastases.26 However, CT has been shown to be inaccurate in delineating the superior margin of the tumour in IVC.22,26,27 The CT level of RCC thrombus and pathological specimens has been compared using conventional CT, with an accuracy of 95% on axial scanning alone, but few other studies have reached such precision22,27–29 (Figure 8.2). Studies directly comparing conventional CT to MRI in delineating the thrombus level of extension into the IVC in RCC have shown MRI to be completely accurate for the superior extent of tumour thrombus, whereas CT had a mean diagnostic accuracy of only 65%.22,27–30 Of more concern in that CT has been found to completely miss tumour thrombus in some patients.22,27,29 The accuracy of MRI and CT has also been assessed in parallel, but not directly against each other, with MRI having a greater accuracy at diagnosing the superior extent of

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MANAGEMENT OF RENAL TUMOURS EXTENDING TO INFERIOR VENA CAVA

Tumour thrombus extending to IVC

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Large tumour thrombus in IVC

Figure 8.2 Coronal contrast enhanced CT image of a large renal tumour thrombus extending to inferior vena cava (IVC).

Figure 8.1 Contrast inferior venacavograph illustrating a filling defect in inferior vena cava (IVC) due to tumour thrombus extension from a renal tumour.

thrombus compared to CT.25,31 MRI has also been correlated with CT for overall staging accuracy (74–88% MRI vs. 67–100% CT).32,33 MRI has also been compared with CVC (the previous ‘gold standard’). MRI has been shown to be as accurate as CVC in delineating thrombus level.30,31,34–37 MRI can delineate the exact level of thrombus extension as well as detecting the patency of major vessels with no contrast agent necessary since the signal from the blood flowing through vessels is much lower than that from the tumour thrombus. MRI may also sometimes delineate bland thrombus from tumour thrombus as well as providing multiplanar images31,34,38 (Figures 8.3 and 8.4). Furthermore, in the past, only axial images were available with CT, making image reconstruction difficult, while MRI could. Finally, it has the advantages of being non-invasive, delivers no radiation to the patient and gives information in any of the three orthogonal anatomical planes, making it the new ‘gold standard’.34,38,39 MRI technology has further developed over the recent years. Previously, MRI used spin-echo sequences and was unable to overcome flow-related intraluminal signals from thrombus and external compression of the IVC, creating artefacts that made assessing the signal

difficult.36 Also, respiratory and cardiac motion artefacts compromised the delineation of tumour thrombus extent. To overcome these issues, gradient-recalled echo sequences were introduced for MRI of vascular structures, including tumour thrombus in RCC, with success.40 Furthermore, MR image acquisition has become faster, providing more images in a single breath-hold, reducing movement artefact. It is worth noting that all the data comparing MRI and CT scan have used single detector CT. Over the recent years multidetector CT scan has been developed. It allows faster data acquisition than single-detector CT, with no loss of image quality because of short gantry rotation intervals combined with multiple detectors at each level, providing increased coverage.41 This, along with short interscan delays, allows image acquisitions in multiple phases of renal parenchymal enhancement and contrast agent excretion in the collecting system after giving one bolus of intravenous contrast agent.42 Another advantage of CT is improved spatial resolution, providing high quality three-dimensional datasets of the renal vessels, comparable with angiography and conventional urography.43 In a small cohort of 11 patients the accuracy of multidetector CT was compared to MRI in detecting the presence and level of tumour thrombus in the IVC. Both modalities were found to be equally accurate in identifying the presence of tumour thrombus as well as the level of extent from renal vein to right atrium.44 It appears that improvements in CT technology have closed the accuracy gap

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Tumour thrombus extending to right atrium

Figure 8.4 Axial T2-weighted MRI image demonstrating a renal tumour thrombus extending to inferior vena cava and right atrium.

Figure 8.3 Axial T2-weighted MRI image showing a left renal tumour with extension into the renal vein and IVC. (Courtesy of Dr A Sohaib, Royal Marsden Hospital.)

between CT and MRI in evaluating an IVC tumour thrombus. CT is less expensive and more easily interpretable by both radiologists and urologists, and is usually the first test that identifies the renal mass. Being able to obtain more comprehensive information from CT would obviate the need for additional staging MRI. However, the new multidetector CT needs to be compared with higher Tesla MRI machines that provide more precise anatomical detail while deciding the optimal method of evaluating a renal mass with an IVC tumour thrombus, particularly because MRI has the potential to distinguish bland from tumour thrombus. Currently MRI remains the investigation of choice for imaging patients with IVC tumour thrombus extension. The role of transoesophageal echocardiography (TOE) both pre- and intraoperatively, in delineating the presence and extent of IVC involvement in patients with RCC has also been studied (Figures 8.5 and 8.6). Glazer and Novick in a prospective study evaluated the comparative diagnostic accuracy of preoperative TOE, MRI, and CVC in patients with suspected IVC involvement from a primary retroperitoneal malignancy.45 Confirmation

of the presence and level of IVC involvement in these cases was obtained at the time of surgical exploration. The overall diagnostic accuracy of TOE, MRI, and CT scanning was 85%, 90%, and 75%, respectively. They concluded that MRI is the preferred preoperative vena caval imaging modality on the basis of its accuracy, its non-invasive nature, and the lack of requirement for systemic contrast administration. TOE is more invasive and costly than MRI because the transducer probe must be passed endoscopically into the oesophagus and, at most centres, patients require some form of intravenous sedation. If MRI findings are non-diagnostic, then an additional preoperative imaging study, such as CVC or TOE, is recommended. Notwithstanding this view concerning the limited role of preoperative TOE, various studies have advocated intraoperative use of TOE in patients with RCC and IVC thrombus extension to a level that may require cardiopulmonary bypass.45–56 The advantages of intraoperative TOE include verification of the preoperative level of IVC involvement, guidance for placement of a vena caval clamp, confirmation of complete removal of all IVC thrombus, the ability to monitor cardiac function during surgery, and help in preventing embolization of tumour and air. The latter is particularly important as complete occlusion of the venous return to the heart or massive

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Figure 8.5 Intraoperative transoesophageal echocardiograph showing renal tumour thrombus extending to suprahepatic inferior vena cava (IVC).

Figure 8.6 Transoesophageal echocardiograph showing renal tumour thrombus extending to right atrium.

embolization to the pulmonary artery can occur after dislodgement of tumour thrombus. We use TOE routinely in patients with thrombus extension to the hepatic veins or above.

To minimize operative complications, adequate exposure and a virtually bloodless surgical field in the upper abdomen and retroperitoneum is essential. Because the operation requires opening the IVC when the RCC has invaded it, surgeons must be aware of the precise extent of the thrombus and plan their approach accordingly.13 Objectives of operative management include: (i) maintenance of complete resection of tumour and tumour thrombus, (ii) prevention of tumour embolism, (iii) minimizing blood loss, (iv) maintenance of haemodynamic stability by assuring venous return to the heart, and (v) prevention of vital organ ischaemia. Many surgical techniques have been described. The operative approach depends on the cranial extent of the IVC thrombus because in excising the thrombus, it is essential to obtain control of the IVC above the thrombus before manipulating the intracaval tumour mass, to prevent intraoperative embolization of tumour fragments. As previously mentioned the involvement of vena cava by RCC is classified according to the distal extent of the tumour thrombus. For the purposes of the surgical approach it is helpful to consider the level I and level II tumours together as surgical approach can be very similar and there is usually no need for any complex manoeuvres except for control of the IVC above and below the tumour. Extension of the thrombus up to or beyond the hepatic veins is more challenging.

SURGICAL TECHNIQUE In 1688 Blancardus described inferior vena caval involvement by tumour.57 Except for the few sporadic reports of successful excision of tumour thrombus in the IVC (Berg,58 Rehn,59 and Walters and Priestley60), the operation was considered futile since operative mortality was excessive. Furthermore, a system of staging was missing and many clinicians of that time concluded that extension into the IVC was synonymous with incurability. The other limiting factor was the lack of accurate preoperative knowledge of the presence and extent of IVC thrombus. Later, various investigators reported either an optimistic or fatalistic outlook, depending on their own results.61–64 However, initial reports on the surgical therapy of this entity were generally pessimistic except for sporadic accounts of long-term survivors.18,65,66 During the past three decades there have been steady improvements in surgical techniques and perioperative care, which have dramatically improved the ability to operate on these tumours. Tumour thrombus associated with RCC is no longer considered to have a severely detrimental impact on survival.

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Radical nephrectomy with infrahepatic inferior vena cava involvement Various approaches have been described for dealing with RCC with infrahepatic IVC involvement. However, the most commonly used incisions are subcostal incisions with extension to the contralateral side (chevron incision) or the thoracoabdominal incision based on the eight or ninth rib which can be extended down the abdomen as a paramedian incision. Both of these incisions are transperitoneal. Our preferred incision is the thoracoabdominal approach which provides excellent exposure for performing radical nephrectomy and excising the infrahepatic IVC thrombus. Once intraperitoneal, a selfretaining retractor is positioned and the colon is reflected medially to expose the retroperitoneum. The renal artery is ligated and divided, following which the kidney is completely mobilized outside the Gerota’s fascia. This leaves the kidney attached by only the renal vein. It is important not to carry out any unnecessary manipulation of the renal vein and IVC during the initial dissection in order to reduce the risk of thrombus embolization. Once the kidney is mobilized, the IVC is carefully dissected from the surrounding structures above and below the renal vein. It is important to dissect the IVC free above the level of thrombus so that it can be controlled during thrombus extraction. The opposite renal vein is also dissected and exposed. Once the dissection is complete, the infrarenal vena cava, contralateral renal vein, and vena cava above the tumour thrombus are occluded in that order. This can either be achieved with vascular clamps or using a tape passed around the vessel which is our preferred option. The anterior surface of IVC at the junction of renal vein is then incised over the tumour thrombus and the incision is continued posteriorly with scissors. In most cases there is no attachment of tumour thrombus to the IVC, thus a gentle traction (downwards) on the kidney results in extraction of the thrombus. The specimen is then removed en bloc. Following this the tape around the suprarenal vena cava is loosened slightly, this ensures that any remaining small

fragments of thrombus are flushed free from IVC. Once the caval thrombus is completely cleared, the cavotomy is repaired using a 4-0 prolene vasculature suture. Occasionally, there is direct invasion of the wall of the IVC by tumour at the level of the entrance of the renal vein and beyond. In these circumstances, the involved part of the caval wall should be resected. Following this the caval wall can be closed directly, if the lumen is not narrowed beyond 50% (narrowing of caval lumen by up to 50% does not have any adverse effects), however if further narrowing appears likely then cava can be reconstructed using free grafts such as bovine pericardium. If the IVC is completely occluded, it can be removed since there will be sufficient collaterals to maintain venous return to the heart.

Radical nephrectomy with intrahepatic or suprahepatic IVC involvement Whereas temporary occlusion of the infrahepatic IVC can safely be done for infrahepatic extension of tumour thrombus occlusion of the suprahepatic IVC often causes a profound decrease in venous return resulting in hypotension. Additional disadvantages of the latter manoeuvre when removing an IVC thrombus include back bleeding from hepatic and lumbar veins and occasional swelling of the liver from venous congestion, which interferes with the exposure. Extension of the thrombus up to or beyond the hepatic veins poses a special challenge because of limited access and difficulty in vascular control of this portion of the IVC. In this situation the optimal operative management is debatable especially in the 10–25% of cases in which the thrombus extends above the hepatic veins.1,14–16,67–69 Prevention of major bleeding, embolism from the tumour thrombus, and hepatic/renal dysfunction during dissection has required the development of techniques to manage these problems. The incision depends on surgeon preference and the extent of the thrombus. In our institution, the preferred approach for most patients with complex supradiaphragmatic tumour thrombi and for all patients with right atrial

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tumour thrombi is to employ cardiopulmonary bypass (CPB) with or without hypothermic circulatory arrest. CPB with hypothermia may be associated with platelet dysfunction and when combined with systemic use of heparin result in a risk of coagulopathy and bleeding from the retroperitoneum.70–71 However, if used in appropriately selected patients, the complications rate is minimal with good results. Venovenous bypass72 is an alternative, but not without risk, as complications such as lymphocoele, infection, vessel injury at the point of access, and air embolism have been reported.73 Preoperative MRI and TOE as well as coronary angiogram are performed in patients in whom the need for CPB is anticipated. The patients have continuous intraoperative TOE monitoring. Following anaesthesia, a midline sternotomy incision is made, the pericardium is opened and a tape is placed around the intrapericardial inferior and superior vena cava. Following this a subcostal incision is made and if necessary extended to the contralateral side. The colon is reflected medially and the retroperitoneum is exposed. The kidney is completely mobilized outside the Gerota’s fascia with division of renal artery and ureter, so that the kidney is left only attached by the renal vein. The infrarenal IVC and contralateral renal vein are also exposed. It is worth noting that adequate exposure of the IVC and contralateral renal vein is more difficult to achieve for left-sided renal tumours. For the left renal tumours we expose the IVC by reflecting the small bowel mesentery. It is extremely important to achieve complete haemostasis due to the risk of bleeding associated with systemic heparinization which is necessary for cardiopulmonary bypass. Following mobilization of the kidney, a final clinical assessment is made as to whether CPB with or without cardioplegia is necessary. If bypass is thought necessary then the right atrium, infrarenal IVC, and ascending aorta are cannulated. We try not to use cardioplegia if at all possible. However in some cases, especially if a large thrombus is present in the right atrium, then circulatory arrest is necessary in our view. To excise the tumour thrombus an incision is made at the entrance of the renal vein to the

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IVC, the incision is carried posteriorly to circumscribe the ostium. If the thrombus extends to the right atrium, then the atrium is opened. The thrombus is then excised intact with the kidney, however this may not be possible, due to friability of thrombus or its adherence to the vascular wall, in which case piecemeal excision of thrombus from above and below may be necessary (Figures 8.7 and 8.8). Continuous monitoring with TOE is invaluable in making certain that all fragments of thrombus are completely removed. Following excision of the thrombus, the IVC is closed with 4-0 prolene suture and the right atrium is also closed. The patient is then taken off the bypass, protamine is given and haemostatic agents are applied to the IVC. It is often necessary to give the patient a platelet transfusion and fresh frozen plasma at the end of the procedure.

SURGICAL OUTCOME Historically, resection of RCC with involvement of the IVC has been associated with a high incidence of morbidity and mortality. Since Berg’s first report, radical nephrectomy with vena cavotomy has become a safe and effective treatment of RCC with IVC thrombus, with operative mortality rates ranging from 2.7% to 13%.1,14,18 Over the recent years, this has reduced further and our operative death rate is 0.48%. However, radical nephrectomy in patients with locally advanced and metastatic RCC is associated with relatively high rates (2–16%) of intraoperative and postoperative complications.5,69,74–76 From the literature, the commonest causes of death are bleeding, myocardial infarction, and intraoperative thrombus embolism.1,14,18 These complications can be minimized by preand intraoperative measures. Comprehensive preoperative cardiac investigations can reduce the rate of myocardial infarction. Performing sternotomy in patients who are likely to need bypass as the first step of the operation reduces the number of deaths from thrombus emboli by reducing the time needed to put the patient on bypass to deal with the problem. The risk of bleeding is minimized by careful attention to haemostasis.

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Figure 8.8 Radical nephrectomy specimen demonstration renal tumour thrombus extending into the right atrium. The distal part of the thrombus in the atrium is bulbous and is attached to the main tumour via a thin stalk-like tumour thrombus. (See Colour Plate Section).

Figure 8.7 Radical nephrectomy specimen demonstration renal tumour extending into the renal vein and suprahepatic inferior vena cava. The tumour thrombus and kidney are excised en bloc. (See Colour Plate Section).

Postoperatively systemic complications may occur as after any major surgical procedure. These include myocardial infarction, congestive cardiac failure, stroke, deep vein thrombosis, pulmonary embolus, atelactasis, and pneumonia. Postoperative generalized paralytic ileus or a functional obstruction caused by a localized ileus of bowel overlying the operated renal bed, may occur. Secondary haemorrhage may also occur which could lead to re-operation. Renal insufficiency is one of the commonest complications of this procedure. In the majority of patients this is minor and temporary. However, in some patients temporary dialysis may be needed.

ONCOLOGICAL OUTCOMES RCC invades the venous system in 4–9% of newly diagnosed patients.4,77–79 RCCs that form venous thrombus are aggressive tumours. They are associated with poor prognosis and are more likely to be larger, have higher Fuhrman grades, contain sarcomatoid features and be associated with metastases. However, taking these adverse prognostic factors into account, venous extension of tumour thrombus,

per se, does not necessarily reflect a worse prognosis for the patients. Early studies indicated an adverse prognosis in patients with venous extension80–84 however, in these studies multivariate analysis was not performed so the worse prognosis in patients with IVC thrombus extension may have been due to other adverse prognostic factors such as lymph node involvement. More recent studies have not shown that venous extension alone imparts an adverse prognosis compared to those with other adverse prognostic factors.85 The prognostic significance of extent of tumour thrombus extension is the other factor that needs to be considered. Although some series have indicated that the cephalad extent of the tumour thrombus may be a negative prognostic factor,1,8,12,18,86,87 other series have not identified IVC tumour thrombus level as a negative prognostic indicator.5,14,18,80,85,87–94 Furthermore, most studies have found no difference in survival based on involvement of renal vein versus the IVC.14,80,86,95 However, it has been suggested recently that long-term survival may be significantly better in patients with renal vein involvement than IVC involvement.87 In 1972, it was recognized that venous extension by tumour thrombus was a potentially curable lesion with a 55% 5-year survival rate, provided that complete removal could be achieved.61 After this report, various investigators have reported their series for patients undergoing nephrectomy and IVC

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thrombus excision. Reported 5-year survival rate for these patients range from 30% to 72%.1,2,4,6,16,18,67,68,88,94,96,97 However, it is worth noting that in order to obtain long-term survival, it is important that along with nephrectomy the tumour should be excised completely from the IVC, as demonstrated by Sosa and colleagues,18 Nesbitt et al5 and Hatcher et al.4 In their series no patient with incomplete local resection (leaving the tumour thrombus in the IVC) survived long term. One-third of patients with an IVC thrombus will also have one or more metastatic lesions.85,98 The role of surgery in the management of these patients remains controversial. Several reports stress that the presence of metastases is a contraindication to IVC thrombectomy.1,2,4,16,80,94,97 This is because in the reported series of patients with metastatic disease who undergo resection of the primary tumour and an IVC thrombus survival rates have been less than 15% 5 years after surgery.6,14,68,81,82,99,100 On the other hand, a number of authors point out the benefit of surgical resection of the primary tumour in patients with or without IVC thrombus when performed before or after immunotherapy or in conjunction with resection of solitary metastases.74–76,101–104 Recent reports, which are similar to treatment protocol in our unit, recommend aggressive management combining surgery (including excision of metastasis) and immunotherapy in appropriately selected patients.5,14,86,105 Furthermore, extraction of the IVC thrombus and resection of the primary tumour provide palliation of obstructive symptoms from the thrombus and pain due to local extension of the primary tumour. Novick et al.16 implied a palliative role for surgery in some patients with IVC thrombi and metastases who experience severe disability from intractable oedema, cardiac dysfunction, or associated local symptoms such as abdominal pain or haematuria. While the 5-year survival rate was only 11%, patients often reported improvement in local symptoms. Furthermore, although the potential for perioperative morbidity may be slightly higher in patients with concomitant metastatic disease and a thrombus, long-term survival is comparable to that of patients without

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a IVC thrombus.74–76,101 Therefore, we feel that patients with an IVC thrombus should be given the option to have the thrombus removed as long as it is undertaken in the setting of biological therapy protocols or aggressive surgical resection of metastases. Patients should be informed and have understood that long-term survival in these setting may be poor.

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71. Stewart JR, Carey JA, McDougal S et al. Cavoatrial tumour thrombectomy using cardiopulmonary bypass without circulatory arrest. Ann Thorac Surg 1991; 151: 717–22. 72. Obadia JF, Clavel JP, Bonnefoy E et al. Surgery for cavoatrial extension of renal malignant tumours using a venovenous shunt. Br J Urol 1997; 80: 812–14. 73. Browning AJ, Eardley I, Joyce AD et al. Percutaneous veno-venous bypass in surgery for renal cell carcinoma with associated vena caval tumour thrombus. BJU Int 1999; 83: 850–2. 74. Franklin J, Figlin R, Rauch J et al. Cytoreductive nephrectomy in the management of metastatic renal cell carcinoma: the UCLA experience. Semin Urol Oncol 1996; 14: 230–6. 75. Rackley R, Novick A, Klein E et al. The impact of adjuvant nephrectomy on multimodality treatment of metastatic renal cell carcinoma. J Urol 1994; 152: 1399–403. 76. Walther MM, Alexander RB, Weiss GH et al. Cytoreductive surgery prior to interleukin-2-based therapy in patients with metastatic renal cell carcinoma. Urology 1993; 42: 250–8. 77. Pagano F, Dal Bianco M, Artibani W et al. Renal cell carcinoma with extension into the inferior vena cava: problems in diagnosis, staging and treatment. Eur Urol 1992; 22: 200–3. 78. Casanova GA, Zingg EJ. Inferior vena caval tumour extension in renal cell carcinoma. Urol Int 1991; 47(4): 216–18. 79. Hoehn W, Hermanek P. Invasion of veins in renal cell carcinoma – frequency, correlation and prognosis. Eur Urol 1983; 9(5): 276–80. 80. Ljungberg B, Stenling R, Osterdahl B et al. Vein invasion in renal cell carcinoma: impact on metastatic behavior and survival. J Urol 1995; 154(5): 1681–4. 81. McNichols DW, Segura JW, DeWeerd JH. Renal cell carcinoma: long-term survival and late recurrence. J Urol 1981; 126(1): 17–23. 82. Siminovitch JM, Montie JE, Straffon RA. Prognostic indicators in renal adenocarcinoma. J Urol 1983; 130(1): 20–3. 83. Virdi JS, Kelly DG. Prognostic value of renal venous involvement in renal carcinoma. Br J Urol 1992; 69: 481–5. 84. Sene AP, Hunt L, McMahon RF et al. Renal carcinoma in patients undergoing nephrectomy: analysis of survival and prognostic factors. Br J Urol 1992; 70(2): 125–34. 85. Ficarra V, Righetti R, D’Amico A et al. Renal vein and vena cava involvement does not affect prognosis in patients with renal cell carcinoma. Oncology 2001; 61(1): 10–15. 86. Kim HL, Zisman A, Han K et al. Prognostic significance of venous thrombus in renal cell carcinoma. Are renal vein and inferior vena cava involvement different? J Urol 2004; 171(2 Pt 1): 588–91.

87. Moinzadeh A, Libertino JA. Prognostic significance of tumor thrombus level in patients with renal cell carcinoma and venous tumor thrombus extension. Is all T3b the same? J Urol 2004; 171: 598–601. 88. Glazer AA, Novick AC. Long-term followup after surgical treatment for renal cell carcinoma extending into the right atrium. J Urol 1996; 155(2): 448–50. 89. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–61. 90. Gettman MT, Christopher BW, Blute ML et al. Primary surgical treatment for renal cell carcinoma with renal vein, vena cava, or atrial extension: identification of variables, including patient comorbidity, which portend poor outcome. J Urol 2001; 165(Suppl): 158. [abstract 648.] 91. Gettman MT, Blute M L, Spotts B et al. Pathologic staging of renal cell carcinoma: significance of tumor classification with the 1997 TNM staging system. Cancer 2001; 91(2): 354–61. 92. Staehler G, Brkovic D. The role of radical surgery for renal cell carcinoma with extension into the vena cava. J Urol 2000; 163(6): 1671–5. 93. Kuczyk MA, Bokemeyer C, Kohn G et al. Prognostic relevance of intracaval neoplastic extension for patients with renal cell cancer. Br J Urol 1997; 80(1): 18–24. 94. Montie JE, El Ammar R, Pontes JE et al. Renal cell carcinoma with inferior vena cava tumor thrombi. Surg Gynecol Obstet 1991; 173(2): 107–15. 95. Rabbani F, Hakimian P, Reuter VE et al. Renal vein or inferior vena caval extension in patients with renal cortical tumors: impact of tumor histology. J Urol 2004; 171(3): 1057–61. 96. Slaton JW, Balbay MD, Levy DA et al. Nephrectomy and vena caval thrombectomy in patients with metastatic renal cell carcinoma. Urology 1997; 50(5): 673–7. 97. Suggs WD, Smith RB III, Dodson TF et al. Renal cell carcinoma with inferior vena caval involvement. J Vasc Surg 1993; 18(3): 349–55. 98. Lokich JJ, Harrison JH. Renal cell carcinoma: natural history and chemotherapeutic experience. J Urol 1975; 114: 371–4. 99. Kaplan S, Ekici S, Dogan R et al. Surgical management of renal cell carcinoma with inferior vena cava tumor thrombus. Am J Surg 2002; 183(3): 292–9. 100. Kovacs G, Akhtar M, Beckwith BJ et al. The Heidelberg classification of renal cell tumours. J Pathol 1997; 183(2): 131–3. 101. Wolf JS Jr, Aronson FR, Small EJ et al. Nephrectomy for metastatic renal cell carcinoma: a component of systemic treatment regimens. J Surg Oncol 1994; 55(1): 7–13. 102. Levy DA, Slaton JW, Ellerhorst J et al. Feasibility of cytoreductive surgery before systemic biologic therapy in carefully selected patients with metastatic renal cell carcinoma. J Urol 1998; 159(4): 1168–73.

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103. Spencer WF, Linehan WM, Walther MM et al. Immunotherapy with interleukin-2 and alphainterferon in patients with metastatic renal cell carcinoma with in situ primary cancers: a pilot study. J Urol 1992; 147(1): 24–30. 104. Fleischmann JD, Kim B. Interleukin-2 immunotherapy followed by resection of residual renal cell carcinoma. J Urol 1991; 145(5): 938–41.

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105. Naitoh J, Kaplan A, Dorey F et al. Metastatic renal cell carcinoma with concurrent inferior vena caval invasion: long-term survival after combination therapy with radical nephrectomy, vena caval thrombectomy and postoperative immunotherapy. J Urol 1999; 162(1): 46–50.

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Laparoscopic radical nephrectomy and laparoscopic partial nephrectomy for renal cell carcinoma

9

David Hrouda, Mathias Winkler

LAPAROSCOPIC RADICAL NEPHRECTOMY Since its introduction in 1991 by Clayman et al1 laparoscopic radical nephrectomy has rapidly become the standard of care for the treatment of most patients with localized renal tumours.2–4 Classically, radical nephrectomy was peformed openly after the original description by Robson et al in 1963.5 Following Robson’s principles of oncological renal surgery Gerota’s fascia was removed including perinephric fat to achieve adequate margins. Handling of the specimen before ligation of renal artery and vein was avoided in order to minimize the risk of tumour emboli. Much has changed since then and the drive to preserve maximal renal function coupled with the excellent oncological outcome of open and laparoscopic partial nephrectomy in addition to a downward stage shift has cast some doubt on Robson’s principles in contemporary management of renal tumors.6–8 Taking into account some technical improvements in instrumentation and camera systems and increasing surgical experience, laparoscopic radical nephrectomy has been established as the low morbidity, minimally invasive alternative to open radical nephrectomy with comparable oncological efficacy.2,3,9,10

Indications As with most new surgical techniques, indications change with increasing surgical experience, advances in surgical technology and an

expansion of the surgeon’s ‘comfort zone’. Initially, only small renal tumours (T1–2 N0 M0) in patients with normal contralateral kidney were considered for laparoscopic radical nephrectomy,7 supported by 5-year outcome figures (Table 9.1).11 At present, many small peripheral renal tumours < 4 cm diameter are considered for laparoscopic partial nephrectomy provided the patient is prepared to accept slightly higher complication rates and can tolerate a prolonged general anaesthetic. At the other end of the spectrum feasibility and safety data have supported the expansion of indications for laparoscopic radical nephrectomy to include larger tumours (T1–3a).11,16,17 However, adequate laparoscopic experience is mandatory before performing radical nephrectomy for large T2 tumors.16 In a patient population ever increasing in age, and fitness for surgery, anaesthesia becomes a major issue. The use of laparoscopic techniques has been shown to benefit octogenarians and probably helped to raise the age limit for radical treatment of renal tumours.18 The same is also true for morbidly obese patients and patients with previous abdominal surgery.19 The treatment results for metastatic renal cell carcinoma are disappointing but the response rates to immunotherapy are generally better for patients who have undergone cytoreductive nephrectomy. When compared to open cytoreductive nephrectomy, patients undergoing laparoscopic surgery have a shorter length of stay and reduced perioperative blood loss,

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Table 9.1

Reports of survival analysis after laparoscopic versus open radical nephrectomy Cancer-specific survival (%)

Study 12

Chan et al Ono et al9

Portis et al13 Saika et al14 Permpongkosol et al15

Disease-specific survival (%)

No. of patients

Approach

Follow-up (months)

Local recurrence

5-year

10-year

5-year

10-year

67 54 103 46 64 69 195 68 67 54

Lap Open Lap Open Lap Open Lap Open Lap Open

36 44 29 39 54 9 40 65 73 80

0 0 1 0 1 1 0 0 0 0

– – – – 98 92 94 94 97 89

– – – – – – – – 97 86

95 86 95 90 92 91 91 87 94 87

– – – – – – – – 94 87

and most importantly receive systemic therapy sooner after surgery (36 days versus 61days).20 Thus laparoscopic cytoreductive nephrectomy, presumably because of a smaller surgical insult and shorter convalescence, may be particularly advantageous in allowing this group of patients to receive prompt systemic treatment. The presence of level I tumour thrombus in the renal vein was considered a relative contraindication to laparoscopic radical nephrectomy. Albeit an advanced procedure requiring considerable experience laparoscopic radical nephrectomy is now possible for this indication after the Cleveland Clinic group demonstrated the feasibility, and safety with the sound adherence to oncological principles.21 An estimated blood loss of 354 mL, an operative time of 3.3 hours and a hospital stay of 2.3 days was reported for eight patients.21 Only one patient required conversion because of bleeding and a tumour size of 20 cm. All surgical margins were negative for cancer. Concomitant regional lymphadenectomy is unnecessary in patients with clinically negative lymph nodes and does not offer a survival advantage.22 In selected patients with enlarged regional lymph nodes concomitant laparoscopic lymphadenectomy is feasible and might offer improved survival in combination with immunotherapy or may improve symptom control.19,23 The known absolute contraindications for laparoscopic radical nephrectomy are uncontrolled bleeding diathesis, ascites, excessive

tumour size with or without invasion of contiguous structures (T4), level II–IV renal vein tumour thrombus, excessive respiratory or cardiac risk factors precluding pneumoperitoneum and general anaesthetic. Most known relative contraindications are now acceptable indications in experienced hands as discussed earlier.

Advantages of laparoscopic radical nephrectomy The minimally invasive nature of laparoscopic radical nephrectomy continues to appeal to patients since the initial report of reduced analgesic requirement and time to full convalescence compared to open radical nephrectomy by McDougall et al in 1996 and Ono et al in 1997.4,24 These findings have been confirmed in numerous contemporary reports10,12,17,25,27 (Table 9.2). A randomized controlled study of open versus laparoscopic radical nephrectomy does not exist and we have to look elsewhere for level II evidence. Only transplant surgeons have made the effort to compare open versus laparoscopic live donor nephrectomy.29–32 Although the technique of donor nephrectomy is different the surgical approaches are similar. The results may therefore be applicable to radical nephrectomy patients. Not surprisingly, a significantly increased operating time for the laparoscopic approach was consistently reported.30–32 Analgesic requirements were

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LAPAROSCOPIC RADICAL NEPHRECTOMY AND LAPAROSCOPIC PARTIAL NEPHRECTOMY

Table 9.2

119

Laparoscopic radical nephrectomy; review of peri- and postoperative outcome

Study Barret et al25 Dunn et al10 Janetschek et al26 Cicco et al27 Chan et al12 Gill et al17 Shuford et al28 Ono et al23

No. of patients

Conversion (%)

Blood loss (mL)

Operating time (h)

Complications (%)

Hospital stay (days)

72 61 73 50 67 100 33 60

8 – 4 6 1.5 2 0 1.6

– 172 170 150 289 212 240 255

2.9 5.5 2.4 2.4 4.2 2.8 – 5.2

10 5 4 8 15 3 15 8.3

4.4 3.5 7.4 6 3.8 1.6 1.5 –

similar29 or marginally reduced in the laparoscopic group but only during motion.31 Despite reduced oral analgesic prescription at discharge29 hospital stay was generally not statistically different and varied in both groups from 2 to 7 days.29,31 The median return to heavy normal activity and driving a vehicle was twice as long in the open nephrectomy group.30 Perhaps the most striking achievement and the most appealing attribute of the laparoscopic approach are the profound reduction of time to full convalescence and the resulting reduced loss of income.

Technique and surgical approaches The laparoscopic techniques have to follow established principles of renal cancer surgery and as such mimic the surgical technique of open radical nephrectomy. The intact kidney, including perinephric fat, ipsilateral adrenal gland, Gerota’s fascia, lymph nodes and proximal ureter is removed after early ligation of renal artery and vein.5 This radical technique has recently been challenged and the routine excision of the ipsilateral adrenal gland and extended lymphadenectomy are considered unnecessary in routine cases by some authors.11,33 In addition, for smaller renal tumours (< 4 cm diameter) the oncological equivalence of the nephron-sparing approach has cast further doubt on traditional radical nephrectomy according to Robson.5,8,11 Three different surgical approaches are commonly used for laparoscopic radical nephrectomy: hand-assisted, transperitoneal, and retroperitoneal. The hand-assisted approach

Concalescence (weeks) – 3.6 – – – 4.2 – 3.3

was popular with novice laparoscopists and was claimed to be technically easier and shorter than laparoscopic radical nephrectomy.34,35 The technique of hand-assisted laparoscopic nephrectomy is similar to the transperitoneal technique. The non-dominant hand is placed in the abdomen and facilitates mobilization and retraction. The specimen is removed through the incision for the hand port, hence no need for specimen morcellation. Operating time was shown to be shorter in a randomized controlled study of all 3 approaches.36 However, handassisted laparoscopic nephrectomy had the greatest risk for hernia formation. Incision size, hospital stay, and time to normal daily activity were less for the transperitoneal approach. With increasing familiarity of laparoscopic surgery the hand-assisted approach appears to become less attractive, it may though offer an alternative to conversion to open laparotomy. Both transperitoneal and retroperitoneal approaches are frequently used and can be performed efficiently and effectively with no significant difference in randomized controlled studies.37,38 Laparoscopists should have both techniques in their armamentarium. Access for the transperitoneal approach is most safely obtained with the open Hassan technique. We use a three-port technique for left-sided tumours and one additional port for retraction of the liver for right-sided tumours. Additional ports can be placed as required. The initial dissection begins with the medial reflection of the colon. The dissection is taken further to mobilize the duodenum medially and divide liver adhesions and the reno-colic ligament on the right side. On the left side,

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Table 9.3 Comparative studies of open radical nephrectomy versus laparoscopic radical nephrectomy with emphasis on complications Study Dunn et al10 Ono et al23 Abbou et al2 Stifelman et al43 Walther et al44 Shuford et al28

Operative technique

No. of patients

Minor complications (%)

Major complications (%)

Total (%)

Open Lap Open Lap Open Lap Open Lap Open Lap Open Lap

33 61 40 60 29 29 20 74 19 11 41 33

45 34 2.5 8.3 10 0 6 4 0 9 10 12

9 3 5 5 17.2 6.9 10 8 18 9 0 3

54 37 7.5 13 27.2 6.9 16 12 18 18 10 15

early division of reno-colic and spleno-colic ligaments facilitate retraction of the spleen and mobilization of the left colon. The vena cava on the right or the aorta on the left are then identified and the ureter and gonadal vessels are exposed and divided. Following the gonadal vein cranially will lead to the renal hilum and helps to identify the renal vein. The renal artery and renal vein are divided sharply between clips or with an Endo-GIA vascular stapler (Ethicon Endosurgical, Cincinnati, OH, USA). Further dissection proceeds from the upper pole distally. The adrenal gland is spared when appropriate. The specimen is removed with the help of a specimen retrieval bag through an enlarged distal port incision. Other methods of specimen removal are the transvaginal route,39 Pfannenstiel’s incision,40 or specimen morcellation. The major advantage of the transperitoneal approach is surgeon’s familiarity with intraperitoneal anatomical landmarks and plenty of working space. In addition, a cosmetically appealing and low morbidity Pfannenstiel’s incision can be utilized for specimen extraction. The obvious disadvantages are the need to handle intra-abdominal organs with the potential for recognized or unrecognized injury, although this is relatively uncommon. The technique for the retroperitoneal approach is described in detail elsewhere.41,42

The major difference is the use of a balloon dilator to dissect the retroperitoneal space and approach the renal hilum posteriorly. This guarantees early control of the renal artery and vein which can occasionally be difficult with the transperitoneal route. In theory the avoidance of the peritoneal space should reduce the incidence of postoperative ileus and injury to intraperitoneal structures. This is not borne out by the available evidence from randomized controlled studies. Desai et al and others demonstrated no significant difference in terms of blood loss, complications, analgesia requirements and hospital stay.37,38 The retroperitoneal approach was associated with a shorter operating time.

Safety of laparoscopic radical nephrectomy As mentioned earlier there have been no randomized controlled study of laparoscopic versus open radical nephrectomy. Several retrospective comparative studies confirm a low complication rate, reduced transfusion rate, and reduced hospital stay for laparoscopic radical nephrectomy (Tables 9.2 and 9.3). A review of 404 retroperitoneoscopic procedures for various pathologies highlighted a very low rate of vascular injuries (1.7%) and bowel injuries (0.25%).45 Control was achieved without conversion for most cases. Although most

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121

of the studies in Tables 9.2 and 9.3 are a mixture of retroperitoneal, transperitoneal, and hand-assisted approaches and the groups are not always comparable in terms of demographics and preoperative variables, a trend towards lower morbidity for laparoscopy becomes apparent.

include more advanced tumour stages. In our view laparoscopic radical nephrectomy has become the new ‘gold standard’ of treatment for organ-confined renal tumours.

Oncological outcome

The large increase in the use of abdominal imaging throughout the Western world is thought to be responsible for an increase in the incidence of smaller renal tumours. The biological potential of small renal cell carcinomas of less than 4 cm diameter tends to be more favourable than for the larger tumours. Thus, for these tumours, open partial nephrectomy (nephron-sparing surgery) offers oncological control that is comparable to radical (total) nephrectomy with preservation of renal function.48 Open partial nephrectomy, initially reserved for patients with bilateral tumours, tumour in a solitary kidney or patients with chronic renal impairment, has become an accepted standard of care for peripheral tumours of 4 cm diameter where the contralateral kidney is normal.

As both the open and the laparoscopic approach follow the same oncological principles differences in oncological outcome are unlikely. This notion was supported by the findings of numerous studies which consistently showed similar specimen weight and margin status.9,14,15,17,34,42 Although the safety and the immediate oncological adequacy are well documented the most important issue is long-term cancer control. Table 9.1 illustrates 5-year and 10-year outcomes of available retrospective, comparative studies of decent sample size. No significant difference for both local recurrence rates and disease-specific survival can be demonstrated. Five-year cancer-specific survival for laparoscopic and open radical nephrectomy was 97% and 89% for the study with the longest follow-up, respectively.15 These survival figures are maintained at 10 years. The largest study published to date revealed similar figures of 94% and 94% cancerspecific survival for laparoscopic and open radical nephrectomy.14 There is a theoretical risk of tumour recurrence at the port sites. This has been observed in very few cases and is generally related to high-grade disease and the use of specimen morcellation.46 Rassweiler et al estimated risk of port-site metastasis at 0.18% in a series of 1098 laparoscopic procedures for urological malignancies.47 However, it is transitional cell carcinoma rather than renal cell carcinoma that accounts for the majority of case reports of port site recurrence. Laparoscopic radical nephrectomy has been performed on more than 6000 patients over the past 10 years.15 It is evident from long-term follow-up that this procedure is oncologically equivalent to open radical nephrectomy. Indications have expanded to

LAPAROSCOPIC PARTIAL NEPHRECTOMY

Indications In many centres the patient with a renal mass < 4 cm is offered either a laparoscopic radical nephrectomy or open partial nephrectomy. There is some evidence that the introduction of the less invasive laparoscopic approach to radical nephrectomy has resulted in reversion to a ‘nephron-wasting’ approach to the smaller renal tumours (Bhalla et al AUA 2005). The uptake of laparoscopic partial nephrectomy has lagged considerably behind laparoscopic radical nephrectomy, mainly because it is a technically difficult procedure requiring laparoscopic suturing to close the pelvicalyceal system and secure haemostasis. However, although as yet laparoscopic partial nephrectomy cannot be considered the ‘gold standard’, it is certainly an accepted standard of care. In many centres, laparoscopic partial nephrectomy is reserved for small exophytic peripheral tumours away from the hilum.

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Table 9.4 Contraindications for laparoscopic partial nephrectomy Absolute Renal vein thrombus Multiple tumours Bleeding diathesis Lymph node metastases Relative Previous renal surgery Central tumours Endophytic tumours Tumours invading the collecting system Tumours invading the renal sinus Tumour in a solitary kidney Chronic renal failure

Patients with complex tumours are offered the open approach (Table 9.4). However, laparoscopic partial nephrectomy is an evolving technique and recent data suggest that in skilled hands the indications may be expanded. It is technically feasible to perform partial nephrectomy laparoscopically in cases of solitary kidney.49 In 22 cases of tumour in a solitary kidney, two patients were converted to open, surgical margins were negative in all patients and one patient required temporary haemodialysis. The mean reduction in glomerular filtration rate (27%) reflected the median amount of kidney parenchyma excised (23%). It has been demonstrated that laparoscopic partial nephrectomy is feasible for hilar tumours. In 25 patients, using en bloc hilar clamping with cold excision and suture reconstruction, the mean warm ischaemia time was 36.4 minutes with negative margins in all patients and no kidney lost for technical reasons.50 Laparoscopic partial nephrectomy may also be feasible for selective patients with synchronous ipsilateral renal tumours. The Cleveland Clinic approach includes en bloc partial nephrectomy encompassing both tumours, individual excisions of renal tumours during the same procedure and a combination of partial nephrectomy with the other tumour treated by cryoablation. All cases (n = 13) were completed successfully without need for open conversion.51

Technique Laparoscopic partial nephrectomy may be performed by either transperitoneal or retroperitoneal routes. The transperitoneal access offers a larger working space and superior instrument angles and is the better approach for anterior tumours and large or deeply infiltrating posterior tumours. The retroperitoneal approach, although more technically demanding, provides better access for posterior and particularly posteromedial tumours. In the Cleveland Clinic practice, transperitoneal laparoscopic partial nephrectomy was associated with larger tumours, more calyceal repairs and longer ischaemic time and this is reflected in the slightly longer length of stay (2.9 days vs. 2.2 days for retroperitoneal).52 The technique of laparoscopic partial nephrectomy requires exposure of the hilar vessels to allow cross-clamping. The kidney is mobilized and the perinephric fat incised around the tumour to expose healthy renal parenchyma around the tumour. Some surgeons excise small tumours without crossclamping of the renal vessels. This is certainly feasible for smaller peripheral tumours but evidence suggests that cross-clamping is associated with reduced peroperative blood loss (p < 0.05) and lower positive surgical margins rate (3.4% vs. 12.5%).53 Thus, a bloodless field appears preferable. The tumour depth and position with respect to collecting system may be assessed using a laparoscopic ultrasound probe. This is highly desirable for excising tumours which are endophytic or complex but is regarded as non-essential by most surgeons when excising the majority of exophytic tumours. Tumour excision is performed either with cold scissors or a harmonic scalpel and placed in a laparoscopic bag. Cold excision has the advantage of allowing a clear view of the macroscopic appearance of the margins whereas the charring associated with instruments that use heat to cut may obscure an otherwise obvious positive margin. It has been proved that even a small margin of normal parenchyma provides sufficient clearance.54 Pelvicalyceal entry can be easily identified by injection of

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methylene blue via a previously cystoscopically placed ureteric catheter. The defect is sutured laparoscopically. Haemostasis is achieved in a number of ways. The technique described by Gill involves figure of eight sutures at the site of visible vessels using 2-0 vicryl. Haemostatic tissue bioadhesives comprising gelatin matrix granula component and a thrombin component (e.g. Floseal, Baxter) are applied and renal parenchymal sutures placed over a Surgicell bolster. The hilar cross-clamp may then be removed. A drain is left in situ in case of bleeding or urine leak.55 Others have reported using tissue bioadhesives alone without suturing to achieve haemostasis.56 Mean tumour diameter was 2.8 m and none of 25 patients required blood transfusion.

Warm ischaemia versus cold ischaemia Currently, the majority of laparoscopic partial nephrectomies are performed under warm ischaemia. However, although it is currently believed that warm ischaemic times of greater than 30 minutes are more likely to result in permanent renal injury,57 the true impact of different warm ischaemic times on the human kidney is unknown. The Cleveland Clinic group assessed renal function before and after laparoscopic partial nephrectomy using serum creatinine in patients with a solitary kidney and renal scintigraphy in patients with two functioning kidneys. In the latter group, with a warm ischaemic time of 30 minutes the function in the operated kidney was reduced by a mean of 29%. In the solitary kidney group the mean creatinine at baseline and at 5 months follow up was 1.2 mg/dL and 1.8 mg/dL, respectively. Advancing age and pre-existing azotaemia increased the risk of renal dysfunction after laparoscopic partial nephrectomy.58 A study from Johns Hopkins suggested that postoperative creatinine levels were not adversely affected by warm ischaemic times of up to 55 minutes.59 The disadvantage of operating under warm ischaemia is that a complex operation is made time-sensitive with very little margin for error.

123

One approach to this problem is to continue to simplify the operation, in particular reduce or eliminate knot tying by the use of tissue bioadhesives and Lapra-Ty clips.60 In order to allow longer operating time and therefore a greater margin for error, a variety of techniques for cold ischaemia have been assessed. Janetschek and colleagues achieved cold ischaemia by continuous perfusion of Ringer’s lactate 4C through the renal artery which was clamped. Fifteen cases were successfully completed with a mean cold ischaemia time of 40 minutes and intraoperative blood loss of 160 mL. There were no significant complications.61 The disadvantage of this technique is that it requires an additional procedure with the presence of a radiologist and there is extra potential for morbidity due to injury of the femoral artery or a renal artery intimal tear. Gill described laparoscopic slush ice hypothermia in 12 patients, achieving nadir renal parenchymal temperatures of 5–19°C.62 The disadvantage is that the technique is cumbersome and time-consuming. Landman and colleagues described renal hypothermia by retrograde endoscopic cold saline perfusion achieving renal cortex temperatures of 24°C.63 This technique has the advantage of simplicity. However, once the collecting system is entered the cold perfusate leaks out and this may compromise kidney cooling. Which technique is best and when it is necessary remains to be established.

Complications There are few large series of laparoscopic partial nephrectomy. Thus, the current reports reflect an operation in evolution (Table 9.5). Haemorrhage and urine leak are the most important significant complications. The Cleveland Clinic group reported a 9.5% incidence of haemorrhage in their initial 200 patients but this has dropped to 3% in subsequent cases following the introduction of Floseal. Intraoperative bleeding from the renal parenchyma remains the greatest technical challenge. Laparoscopic suturing of the vessels still appears to be the best method of secure haemostasis. The technical skill

Ramani et al66 Rassweiler et al67 Link et al64 Wille et al65

Study

2.9 2.3 2.6 3

53

217

44

Mean tumour size (cm)

200

Number

Variable

In 75%

Variable

Yes

Hilar control

Floseal

Suture/bolsters

Various

Suture/bolsters

Haemostasis

N/A

385

725

247

Mean blood loss (mL)

210

186

191

200

Mean operating time (min)

4.5

1.4

10

4.5

Urine leaks (%)

16

3.5

0

1

Positive margins (%)

2.3

1.8

10

9.5

Haemorrhage (%)

0

0.8

8

1

Conversion to open (%)

20.5

12

6.5

Reintervention (%)

15

24

36

9.7

Follow-up (months)

6:09 PM

Laparoscopic partial nephrectomy series

124

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Table 9.5



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required for laparoscopic suturing and the time-sensitive nature of the operation under warm ischaemia probably explain the greater risk of perioperative haemorrhage in comparison with the open technique. Nevertheless, the complication rates are acceptable compared to series of open partial nephrectomy. Urinary leaks occurred in 1.4–10% of patients in the literature compared to an overall incidence of 6% in open partial nephrectomy.

7.

8.

9.

Oncologic outcomes The incidence of positive margins gives some indication of oncological efficacy. Positive margin rates range between 0% and 16%, although the latter is in a relatively small cohort of patients and may reflect the learning curve (see Table 9.2). In a comparative analysis of open and laparoscopic partial nephrectomy at the Cleveland Clinic, 3 of 100 patients in the laparoscopic group had positive surgical margins compared to none in the open group.68 At a mean of 3 years, 46 of 48 patients had no evidence of disease, the recurrences being in a patient with von Hippel–Lindau disease in one patient and distant to the original tumour site in another.69 Laparoscopic partial nephrectomy is a procedure in its infancy therefore the efficacy of long term cancer control is yet to be established.

10.

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56. Richter F, Schnorr D, Deger S et al. Improvement of hemostasis in open and laparoscopically performed partial nephrectomy using a gelatin matrix-thrombin tissue sealant (FloSeal). Urology 2003; 61(1): 73–7. 57. Novick AC. Renal hypothermia: in vivo and ex vivo. Urol Clin North Am 1983; 10(4): 637–44. 58. Desai MM, Gill IS, Ramani AP et al. The impact of warm ischaemia on renal function after laparoscopic partial nephrectomy. BJU Int 2005; 95(3): 377–83. 59. Bhayani SB, Rha KH, Pinto PA et al. Laparoscopic partial nephrectomy: effect of warm ischemia on serum creatinine. J Urol 2004; 172(4 Pt 1): 1264–6. 60. Orvieto MA, Chien GW, Laven B et al. Eliminating knot tying during warm ischemia time for laparoscopic partial nephrectomy. J Urol 2004; 172(6 Pt 1): 2292–5. 61. Janetschek G, Abdelmaksoud A, Bagheri F et al. Laparoscopic partial nephrectomy in cold ischemia: renal artery perfusion. J Urol 2004; 171(1): 68–71. 62. Gill IS, Abreu SC, Desai MM et al. Laparoscopic ice slush renal hypothermia for partial nephrectomy: the initial experience. J Urol 2003; 170(1): 52–6. 63. Landman J, Venkatesh R, Lee D et al. Renal hypothermia achieved by retrograde endoscopic

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cold saline perfusion: technique and initial clinical application. Urology 2003; 61(5): 1023–5. Gill IS, Matin SF, Desai MM et al. Comparative analysis of laparoscopic versus open partial nephrectomy for renal tumors in 200 patients. J Urol 2003; 170(1): 64–8. Link RE, Bhayani SB, Allaf ME et al. Exploring the learning curve, pathological outcomes and perioperative morbidity of laparoscopic partial nephrectomy performed for renal mass. J Urol 2005; 173(5): 1690–4. Wille AH, Tullmann M, Roigas J, Loening SA, Deger S. Laparoscopic partial nephrectomy in renal cell cancer – results and reproducibility by different surgeons in a high volume laparoscopic center. Eur Urol 2006; 49(2): 337–42; discussion 342–3. Ramani AP, Desai MM, Steinberg AP et al. Complications of laparoscopic partial nephrectomy in 200 cases. J Urol 2005; 173(1): 42–7. Rassweiler JJ, Abbou C, Janetschek G, Jeschke K. Laparoscopic partial nephrectomy. The European experience. Urol Clin North Am 2000; 27(4): 721–36. Allaf ME, Bhayani SB, Rogers C et al. Laparoscopic partial nephrectomy: evaluation of long-term oncological outcome. J Urol 2004; 172(3): 871–3.

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Surgical treatment of renal cell carcinoma metastatic to the thorax

10

John E Pilling, Peter Goldstraw

INTRODUCTION

Site of metastases

Renal cell carcinoma is characterized by its late presentation, often with metastatic disease, and resistance to radiotherapy and chemotherapy. The thorax is the commonest, and often sole, site of metastatic spread. Surgery has been utilized to cure and palliate metastatic disease to the thorax with increasing frequency in the past 30 years.

Pulmonary

RELAPSE PATTERN OF RENAL CELL CARCINOMA Frequency of metastases At least 25% of patients diagnosed with renal cell carcinoma have metastases at presentation.1 Patients who undergo radical nephrectomy for presumably localized disease have a one-third chance of subsequent relapse. Less than 5% of these are local.2,3

Timing of Metastases Among those patients who undergo potentially curative nephrectomy the median time to relapse is 18 months with 85% of relapses occurring within 3 years of surgery for the primary tumour.2,3 Of those patients who will get metastatic disease over half have evidence of metastases at presentation,4 71% will have developed metastases within 1 year,5 and 90% within 2 years of the initial diagnosis.4

Two-fifths of patients with metastatic disease have disease located in a single organ, threequarters of which are confined to the lung.4 In addition the lungs are affected in threequarters of those with metastases to multiple organs. More than half of those patients with pulmonary metastases have additional deposits in the mediastinal lymph nodes.6 In most patients pulmonary metastases are asymptomatic being detected by radiological screening (Figure 10.1). Symptoms, such as cough, haemoptysis, recurrent chest infections, dyspnoea, and chest pain lead to the discovery of lung deposits in 11–28% of patients with pulmonary metastases from renal cell carcinoma.7,8 In several series in which pulmonary metastasectomy was performed for renal cell carcinoma, the metastases were single in 38–50% of patients; two to four lesions were found in 22–39%, and in 10.5–37% of patients five or more metastases were found at surgery.7,9,10 It is important to remember alternative diagnoses, especially when solitary, in smokers and when there is no previous radiological result from which one may infer the growth rate of the lesion. Quint et al11 described a group of 31 patients with solitary pulmonary nodules (SPN) found on computed tomography (CT) scans of patients with known extrapulmonary carcinomas. Sixteen

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Pleural disease Recurrent pleural effusions occur in one-half of patients with metastatic malignancy. They are usually symptomatic, erode the patient’s quality of life and interfere with treatment.13 Malignant pleural effusion is usually associated with lung metastases in renal cell carcinoma and the pleura is rarely the only site of relapse.14,15

Natural history of metastatic renal cell carcinoma Figure 10.1 Chest radiograph showing bilateral cannonball deposits.

(52%) were proven to be metastases, 13 (42%) were primary lung cancers, and 2 (6%) were benign lesions. Smokers were 3.5 times more likely to have a primary lung cancer than nonsmokers. No patient under 45 years developed a primary lung cancer.

Nodal spread In a study of 554 patients in whom renal cell carcinoma was diagnosed for the first time at autopsy, 119 had metastatic spread of which nodal metastases were present in 80 and absent in 39. In the 80 cases of nodal disease the mediastinal nodes were involved in 52 cases (65%). Forty-nine of the 52 patients with mediastinal nodal disease also had pulmonary metastases.6 Data on the frequency of unsuspected nodal involvement in patients who undergo pulmonary metastasectomy for renal cell carcinoma are limited as nodal dissection is usually performed only when abnormal nodes are detected on preoperative imaging or at thoracotomy. This occurred in 12.5%7 to 35%9 of patients in two studies. There are two series in which pulmonary metastasectomy for metastatic renal cell carcinoma was routinely accompanied by hilar and mediastinal nodal dissection. Pfannschmidt et al12 reported nodal involvement in 29% of 191 patients and Fourquier et al8 showed hilar nodal involvement in 12% and mediastinal node deposits in 10% of 50 patients in their series.

Survival of patients with metastatic renal cell carcinoma is 40–48% at 1 year, 24–27% at 2 years, and 9–11% at 5 years with a median survival of 11 months.4,5 Isolated pulmonary relapse, in a report of 52 patients, had a median survival of 22 months.4 In most patients the tumour grows relentlessly until the death of the host, although there is a group where the tumour enters a period of spontaneous stabilization or slow growth.

Spontaneous regression More than 60 cases have been reported of spontaneous regression of metastatic renal cell carcinoma. Although most commonly reported in pulmonary metastatic disease, spontaneous regression has also been reported to occur in metastases in bone, brain, pulmonary hilar lymph nodes and liver.16 Regression has often, but not exclusively, been associated with ablation of the primary tumour, usually by surgical excision but occasionally by radiotherapy or embolization. The incidence of regression is hard to determine as the denominator is not given. It is a rare event but has been reported to occur in < 1–7% in several series.5,17,18 The duration of regression is variable and unpredictable.

PULMONARY METASTASECTOMY Historical note The first operation at which a pulmonary metastasis was resected was in 1882 by Weinlechner following its incidental intraoperative discovery

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SURGICAL TREATMENT OF RENAL CELL CARCINOMA METASTATIC TO THE THORAX

during resection of a chest wall sarcoma.19 The first reported elective resection of a pulmonary metastasis with prolonged survival was for renal adenocarcinoma in 1939.20 Following these early reports the application of pulmonary metastasectomy was limited. With the evolution of safer thoracic surgical and anaesthetic techniques and an improved understanding of the oncological value of metastasectomy the operation became routine in a limited number of surgical oncology departments. The publication of the International Registry of Lung Metastases21 broadened the use of this surgical approach to metastatic disease. Currently, in specific circumstances, pulmonary metastasectomy is the standard of care for patients with metastatic disease to the lungs and is used in the treatment of synchronous and metachronous lung deposits.

Principles of metastasectomy The aim of pulmonary metastasectomy is to cure the patient’s disease or, where cure is subsequently shown not to be feasible, to have extended survival. Pulmonary metastases are usually asymptomatic and their resection on grounds of palliation is rarely justified. The principles of selection of patients for surgery have evolved in an effort to avoid futile surgery. • The primary tumour must have been controlled, usually by complete resection, or its control must be assured by the appropriate specialist. Occasionally curative treatment of the primary tumour might require extensive and mutilating surgery which would only be considered to be justified if prior resection of the pulmonary metastases could be achieved. In such unusual circumstances multidisciplinary discussions are necessary to decide the appropriate sequence of operations. • Absence or resectability of any extrapulmonary deposits. Complete restaging investigations, appropriate to the relapse patterns of the primary tumour, must be performed prior to consideration of pulmonary metastasectomy. A period of

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observation of the patient’s disease may be appropriate to avoid futile surgery as disease progression may be found to be rapid or widespread. Such a delay would be unwise if the volume or distribution of disease meant a delay would lead to unresectability or necessitate a more extensive resection. • The patient must be fit to undergo the necessary pulmonary resection. This includes an assessment of comorbid conditions, especially respiratory and cardiovascular status, past medical history and medication and, critically, the patient’s attitude to aggressive management. • Complete resection of the lung metastases, by one or more operations, should be deemed feasible on the imaging evidence. Completeness of resection is the single most important factor which determines benefit from pulmonary metastasectomy. Occasionally if there is doubt as to resectability on imaging studies the patient may wish an exploratory operation to assess resectability rather than being denied possibly useful surgery. The radiological assessment will also give some indication of the extent of pulmonary resection necessary to achieve complete resection of all of the lung deposits. This will inform the assessment of cardiopulmonary reserve required if the patient is to be offered surgery.

Assessment for metastasectomy Computed tomography With experience a CT study of the chest will allow a treatment strategy to be developed. This will be based on the number, position, size, and expected consistency of the lung deposits (Figure 10.2). The best operative approach, the number of operations, their sequence and the probable extent of lung resection will be discussed with the patient. Any evidence of nodal disease in the hilum of the lung will raise the question as to whether formal, parenchymal resection may prove necessary at surgery. This may involve segmentectomy or lobectomy but pneumonectomy is

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a

b

Figure 10.2 CT scans of the thorax showing (A) two small peripheral left-sided lesions (arrows). (B) A more central lesion in the lingular with small satellite nodule (arrow) above it. The surgeon might anticipate an anatomical resection to be required making a lateral thoracotomy the most suitable approach. A staged approach would then be necessary for bilateral disease.

rarely justified in first time metastasectomy. CT has generally been reported to underestimate the number of pulmonary nodules found at thoracotomy by around 30%.22 In a series of 72 patients with pulmonary metastases CT was inaccurate in 30, predicting too many nodules in 12 and too few in 18.23 In a series of 14 patients believed to have a solitary pulmonary metastasis on CT, 7 were found to have additional malignant nodules and 3 additional benign lesions.24 Thus while CT is used to guide preoperative decisions a thorough re-evaluation is mandatory at surgery. Spiral CT scanning is undoubtedly more accurate at determining the number of metastases but initial reports suggest lung palpation is still required to identify all disease.25 In a series of 34 patients undergoing 41 pulmonary metastasectomy operations, and studied preoperatively by spiral CT, Parsons et al found 88 malignant nodules of which only 69 had been identified preoperatively (78% sensitivity).25 Spiral CT predicted the correct number of nodules in only 17 of the 41 resections (41%). It is interesting to note that all the nodules missed by spiral CT were less than 10 mm in diameter. Seven nodules predicted by CT could not be identified on bimanual palpation of the lung. It is not known whether these were false positive cases or, as seems

more likely, the sensitivity of CT now exceeds the sensitivity of the surgeon’s fingers! 18

F deoxyglucose position emission tomography

Position emission tomography (PET) is still a relatively new technology which is currently being investigated. It may have a role in characterizing lung lesions and staging patients before they are subject to surgical intervention. False-positive PET scans of pulmonary nodules have been reported with tuberculosis, pneumonia, aspergillosis, histoplasmosis, cryptococcus, lung abscess, and neurofibroma.26–28 Falsenegative PET results have been reported in malignant lesions less than 10 mm in diameter and in well differentiated tumours with a low mitotic rate and slow growth.29,30 When, analysing the results of PET in patients with an extrathoracic malignancy and an SPN, PET was found to have an accuracy of 91% in differentiating malignant from benign nodules.31 In their series of 86 patients with suspected pulmonary metastases deemed suitable for metastasectomy on the basis of CT, Pastorino et al32 excluded 19 patients from surgery due to PET findings of extrapulmonary metastasis (11), recurrence at the primary site (2), mediastinal adenopathy (2) or benign lung lesions (4). Overall PET sensitivity for detection of lung

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Figure 10.3 (A) An axial cut from a CT of the thorax (lung windows) showing an ovoid left lower lobe lesion. (B) FDG-PET scan of the same patient showing an FDGavid lesion in a similar position in the left lower lobe. (C) Fused images of the CT and FDG-PET showing the left lower lobe lesion seen on CT is the FDG-avid mass seen on FDG-PET (See Colour Plate Section).

metastases was 87% and for detection of distant metastases was 85%. PET was superior to CT in assessing mediastinal nodal status (sensitivity PET 100% vs. CT 71%). Chang et al33 studied 15 patients with renal cell carcinoma and an indeterminate SPN by PET scan, using a standard uptake value of > 2.5 to define malignancy. All lesions were then resected. In 9 cases the PET was true positive, in 4 true negative, in 1 false positive (a tuberculoma), and in 1 false negative. Overall the PET sensitivity was 90% and specificity was 80%. Majhail et al34 used PET in patients with renal cell carcinoma and suspected distant spread on CT. Thirty-six sites of possible metastatic disease were identified and all were biopsied or resected. They showed a sensitivity

of 63.6% and a specificity of 100%, the mean diameter of false-negative lesions was 10 mm. Where PET is used following CT it alters the proposed surgical management in half of the patients.35 The role of PET will undoubtedly expand as it becomes more widely available and anatomical detail improves with correlation of PET and CT images (Figure 10.3).

Fitness for surgery The initial assessment of patients for thoracic surgery comprises a careful medical history and clinical examination. All comorbid conditions should be evaluated for their impact on the risks of surgery. The patient’s condition should be optimized prior to a final assessment. It is

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patient is complete they should have the opportunity to discuss the risks and benefits of surgical treatment with a thoracic surgeon.

Surgery Principles

Figure 10.4 A left-sided double lumen tube. The blue cuff is positioned in the left main bronchus and the left lung can be ventilated via the terminal orifice (arrowhead). The red cuff is inflated in the trachea and the right lung can be ventilated via the tracheal lumen (arrow).

important that an assessment of the patient’s exercise tolerance is made. All patients should undergo spirometry (forced expiratory volume in 1 second [FEV1] and forced vital capacity [FVC]) and have an electrocardiogram. While advanced age does not preclude thoracotomy and pulmonary resection older patients are more likely to require intensive perioperative support and have a higher rate of complications. Spirometry provides a limited assessment of lung function. An FEV1 over 1.5 L in a patient without evidence of interstitial lung disease or disproportionately severe dyspnoea does not require further tests prior to surgery.36 The British Thoracic Society guidelines refer to assessment of fitness for lung cancer surgery, in which lobectomy is the minimum resection, their use in this setting is reasonable but more liberal values may be appropriate in patients undergoing more limited resection. If patients are borderline on simple spirometry more detailed pulmonary function tests are necessary, including exercise testing and measurement of gas exchange using transfer factor (TLCO). Once the evaluation of the

All patients undergoing major thoracic surgery for malignant disease are given prophylactic antibiotics and prophylaxis against thromboembolic disease, the latter commencing the evening prior to surgery. Thoracic surgery is performed under general anaesthetic. Control of the lung must be gained to allow the lung to be collapsed and inflated as necessary for palpation and resection of nodules. This is most commonly achieved by insertion of a double lumen endotracheal tube (Figure 10.4). Postoperative pain control is of paramount importance in reducing postoperative complications and should be discussed with the patient prior to surgery. Patients must be able to take deep breaths, mobilize, and expectorate their secretions. Strategies for pain relief include patient-controlled opioid analgesia, insertion of a paravertebral cathether, intercostal nerve blocks, and insertion of an epidural catheter. Prior to performing metastasectomy the internal anatomy of the airways should be examined by bronchoscopy. This will aid placement of the endobronchial tube, facilitate formal lung resection and previously unrecognized endobronchial malignancy may also be recognized.8

Incisions A variety of surgical approaches are used in the resection of pulmonary metastases. • Posterolateral thoracotomy. A lateral or posterolateral incision describing a curve around the tip of the scapula. The latissimus dorsi and serratus anterior are either divided or mobilized and the chest usually entered via the fifth intercostal space (Figure 10.5). This incision allows optimal access to all parts of the lung for palpation and excision of metastases and is especially valuable if an

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Figure 10.5 The lung seen via a lateral thoracotomy. A peripheral metastasis has been marked with a suture prior to excision with the diathermy. (See Colour Plate Section).

Figure 10.6 The set-up in the operating theatre for video-assisted thoracoscopic surgery. The patient is in the left lateral position, the thoracoscope has been inserted, and the image viewed on the two monitors.

anatomical pulmonary resection is thought to be probable. It can be extended into a thoracolaparotomy if it is necessary to enter the abdomen. It allows access to only one hemithorax but bilateral disease may be dealt with by sequential thoracotomies, usually performed 4–8 weeks apart. • Median sternotomy. A vertical incision is made from the sternal notch to xiphisternum. The sternum is divided using a bone saw and both pleural cavities can be explored. Sternotomy is a less painful incision than a posterolateral thoracotomy and has the advantage of allowing bilateral deposits, if otherwise suitable (see below) to be dealt with at a single operation. Respiratory function recovers more quickly than with thoracotomy.37 A sternotomy gives poor access when resecting metastases that are placed medially and posteriorly in the lower lobes, especially the left.38 Repeat sternotomy for recurrent disease is feasible and safe if the pericardium has not been opened at the first operation.38 • Video-assisted thoracoscopic surgery (VATS). Advances in endoscopic technology and techniques have allowed the use of VATS for pulmonary metastasectomy. VATS is attractive to surgeons as it allows minimally invasive techniques to be used, avoiding major incisions (Figure 10.6). In series with historical controls

postoperative drainage time and length of stay were reduced by VATS.39 Patients with bilateral disease can undergo bilateral procedures either under the same anaesthetic, or staged within a week.40 A major disadvantage of VATS is the inability to palpate the lung bimanually, standard VATS ports only allow for finger or solid probe palpation. VATS is usually successful in locating peripheral lesions predicted on preoperative CT scans.41 There are a number of methods to assist in locating nodules seen on preoperative imaging including CT-guided needle insertion and methylene blue marking.39 One trial of VATS for metastasectomy was abandoned. The protocol required that following VATS excision conversion to thoracotomy was undertaken to assess the accuracy with which the number of lesions was identified at VATS. On conversion from VATS to thoracotomy 78% of patients (14 of 18) had additional nodules that had not been identified, and were not therefore resected by VATS. VATS failed to resect nodules that were shown subsequently to be malignant in over half of the patients.24 There have also been a number of reports of local recurrence following VATS metastasectomy, and recurrence at the port site has been experienced.42–44

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Because of these limitations VATS has not been taken up widely for metastasectomy. The International Registry recorded only 2% of procedures were performed by VATS.21 While the place of VATS for the diagnostic excision of an SPN is no longer disputed there is debate as to its correct deployment in therapeutic metastasectomy.45

Choice of approach As a general rule a lateral thoracotomy is the approach of choice for unilateral deposits and a median sternotomy is the standard approach for bilateral deposits. Exceptions to this rule include bilateral deposits in the following circumstances, in which staged, bilateral thoracotomies may be preferable: • A large number of lesions (> 10 each side) which may require multiple local excisions, leaving the lung contused and temporarily malfunctioning. • Where large lesions are posteriorly placed in the lower lobes. Retraction of the lobe may hamper cardiac output, especially when mobilizing the left lung. Lateral thoracotomy is the standard approach in such cases but others have recommended a transverse bilateral thoracotomy (clam shell incision) or a combined sternotomy and VATS approach.46 • Where lesions are centrally placed and adjacent to hilar structures. In such circumstances formal resection, segmentectomy or lobectomy, are more safely performed via a lateral thoracotomy. • When the consistency of the metastases is close to that of lung parenchyma. In these cases, not usually of renal origin, the additional manipulation required at sternotomy may disseminate the deposit into surrounding lung parenchyma. Some surgeons advocate median sternotomy even in patients assessed to have unilateral deposits since in nearly half of all patients with unilateral disease on preoperative imaging bilateral deposits were found on

lung palpation.38 Roth et al47 confirmed that 45% of the patients undergoing pulmonary metastasectomy via median sternotomy for sarcoma had unexpected bilateral disease. However, the resection of these occult contralateral metastases did not influence survival.

Intrathoracic procedures Once the thoracic cavity has been entered the lung must be carefully and completely explored in a search for disease. Correlation with preoperative imaging is important and the surgeon should take care to identify all lesions predicted on the CT scan. It is not unusual for additional lesions to be found. These may or may not be significant but all lesions should be excised for pathological assessment. As each lesion is palpated it is marked with a suture prior to commencing any resections. Peripheral lesions can be resected by local excision using diathermy to remove the lesion with a small cuff of normal tissue and the defect repaired with sutures. There are a number of commercially available staple guns which safely and quickly allow wedge resection to be performed. We rarely use them as when stapling in a straight line to remove a spherical metastasis, the staple line must at one point be too close to the lesion and at another too far away, risking incomplete resection or resecting excess parenchyma. Staples left in the lung cause distortion of the parenchyma and the ‘shatter’ induced creates difficulty in interpreting subsequent CT scans.

Operative procedures Pulmonary In the majority of cases all of the pulmonary metastases can be removed with sublobar excisions. In the International Registry of Lung Metastases in 67% of cases all of the metastases could be resected by local or wedge resection and in another 9% of cases segmentectomy proved adequate.21 In those series in which metastasectomy was performed for renal cell carcinoma7–10,12 55–79% underwent local or wedge excision and 2–15.4% underwent segmentectomy.

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Position of the lesion at the hilum of the lung may require a greater anatomical resection to allow an adequate margin of excision. While lobectomy is usually well tolerated most surgeons would avoid pneumonectomy in metastatic disease in all but the most unusual circumstances. Only 3% of patients in the International Registry underwent pneumonectomy whereas 21% had a lobectomy.21 In a series of pulmonary metastasectomy for renal cell carcinoma lobectomy was performed in 7–36% of cases and pneumonectomy in 0–10% of patients.7–10,12 Mediastinal In non-small cell lung cancer evaluation of nodal disease is important to ensure complete resection with the least loss of lung tissue. While different techniques have been used a standardized method was agreed at a recent workshop.48 This technique is termed ‘systematic nodal dissection’ (SND) and recommends the removal of at least three separate mediastinal nodal stations and another three hilar nodal stations, identified according to their location on a ‘nodal chart’ prior to proceeding with lung resection.49 There is no agreement regarding the need to assess nodal spread in operations for pulmonary metastases. In one series of patients undergoing pulmonary metastasectomy, in whom preoperative imaging of the mediastinum had been normal, SND was routinely performed. Unexpected nodal deposits were found in 14.3% of all patients and 18% of those with renal cell carcinoma.50 The median survival of patients without nodal involvement was longer at 32 months compared with 22 months for those with nodal disease (p = 0.37). In studies in renal cell carcinoma, the impact of nodal disease on prognosis has been variable. One study found no influence on prognosis,12 in another there was a trend towards a poorer prognosis,8 while in a third nodal disease had a statistically significant impact on prognosis.9 Complete resection of all metastatic disease is imperative if a cure is to be obtained. Nodal deposits may well have an impact on the prospects of complete resection and will certainly influence the extent of resection necessary to

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achieve complete resection. Nodes in the pulmonary hilum can only be properly assessed at thoracotomy but any suggestion of mediastinal nodal deposits on preoperative imaging can be assessed using mediastinoscopy. This allows the biopsy of nodes from the upper mediastinum and is a relatively safe procedure.51 Nodal deposits may become apparent for the first time at thoracotomy. While all surgeons would agree that such incidentally found abnormal nodes should be resected, the role of routine SND during pulmonary metastasectomy has yet to be proved to be of any therapeutic benefit. Further data are required before a consensus on the place of SND in pulmonary metastasectomy can be reached.

Results Operative mortality and morbidity With careful preoperative selection and postoperative care pulmonary metastasectomy is a safe procedure. The International Registry of Lung Metastases, based on 5206 cases, reported 30day inhospital mortality of 1.3%. As expected the mortality rose with increasing extent of pulmonary resection (0.6% for sublobar resections, 1.2% for lobectomies, and 3.6% for pneumonectomies).21 The reported series of pulmonary metastasectomy for renal cell carcinoma have mortality ranging from 0% to 2.1%.7–10,12 In these same series postoperative complications were reported in up to 10% of patients, the majority being atrial fibrillation and prolonged postoperative drainage.

Survival post-metastasectomy Analysis of data from the International Registry of Lung Metastases demonstrated improved survival with complete resection (36% vs. 13% for incomplete resection at 5 years) (Figure 10.7). Among those with complete resection a disease-free interval greater than 36 months and single rather than multiple metastases also defined a better prognosis.21 In their series Fourquier et al8 reported a median survival following pulmonary metastasectomy for renal cell carcinoma of 25

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100 resection

patients

deaths

4572 634

2359 447

complete incomplete

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logrank chi2 = 245.8 (1df) 60

40

20

0 0

60

120

180

254 5

78 1

months Patients at risk: complete incomplete

809 35

Figure 10.7 Comparison of the survival of patients undergoing complete versus incomplete metastasectomy taken from the International Registry of Lung Metastases. Survival after complete resection of pulmonary metastases was 36% at 5 years and 26% at 10 years. (Reprinted from Journal of Thoracic and Cardiovascular Surgery, 113, Pastorinoll, Buyse M, Friedel G, Ginsberg RJ, Girard P, Goldstraw P, Johnston M, McCormack P, Pan H, Putman JB. Long term results of lung metastasectomy: prognostic analysis based on 5206 cases, 37–49, © 1997, with permission from American Association for Thoracic Surgery.)

months. Five-year survival for the 90% of patients who had a complete resection was 44% compared with 20% for those who had incomplete resection (p = 0.02). In cases in which complete resection was achieved, the presence of nodal involvement showed a trend towards a poorer prognosis but this was only statistically significant in those with mediastinal nodal deposits. Pfannschmidt et al12 reported a 5-year survival of 37% with a complete resection rate of 78% following pulmonary metastasectomy for renal cell carcinoma. Complete resection significantly influenced prognosis with 5-year survival of 41.5% compared with 22.1% in the incomplete group (p = 0.03). For those patients who underwent complete resection a disease-free interval greater than 23 months, having fewer than seven metastases, and being free of nodal disease predicted a better prognosis. No difference in survival was found comparing hilar with mediastinal nodal involvement.

Piltz et al10 demonstrated the prognostic importance of complete resection and of nodal status at nephrectomy following pulmonary metastasectomy for renal cell carcinoma. Patients who underwent complete resection had a 5-year survival of 33%. Cases in which the maximum diameter of any pulmonary metastasis was less than 4 cm or there was absence of nodal disease were associated with improved prognosis. Cerfolio et al7 reported results for complete resection in 94 patients with pulmonary metastases from renal cell carcinoma with a 5-year survival rate of 35.7%. Number of pulmonary metastases (5-year survival for solitary metastasis 45.6% vs. 26% for multiple) and disease-free interval (5-year survival for disease-free interval > 3.4 years 45.4% vs. 26% for disease-free interval < 3.4 years) influenced survival. Murthy et al9 report a series of pulmonary metastasectomy for renal cell carcinoma with a complete resection rate of 68%; overall

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survival was 31% at 5 years. Again, complete resection was the strongest predictor of survival (5-year survival 42% vs. 8% in incomplete resection). Other factors associated with a poor outcome included larger pulmonary nodule, greater number of involved lymph nodes, a lower preoperative FEV1 and shorter disease-free interval. Increasing number of nodules predicted a greater likelihood of incomplete resection but did not influence survival if all disease could be resected.

Relapse patterns after pulmonary metastasectomy There are few data available for the pattern of relapse observed following pulmonary metastasectomy for renal cell carcinoma. The International Registry documented recurrence in 53% of patients following complete pulmonary metastasectomy, at a median interval of 10 months.21 Recurrence is most commonly seen in the ipsilateral lung followed by bilateral pulmonary relapse and disseminated disease with the isolated contralateral lung relapse the least likely.

Repeat metastasectomy Any patient who has already undergone pulmonary metastasectomy and who presents with new lung lesions should be evaluated for repeat metastasectomy. In the International Registry one-fifth of patients underwent redo surgery, with excellent results, similar to those of first-time surgery, and a 5-year survival of 44%.21 Cerfolio et al7 reported that of 96 patients who underwent pulmonary metastasectomy for renal cell carcinoma, 11 went on to have further pulmonary metastases resected with a 5-year survival at 30.8%, similar to the 33.3% survival achieved for first time metastasectomy. Piltz et al10 reported repeat surgery in 12% of their series with a median survival of 40 months, again not statistically different from those undergoing a first time procedure. Pfannschmidt et al12 performed repeat metastasectomy between two and four times in

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14.6% of their patients with no difference in morbidity, mortality or postoperative survival compared with first time surgery. Fourquier et al8 also report a 42% 5-year survival rate in the 24% of patients undergoing repeat surgery in their series.

Pulmonary metastasectomy in the presence of extrapulmonary metastatic disease In the series of Cerfolio et al7 of 96 patients undergoing pulmonary metastasectomy for renal cell carcinoma, 34 patients also underwent excision of a solitary extrathoracic metastasis (11 bone, 10 brain, 8 abdominal, 2 scalp, and 1 each in thyroid, pancreas, and neck). The survival of these unusual cases was no different from the overall results with 37% survival at 5 years. Murthy et al9 reported 92 patients undergoing pulmonary metastasectomy of which 11 had extrathoracic metastases. Complete resection was possible in five of these patients. The little evidence available suggests that, in those patients able to tolerate such surgery and where complete resection is possible, aggressive, combined surgical excision of pulmonary and limited extrathoracic disease should be undertaken.

NON-PULMONARY THORACIC METASTASES Endobronchial disease Presentation Endobronchial tumour deposits can present with haemoptysis, wheeze, dyspnoea or recurrent infections due to partial or complete bronchial obstruction. Pure endobronchial disease is extremely rare; most patients also have pulmonary parenchymal metastases. In their series of 50 patients undergoing pulmonary metastasectomy for renal cell carcinoma Fourquier et al8 described seven patients with endobronchial tumour. In a series of 27 patients treated for endobronchial disease from non-bronchogenic primaries 44% originated from renal cell carcinoma.52

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Treatment When the patient fulfils the criteria for pulmonary metastasectomy endobronchial disease should be resected along with any pulmonary parenchymal lesions. Formal anatomical resection is necessary. If possible tumours in the main bronchus should undergo sleeve resection rather than pneumonectomy so as to preserve lung parenchyma. A number of palliative options are available where metastasectomy is not appropriate. Endobronchial tumour can be disobliterated mechanically, with diathermy,53 laser, or photodynamic therapy.52 The bronchus can then be held open with a stent.54 Such measures are successful in providing palliation but the patient’s life expectancy is limited to a median of 4 months.52

Figure 10.8 A Denver pleuroperitoneal shunt. The shorter limb is inserted into the thorax the longer limb into the peritoneum and the chamber lies subcutaneously superficial to the costal margin. The chamber contains a one way valve and can be compressed against the ribs by the patient to pump fluid out of the chest.

Malignant pleural effusion Diagnosis There are numerous causes for pleural effusion. A blind pleural biopsy can be undertaken at the time of drainage but the sensitivity of these techniques remains relatively low.55 A CT or ultrasound-guided biopsy enhances the sensitivity if the pleura is thickened to over 80%.56 VATS pleural biopsy is successful in obtaining a diagnosis in nearly 100% of patients57 as the entire pleura can be examined and multiple biopsies taken from abnormal areas. A further advantage is the option of performing a palliative procedure under the same anaesthetic.

Selection of treatment options Patients with metastatic malignancy have multiple causes of dyspnoea and the effusion may not be the dominant factor. It is therefore imperative that patients are carefully assessed to determine the optimum treatment strategy. If patients do not derive symptomatic benefit from drainage of their effusion then a palliative procedure would only expose them to the risks of anaesthesia and surgery without any benefit. A diagnostic procedure may still be warranted. If on draining the effusion the lung reexpands such that there is apposition between

the parietal and visceral pleura then a pleurodesis can be performed. Talc is insufflated into the pleural space via a single VATS port after appropriate biopsies have been obtained. If the lung is trapped and does not re-expand on drainage of the effusion then a pleuroperitoneal shunt can be inserted to stop the effusion re-accumulating (Figure 10.8). In patients who are not fit for general anaesthetic but benefit from drainage of their effusion a procedure can be performed under local anaesthetic. If the lung re-expands then talc slurry can be injected via the intercostal drain to perform a pleurodesis, if the lung is trapped then a long-term drain such as a Pleur-XMT drain can be inserted. This allows the patient, their relatives or carer to remove fluid at home as the need arises. Unfortunately neither of these approaches allow biopsies to be obtained.

Results VATS talc pleurodesis has been shown to be effective in palliating malignant pleural effusion in more than 90% of patients57,58 with low inhospital mortality (< 5%). Pleuroperitoneal shunts are safe to insert and achieve effective palliation in more than 90% of suitable cases.59 Pleurodesis via an intercostal drain with talc

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slurry is less successful, around 80%, but avoids the risk of a general anaesthetic.60 Patients with a malignant effusion who are fit enough to undergo surgical palliation have a median life expectancy of 8 months.59

SUMMARY Thoracic surgery has a role in the diagnosis and treatment of pulmonary metastases and malignant pleural effusions. Pulmonary metastases are a common problem in renal cell carcinoma. Pulmonary metastasectomy is a safe and effective treatment modality which, if offered to appropriately selected patients, offers significantly increased life expectancy with low perioperative mortality and morbidity. Repeat metastasectomy, while less often feasible, has results very similar to first time surgery.

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11. Quint LE, Park CH, Iannettoni MD. Solitary pulmonary nodules in patients with extrapulmonary neoplasms. Radiology 2000; 217: 257–61. 12. Pfannschmidt J, Hoffmann H, Muley T et al. Prognostic factors for survival after pulmonary resection of metastatic renal cell carcinoma. Ann Thorac Surg 2002; 74: 1653–7. 13. Sahn AS. Malignancy metastatic to the pleura. Clin Chest Med 1998; 19(2): 351–61. 14. Ohnishi H, Abe M, Hamada H et al. Metastatic renal cell carcinoma presenting as multiple pleural tumours. Respirology 2005; 10: 128–31. 15. Kutty K, Varkey B. Incidence and distribution of intrathoracic metastases from renal cell carcinoma. Arch Intern Med 1984; 144: 273–6. 16. Lokich J. Spontaneous regression of metastatic renal cancer. Am J Clin Oncol 1997; 20(4): 416–18. 17. Oliver RT, Nethersell AB, Bottomley JM. Unexplained spontaneous regression and alpha interferon as treatment for metastatic renal cell carcinoma. Br J Urol 1989; 63(2): 128–31. 18. Snow RM, Schellhammer PF. Spontaneous regression of metastatic renal cell carcinoma. Urology 1982; 20(2): 177–81. 19. Weinlecher J. Tumoren an der Brustwand und deren Behandlung (Resection der Rippen) Eroffnung der Brusthohle und partielle Entfernung der Lunge. Wien Med Wschr 1892; 32: 590. [In German] 20. Barney JD, Churchill EJ. Adenocarcinoma of the kidney with metastasis to the lung. J Urol 1939; 42: 269–76. 21. Pastorino U, Buyse M, Friedel G et al. Long term results of lung metastasectomy: Prognostic analysis based on 5206 cases. J Thorac Cardiovasc Surg 1997; 113: 37–49. 22. Chang AE, Schaner EG, Conkle DM et al. Evaluation of computed tomography in the detection of pulmonary metastases: a prospective study. Cancer 1979; 43: 913–16. 23. McCormack PM, Ginsberg KB, Bains MS et al. Accuracy of lung imaging in metastases with implications for the role of thoracoscopy. Ann Thorac Surg 1993; 56: 863–6. 24. McCormack PM, Bains MS, Begg CB et al. Role of video-assisted thoracic surgery in the treatment of pulmonary metastases: results of a prospective trial. Ann Thorac Surg 1996; 62: 213–17. 25. Parsons AM, Detterbeck FC, Parker LA. Accuracy of helical CT in the detection of pulmonary metastases: Is intraoperative palpation still necessary? Ann Thorac Surg 2004; 78: 1910–18. 26. Strauss LG. Fluorine-18 deoxyglucose and false positive results: A major problem in the diagnostics of oncological patients. Eur J Nucl Med 1996; 23: 1409–15. 27. Knight SB, Delbeke D, Stewart JR, Sandler MP. Evaluation of pulmonary lesions with FDG-PET. Comparison of findings in patients with and without a history of prior malignancy. Chest 1996; 109: 982–8.

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28. Lowe VJ, Duhaylongsod FG, Patz EF et al. Pulmonary abnormalities and PET data analysis: A retrospective review. Radiology 1997; 202: 435–9. 29. Erasmus JJ, McAdams HP, Patz EF et al. Evaluation of primary pulmonary carcinoid tumours using positron emission tomography with 18F-fluoro-deoxyglucose. AJR Am J Roentgenol 1998; 170: 1369–73. 30. Higashi K, Ueda Y, Seki H et al. Flourine-18-FDG PET imaging is negative in bronchoalveolar lung carcinoma. J Nucl Med 1998; 39: 1016–20. 31. Hsu WH, Hsu NY, Shen YY, Yen RF, Kao CH. Differentiating solitary pulmonary metastases in patients with extrapulmonary neoplasms using FDGPET. Cancer Invest 2003; 21(1): 42–57. 32. Pastorino U, Veronesi G, Landoni C et al. Fluorodeoxyglucose positron emission tomography improves preoperative staging of resectable lung metastasis. J Thorac Cardiovasc Surg. 2003; 126: 1906–10. 33. Chang CH, Shiau YC, Shen YY et al. Differentiating solitary pulmonary metastases in patients with renal cell carcinoma by 18 F-fluoro-2-deoxyglucose positron emission tomography – a preliminary report. Urol Int 2003; 71: 306–9. 34. Majhail NS, Urbain JL, Albani JM et al. F-18 Flourodeoxyglucose positron emission tomography in the evaluation of distant metastases from renal cell carcinoma. J Clin Oncol 2003; 21: 3995–4000. 35. Ramdave S, Thomas GW, Berlangieri SU et al. Clinical role of F-18 flourodeoxyglucose positron emission tomography for detection and management of renal cell carcinoma. J Urol 2001; 166: 825–30. 36. British Thoracic Society. Guidelines on the selection of patients with lung cancer for surgery. Thorax 2001; 56: 89–108. 37. Cooper JD, Nelems JM, Pearson FG. Extended indications for median sternotomy in patients requiring pulmonary resection. Ann Thorac Surg 1978; 26: 413–20. 38. Johnston MR. Median sternotomy for resection of pulmonary metastases. J Thorac Cardiovasc Surg 1983; 85: 516–22. 39. Dowling RD, Keenan RJ, Ferson PF, Landreneau RJ. Video assisted thoracoscopic surgery of pulmonary metastases. Ann Thorac Surg 1993; 56: 772–5. 40. Yim PC, Lin J, Chan TC et al. Video-assisted thoracoscopic wedge resections of pulmonary metastatic osteosarcoma: Should it be performed? Aust N Z J Surg 1995; 65: 737–9. 41. Dowling RD, Ferson PF, Landreneau RJ. Thoracoscopic resection of pulmonary metastases. Chest 1992; 102: 1450–4. 42. Fry WA, Siddiqui A, Pensler JM, Mostafavi H. Throracoscopic implantation of cancer with a fatal outcome. Ann Thorac Surg 1995; 59: 42–5. 43. Walsh GL, Nesbitt JC. Tumour implants after thoracoscopic resection of a metastastic sarcoma. Ann Thorac Surg 1995; 59: 215–16. 44. Leong K, Tan C, Hsin M, Goldstraw P. Intrapleural tumor dissemination after video-assisted thoracoscopic surgery metastasectomy. Ann Thorac Surg 2003; 75: 1643–5.

45. Dowling RD, Landreneau RJ, Miller DL. Videoassisted thoracoscopic surgery for resection of lung metastases. Chest 1998; 113: 2S-5S. 46. Hazelrigg SR, Naunheim K, Auer JE, Seifert PE. Combined median sternotomy and video-assisted thoracoscopic resection of pulmonary metastases. Chest 1993; 104: 956–8. 47. Goldstraw P. Report on the international workshop on intrathoracic staging. London, October 1996. Lung Cancer 1997; 18: 107–11. 48. Roth JA, Pass HI, Wesley MN et al. Comparison of median sternotomy and thoracotomy for resection of pulmonary metastases in patients with adult soft tissue sarcomas. Ann Thorac Surg 1986; 42: 134–8. 49. Graham AN, Chan KJ, Pastorino U, Goldstraw P. Systematic nodal dissection in the intrathoracic staging of patients with non-small cell lung cancer. J Thorac Cardiovasc Surg 1999; 117: 246–51. 50. Loehe F, Kobinger S, Hatz RA et al. Value of mediastinal lymph node dissection during pulmonary metastasectomy. Ann Thorac Surg 2001; 72: 225–9. 51. Venissac N, Alifano M, Mouroux J. Video-assisted mediastinoscopy: experience from 240 consecutive cases. Ann Thorac Surg 2003; 76: 208–12. 52. Litle VR, Christie NA, Fernando HC et al. Photodynamic therapy for endobronchial metastases from nonbronchogenic primaries. Ann Thorac Surg 2003; 76(2): 370–5. 53. Sakumoto N, Inafuku S, Shimoji H et al. Endobronchial metastasis from renal cell carcinoma: report of a case. Surg Today 2000; 30(8): 744–6. 54. Yim AP, Abdullah VJ, Chan H. A case of bronchial obstruction by metastatic renal cell carcinoma. Surg Endosc 1996; 10(8): 855–6. 55. Baumann M. Closed pleural biopsy: A necessary tool? Pulm Perspect 2000; 17: 1–3. 56. Adams RF, Gray W, Davies RJO, Gleeson FV. Percutaneous cutting needle biopsy of the pleura in the diagnosis of malignant mesothelioma. Chest 2001; 120: 1798–802. 57. Cardillo G, Facciolo F, Carbone L et al. Long term follow up of video-assisted talc pleurodesis in malignant recurrent pleural effusions. Eur J Cardiothorac Surg 2002; 21: 302–6. 58. Petrou M, Kaplan D, Goldstraw P. Management of recurrent pleural effusions: The complementary role of talc pleurodesis and pleuroperitoneal shunting. Cancer 1995; 75 (3): 801–5. 59. Genc O, Petrou M, Ladas G, Goldstraw P. The long term morbidity of pleuroperitoneal shunts in the management of recurrent malignant effusions. Eur J Cardiothorac Surg 2000; 18: 143–6. 60. Erickson KV, Yost M, Bynoe R, Almond C, Nottingham J. Primary treatment of malignant pleural effusions: Video assisted thoracoscopic surgery poudrage versus tube thoracostomy. Am Surg 2002; 68: 955–9.

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Surgery for renal cell cancer bone metastases

11

Stephen R Cannon

INTRODUCTION The skeleton is the third most frequent site of metastatic carcinoma following the lungs and the liver. One-third of all primary cancers have a tendency to disseminate to bone and dissemination from renal cancer is the third most common site of origin following prostate and breast.1 In recent years advances in chemotherapy, immunotherapy, hormone therapy, and irradiation have improved the prognosis and life expectancy of such patients. Therefore the correct orthopaedic management can not only help the control of pain and improve quality of life, but also prevent pathological fracture and in some selected cases lead to ultimate survival. Appropriate treatment of pathological fractures when they do occur can lead to rapid return of functional activity for the patient. Anatomical sites most involved in order of frequency are the spine, pelvis, ribs, skull, and proximal long bones. The high incidence of spinal and pelvic metastases is due to the existence of Bateson’s plexus, a vascular system which forms an interconnecting network of thin-walled veins with low intraluminal pressures extending from the dural sinuses of the skull to the sacrum. As the plexus does not contain valves it allows retrograde embolization of tumour and connects with the venous drainage system of the proximal long bones and major organs, including the kidney. The orthopaedic surgeon can be involved in the treatment of renal metastatic disease at a number of stages. Most commonly it is in the treatment of patients with advanced renal cell carcinoma. The work of Zekri et al2 has

confirmed that firstly, 30% of 103 patients with advanced renal cell carcinoma developed radiologically confirmed skeletal metastases. These are typically lytic, predominantly affecting the axial skeleton and associated with considerable skeletal morbidity. Secondly, patients may present with pathological fracture with or without previously diagnosed renal carcinoma. Here specific care is required, because if the lesion on staging proves to be solitary then resection options which may lead to eradication of the disease are obviously more in the patient’s interest than stabilization. The orthopaedic surgeon is rarely involved at diagnosis of renal cell carcinoma and discovery of bone metastases at staging diagnosis is relatively rare. The incidence appears to be somewhere in the region of 5.9% and the incidence of solitary bone metastases synchronous with diagnosis of the renal primary is only at a level of 1%.3 The appearance on radiographs of the lesion is usually osteolytic, although it can be rarely permeative (Figure 11.1). The appearance is usually aggressive and expansive with both medullary and cortical destruction. Soft tissue extension is common. There often appears to be no periosteal reaction and pathological fracture is very common in both the spine and the long bones (50%). There is little or no potential for union, particularly after radiation therapy. The spontaneous regression of metastases following nephrectomy is reported but unfortunately rare. There have been several reports of surgical removal of one or several metastases leading to long term survival in more than 30% of affected patients.4–6 Cure rates are dependent on location of the

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Figure 11.1 (A) Anteroposterior radiograph of large renal metastasis – distal femur. (B) Lateral radiograph of lytic lesion with cortical destruction.

Table 11.1

Survival following treatment of solitary metastases

Series 9

Fuchs et al Aldlyami10 Capanna11 Cannon (unpublished)

No. of patients

1-year survival (%)

2-year survival (%)

5-year survival (%)

60 129 ? 88

83 86 – 82

45 45 – 47

23 – 35 37

lesions, but are better with metachronous metastases with a long disease-free interval following original nephrectomy and few systemic symptoms.7 This thinking can be applied to osseous lesions and has meant that excisional surgery has become the treatment of choice for renal cell metastases when they present as solitary and late lesions. Aggressive removal and wide resection, often preceded by preoperative embolization to reduce excessive bleeding, is the treatment of choice. Surgery is of course also indicated for small tumours which are resectable without functional impairment. For multiple lesions, prophylactic fixation and prevention of pathological fractures may be more appropriate, combined with radiation or

chemotherapy. The experience of Durr et al is worth emphasizing when patients with metastatic renal cell carcinoma to bone are treated by surgery. Only 50% of cases survived after 1 year, 39% after 2 years and 15% after 5 years.8 However, in eight patients of this series who presented with a solitary metastasis and were treated by wide resection of the metastasis combined with a nephrectomy, mean survival was 69 months. Therefore patients who present at diagnosis with single osteo-metastasis are candidates for aggressive surgical treatment with curative intent. Despite this aggressive approach, there are varying survival rates following resection of a solitary bone metastasis. (Table 11.1) (Cannon, unpublished data and references 9–11).

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SURGERY FOR RENAL CELL CANCER BONE METASTASES

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Table 11.2 Assessment of risk of pathological fracture according to Mirels.15 The numbers for all variable are added.

Site Pain Lesion Size related to diameter of bone

Risk score 1

2

Upper limb Mild Blastic < 1/3

Lower limb Moderate Mixed 1/3 to 2/3

3 Peritrochanteric region On weight bearing Lytic > 2/3

Results: Fracture group, mean score 10 (7–12, SD 1.09); non-fracture group, mean score 7 (4–9, SD 1.28)

BIOMECHANICAL FACTORS Any osteolytic metastatic lesion will obviously affect the strength of bone. The loss of bone reduces the stress transmission and the ability to absorb energy. A stress riser effect is produced, particularly if there is a cortical defect. Cortical defects involving 75% of the diameter cause up to 90% of loss of strength. Cortical or endosteal defects involving 50% of the intact diameter of the cortical bone causes a decrease of 50% in bone strength.12–14 Obviously an estimation of ‘fracture risk’ is a great adjunct to orthopaedic treatment and the following are useful guidelines: • Osteolytic lesions such as seen in renal carcinoma have more risk than mixed or osteoblastic lesions. • Lytic lesions involving 50–75% of the bone diameter fracture very easily. • Those bones which are highly stressed areas, such as the femoral neck are more than likely to fracture than the diaphyseal cortex. Weight-bearing bones are obviously more likely to fracture than non-weightbearing bones. • A lesion in a major long bone of any radiological type or size which shows persistent pain on weight bearing or local progression following irradiation and chemotherapy is likely to fracture. This is a particular problem in renal metastases which tend to be radioresistant. Mirels15 has devised a scoring system based on the analysis of site of pain and radiological appearance, together with size of the lesion.

Patients unlikely to have a fracture had a mean score of 7 (range 4–9) while those who sustain fractures had a mean score of 10 (range 7–12). (Table 11.2).

SURGERY FOR SPECIAL AREAS Pelvis and acetabulum Following the spine, the pelvis is the most frequent site of metastatic renal tumours. Osteolytic lesions of the iliac wings, sacroiliac joint, and anterior pelvic arches carry no risk of mechanical failure and may usually be treated by radiation alone. Surgery is only required for solitary and late metastatic lesions with a good prognosis. Lesions of the periacetabular area are more difficult as they cause severe pain and there is risk of central acetabular protrusion because of mechanical failure. Surgical treatment aims to relieve pain and restore functional weight bearing. The treatment of choice is a cemented total hip replacement using devices which cope with the extensive bone loss that may be present. For large acetabular defects limited to the medial wall, a cemented cup with lateral flanges or a metallic mesh can be utilized. Cement should be used liberally.16 Reinforcement rings or Steinman pins may be placed in the anterior posterior columns to help with long term stability of the construct. After a wide dissection of a solitary lesion or where extensive bone loss is the problem a pelvic prosthesis can be useful (Figure 11.2). Such extensive surgery often carries problems of postoperative instability and long periods of immobilization which may not be justified in patients with a limited

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Figure 11.2 Pelvic replacement of a solitary metastasis of the right hemipelvis.

Figure 11.3 CT pelvis showing acetabular destruction on both sides.

prognosis. Implants are designed from twodimensional X-rays, computed tomography and magnetic resonance scans (Figure 11.3).

Hip and proximal femur The proximal femur is the most common site for pathological fracture. Treatment of renal lytic lesions arising in this area is rarely conservative. Generally prosthetic replacement is recommended and if there is extensive involvement of the proximal femoral shaft either a cemented long-stem prosthesis can be utilized or where excision is required a customized or modular proximal femoral prosthesis can be considered (Figure 11.4). Where excision is not required, the proximal femoral metaphysis can be reconstructed in a number of ways. Simple osteosynthesis with hip screw arrangements or intramedullary devices are not advisable, as these are usually inadequate and fail by metal fatigue in the long term. Augmentation with cement is recommended to try to give some structural integrity to the implant. Even where the patient’s prognosis is poor, i.e. with multiple bony and visceral metastases, the presence of a large lytic area in the subtrochanteric region is perhaps better treated by resection and prosthetic reconstruction than more usual techniques of intramedullary nails and screw plate systems, often augmented with cement, as patients undergoing prosthetic reconstruction with a

Figure 11.4 Proximal femoral replacement with bipolar acetabular reconstruction.

customized or modular prosthesis tend to gain their mobility and pain-free walking much quicker than with other internal reconstruction methods.

Knee and ankle In the lower regions of the long bones the loading forces tend to be compressive and where

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Figure 11.5 Large diaphyseal metaphyseal lesion treated by curettage, cementoma, and plate fixation.

simple osteosynthesis is required curettage, cementoma, and plates are the method of choice (Figure 11.5) Where resection is required the distal femur and proximal tibia can be reconstructed using custom or modular devices which give rapid rehabilitation (Figure 11.6). Techniques using allografts which require long periods of rehabilitation are not recommended.

Shoulder girdle As in common with other lesions, lytic lesions from renal carcinoma in the scapula and clavicle can usually be managed conservatively with analgesics and irradiation, but solitary lesions may require removal. In these areas no real reconstruction is usually required as even resection of the clavicle leaves full function of the upper limb. Lesions in the proximal humeral metaphysis are usually best served by excision of the area and shoulder reconstruction. As the rotator cuff is usually excised in these lesions, stability and function is best achieved by using a bipolar-type prosthesis (Figure 11.7).

Figure 11.6 Custom prosthesis for distal femoral and knee replacement.

Diaphyseal lesions Conservative treatment is rarely indicated for patients with renal metastases in the weight-bearing areas of the femur and tibia. Pathological fractures, if the patient’s prognosis is poor, are best treated by some form of internal fixation, plus or minus cement. If pathological fracture has not occurred in patients with a poor prognosis curettage of the lesion followed by an insertion of cement into the defect with plate fixation represents a relatively straightforward technique. Unfortunately this is often accompanied by significant blood loss as a tourniquet cannot by used in the femur and again embolization techniques may be useful. In renal metastatic disease located

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Figure 11.8 Diaphyseal replacement with cemented customized stems and hydroxyapatite ongrowth.

Figure 11.7

Bipolar humeral prosthesis.

in the diaphysis, which has responded well to adjuvant therapy but requires surgery, the defect can be treated by an intramedullary nail but is probably better fixed by open curettage and filling the cavity with polymethylmethacrylate cement along with a reinforcement buttress plate.17–19 Open curettage of the lesion also has the advantages of various other adjuvants in addition to cement and might be used to control microscopic deposits of tumour within the cavity. These include phenolization, 100% alcohol, and liquid nitrogen. Where resection of a solitary metastasis has occurred in a diaphysis of long bone then reconstruction can be similarly achieved by using a medullary nail supported by cement in patients with a poor prognosis, but where long-term survival

is expected, diaphyseal reconstruction with a custom prosthesis using hydroxyapatite collars is proposed. This will give rapid restoration of gait and long-term fixation without failure of the reconstruction for the duration of the patient’s life (Figure 11.8).

Failure of previous osteosynthesis Renal metastases can be extremely difficult to manage in that occasionally the orthopaedic surgeon undertakes a method of fracture fixation which fails to control the tumour, even if combined with local radiation. The tumour advances and the patient survives without visceral metastases developing. Occasionally such devastating soft tissue disease is present that amputation is required, but usually the situation can be rescued by resection of the area of reconstruction and insertion of a

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a

149

b

Figure 11.9 (A) Implant fixation following failure of intramedullary nail. (B) Implant failure of screw plate fixation in renal cell metastasis.

custom-built or modular prosthesis. This is particularly indicated where not only has the tumour progressed locally but also the internal fixation has failed either by pull-off or fracture of the implant (Figure 11.9).

Guidelines for orthopaedic management It is important that all patients requiring orthopaedic surgery are discussed in an oncological orthopaedic multidisciplinary team, which involves an orthopaedic surgeon, a medical and clinical oncologist, and radiologist. It is obviously important that not only the bony extent of the disease is taken into consideration, but also the Karnofsky status of the patient.20 In metastatic renal disease it would appear that not only the solitary nature of some lesions but also the time interval from the primary diagnosis is important. Similarly the risk of pathological fracture must be taken into account as most of the lesions are lytic. Chemotherapy is usually

not particularly helpful in gaining stability and irradiation tends to be at best partially active. Orthopaedic surgeons are therefore generally guided by classifying patients to one of four classes summarized in Table 11.3. In essence, all patients in classes I, II, and III are referred to an orthopaedic surgeon for consideration of surgery and then referred back for oncological management. Where patients present in class IV, conservative treatment would be followed first, plus or minus irradiation, and the patient only referred back to orthopaedic surgery should there be failure to control symptoms or local progression. The schemata for this process is seen in Table 11.4. This outlines the role of the orthopaedic surgeon in the overall management of the oncological patient.

SPINAL METASTASES Spinal metastases obviously have to be considered separately due to the proximity of

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Table 11.3 I II III IV

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Classification of bony metastasis in renal cancer

Single metastatic lesions occurring either synchronously or within three years of the initial diagnosis Presence of pathological fracture and patients present de novo to orthopaedic surgeons Radiological signs of impending fracture in a major weight-bearing long bone or in the peri-acetabular area Bony deposits occur in the fibula, ribs, sternum or clavicle (non-structural bones) or not representing an impending fracture or lesions in the anterior pelvis, iliac wing or scapula (excluding class I)

Table 11.4

Summary of the protocol for the four classes of patient

Class I

II III IV

Treatment Solitary metastatic lesion Primary with good prognosis (well-differentiated thyroid, prostate, breast sensitive to adjuvants, rectum, clear-cell renal, myeloma, lymphoma) Interval after primary over 3 years Pathological fracture at any site Impending fracture in a major weight bearing bone Osteoblastic lesions at all sites Osteolytic or mixed lesions in non-structural bones (fibula, rib, sternum, clavicle) Osteolytic lesion with no impending fracture in major weight-bearing bone

the spinal cord and cauda equina. Again renal metastases tend to present as purely lytic lesions and may present as perhaps neural compression (Figure 11.10). In general the patients can be classified in a similar way into the four classes outlined in the previous section, but certain local considerations are tantamount in their management. • Class I – This includes patients with a solitary lesion with late onset and with a long life expectancy. Here aggressive surgery and removal of the tumour with appropriate reconstruction would be recommended (Figure 11.11). • Class II – Here the patient has incomplete compression of the cord and includes those with complete compression in the cervical or lumbar regions, but presenting within 6 hours of the acute onset or within 3 days of chronic progression. Here simple decompression and stabilization are recommended. • Class III – Represents those patients with impending vertebral fracture or compression, but here account is taken of their

Consider excision

Stabilization Consider stabilization Leave alone lesions

prognosis. Surgical intervention would be favoured if the patient has a prognosis of greater than 2 years, given their Karnofsky status, has a lesion above the cauda equina, and the lesion involves the whole of the vertebra. Other patients are best managed medically. • Class IV – Represents those patients with multiple vertebral metastases without cord compression or those presenting with complete paraplegia of some standing. Such patients are managed medically. In patients where major surgery would appear to be contraindicated the relatively new technique of vertivoplasty may be indicated. Again such decision making is perhaps best made in a multidisciplinary setting.

DISCUSSION The management of metastatic renal cancer to bone requires a multidisciplinary team approach. Obviously the orthopaedic surgeon is key to most decision making, but requires the advice and discussion of medical oncologist,

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Figure 11.10

Osteoblastic metastases.

radiologists, pathologists, and radiotherapists. Patients with pathological fracture and spinal disease may present as medical and surgical emergencies and rapid access to advice and discussion is important in the correct management of these patients. It is important to recognize Class I patients, who have the best prognosis and certainly complete removal of the lesion may lead to significant long-term survival, although it is recognized that delay of presentation of such lesions for some period following the diagnosis of the renal cancer may lead to a better outcome. In patients who need symptomatic treatment, careful consideration as to the extent and type of surgery utilized is important. What must be avoided are long-term complications due to breakage of osteo-synthetic devices and progression of disease locally. Cement augmentation and strong implants, together with postoperative radiation, are usually helpful in eliminating these poor results. Similarly it is important to recognize those patients which would do better with medical, conservative or palliative treatment, such as radiofrequency ablation, are recognized so that the morbidity of major surgery can be avoided.

151

Figure 11.11 Complex reconstructive surgery for a solitary vertebral metastasis at T6.

REFRENCES 1. Silverburg E. Cancer statistics 1986. CA Cancer J Clin 1986; 36: 9–25. 2. Zekri J, Ahmed N, Coleman RE, Hancock BW. The skeletal metastatic complications of renal cell carcinoma. Int J Oncol 2001; 19(2): 379–82. 3. Henriksson C, Haraldsson G, Aldenborg F, Lindberg S, Pettersson S. Skeletal metastases in 102 patients evaluated before surgery for renal cell carcinoma. Scand J Urol Nephrol 1992; 26(4): 363–6. 4. Alves A, Adam R, Majno P et al. Hepatic resection for metastatic renal tumours: is it worthwhile? Ann Surg Oncol 2003; 10: 705–10. 5. Kavolius JP, Mastorakos DP, Pavlovich C et al. Resection of metastatic renal cell carcinoma. J Clin Oncol 1998; 16: 2261–6. 6. Kierney PC, van Heerden JA, Segura JW, Weaver AL. Surgeon’s role in the management of solitary renal cell carcinoma metastases occurring subsequent to initial curative nephrectomy: an institutional review. Ann Surg Oncol 1994; 1: 345–52. 7. Volkmer BG, Gschwend JE. [Value of metastases surgery in metastatic renal cell carcinoma]. Urologe A 2002; 41: 225–30. [In German] 8. Durr HR, Maier M, Pfahler M, Baur A, Refior HJ. Surgical treatment of osseous metastases in patients with renal cell carcinoma. Clin Orthop 1999; 367: 283–90. 9. Fuchs B, Trousdale RT, Rock MG. Solitary bony metastasis from renal cell carcinoma: significance of

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surgical treatment. Clin Orthop Relat Res 2005; (431): 187–92. Aldlyami E. How aggressive should we be in treating bony renal metastases? Proceedings British Orthopaedic Association, Birmingham, 21–23 September 2005. Capanna R. European Institutional Course Lecture, 1999; 4: 24–34. Pugh J, Sherry HS, Futterman B, Frankel VH. Biomechanisms of pathologic fractures. Clin Orthop 1982; 169: 109–14. Bechtol CO. Bone as a structure. In: Bechtol CO, Ferguson AB, Laing PG, eds. Metals and Engineering in Bone and Joint Surgery. Baltimore: Williams and Wilkins, 1986: 127–142. McBroom RY, Hayes WC, Poon P. Strength reduction of endosteal defects in diaphyseal bone. Trans 32nd. Ann Meet Orthop Res Soc 1986; 249: 11–65.

15. Mirels M. Metastatic disease in long bones: a proposed scoring system for diagnosis impending pathologic fractures. Clin Orthop 1989; 249: 256–64. 16. Harrington KD. Orthopaedic management of extremity and pelvic lesions. Clin Orthop 1995; 312: 136–47. 17. Sim FM. Diagnosis and Management of Metastatic Bone Disease: A Multidisciplinary Approach. New York: Raven Press, 1988. 18. Anderson JT, Erickson JM, Thompson RC Jr, Chao EY. Pathologic femoral shaft fractures comparing fixation techniques using cement. Clin Orthop 1978; 131: 273–8. 19. Sim FM, Daugherty TW, Ivins JC. The adjunctive use of methyl-methacrylate in fixation of pathological fractures. J Bone Joint Surg (Am) 1974; 56–A: 40–8. 20. Karnofsky DA, Burchenal JH. The clinical evaluation of chemotherapeutic agents. In: McLeod E, ed. Evaluation of Chemotherapeutic Agents. New York: Columbia University Press, 1949.

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Adjuvant therapy in renal cancer

12

Axel Walther, David Chao, Martin Gore

INTRODUCTION Metastatic renal cell carcinoma (RCC) remains an incurable condition and the development of adjuvant treatments that can decrease the risk of patients developing metastasis following nephrectomy remains an important goal. A number of prognostic factors have been described that aim to identify those patients with primary RCC who are at risk of relapse.1–6 The approach of identifying such patients is well illustrated by the successful adjuvant strategies that are now standard of care in many of the commoner tumour types, such as breast7 and colorectal8,9 cancer. The agents used in these adjuvant strategies are those with some proven efficacy in the metastatic setting. Unfortunately in renal cancer, despite the use of chemo-immunotherapy, currently there is no good treatment for stage 4 disease, which has hampered the development of adjuvant therapy in renal cancer. Consequently, while a number of studies have addressed the question of adjuvant therapy, most of these were small and did not demonstrate a significant benefit of treatment. However, with the advent of novel agents that appear to be active in stage 4 disease, adjuvant therapy is again becoming an important area of investigation.

ADJUVANT CHEMOTHERAPY Chemotherapy in advanced RCC is largely ineffective when administered either as a single agent or in combination therapy (Table 12.1). As a result, only a small number of trials have investigated the use of cytotoxics in renal cell

carcinoma in the adjuvant setting (Table 12.2). Naito et al randomized 66 patients to either UFT (1:4 mixture of tegafur and uracil) or observation following nephrectomy for earlystage RCC.29 The disease-free survival was 80.5% and 77.1%, respectively, at 5 years and this difference was not statistically significant. Pizzocaro et al randomized 120 patients post nephrectomy to receive either 500 mg medroxyprogesterone acetate three times per week for 1 year or observation.30 The difference in disease-free survival was not statistically significant (67.3% and 66.1%, respectively) at 5 years of follow-up. Masuda et al treated 31 patients with nonmetastatic renal carcinoma with nephrectomy followed by five cycles of vinblastine 5 mg/m2 and adriamycin 30 mg/m2. Patients also received tegafur 900 mg/day for 2–3 years.31 The 1-year, 3-year and 5-year overall survival rates were 100%, 96% and 96%, respectively, at a mean of 4.2 years of follow-up. The authors state that this is significantly better than historical controls. Kuhbock et al treated 13 patients with nephrectomy and metastasectomy to achieve macroscopic tumour clearance and this was followed by vinblastine 5 mg/m2 every 1–3 weeks and CCNU (lomustine) 130 mg/m2 every 6 weeks.32 The authors did not report overall survival but just that 10 of 13 patients were in remission at 3–21 months follow-up. The only suggested benefit of adjuvant chemotherapy in the above studies was in the small, non-randomized trial of Masuda and colleagues which used historical controls.31 This trial was performed in Japan and while these results do not preclude a randomized

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Table 12.1

Overview of common chemotherapy agents trialled in metastatic renal cell cancer

Investigator(s)

Agent

Waters et al, 200410 Jones et al, 200411

Capecitabine, gemcitabine Marimastat, captopril, fragmin Gemcitabine, oxaliplatin Capecitabine Pemetrexed Irinotecan 5-FU, FA, oxaliplatin Thalidomide Temozolomide Liposomal doxorubicin Gemcitabine Tegafur, tamoxifen Vinblastine, ciclosporin Continuous 5-FU Docetaxel Topotecan Fotemustine Taxol Bleomycin

Porta et al, 200412 Wenzel et al, 200313 Thodtmann et al, 200314 Fizazi et al, 200315 Bennouna et al, 200316 Minor et al, 200217 Park et al, 200218 Skubitz et al, 200219 De Mulder et al, 199620 Wada et al, 199521 Warner et al, 199522 Kish et al, 199423 Mertens et al, 199424 Law et al, 199425 Lasset et al, 199326 Einzig et al, 199127 Johnson et al, 197528

Patients evaluated

CR

PR

RR (%)

TTP

MS

19 10

0 0

3 1

15.8 10.0

7.6 –

14.2 –

42 38 32 42 59 24 12 12 37 10 16 61 18 14 16 18 20

0 0 0 0 0 0 0 0 1 1 0 1 0 0 0 0 0

6 0 3 0 0 1 0 0 2 3 0 2 0 0 0 0 0

14.3 0.0 9.4 0.0 0.0 4.0 0.0 0.0 8.1 40.0 0.0 5.2 0.0 0.0 0.0 0.0 0.0

2.5 6.5 5.7 2–3 – – – – 3.7 – – – – – – – –

9.5 – – 8–19 10.6 3.5 6.8 – 12.3 – – 12 – – – – –

CR, complete response; PR, partial response; RR, response rate; TTP, time-to-progression in months; MS, median survival in months.

Table 12.2

Studies of adjuvant chemotherapy in renal cell cancer 5-year DFS (%)

Investigator(s)

Agent

Naito et al, 199729 Pizzocaro et al, 198730

UFT; observation Medroxyprogesterone; observation Vinblastine, adriamycin, tegafur Vinblastine, CCNU

Masuda et al, 199231 Kuhbock et al, 198832

Patients evaluated

Treated group

Untreated group

p value

66 120

80.5 67.3

77.1 66.1

NS NS

31

96a

–

N/A

13

76.9b

–

N/A

DFS, disease-free survival. a 5-year overall survival; b3–21 months DFS. Randomized studies in bold.

clinical trial in the Japanese population, the data do not support the routine use of adjuvant chemotherapy in renal cancer.

ADJUVANT RADIOTHERAPY Kjaer et al randomized 72 nephrectomized patients to either adjuvant radiotherapy of 50 Gy in 20 fractions (to renal bed and ipsi- and contralateral lymphnodes) or observation.33 Sixty-five patients were evaluable for outcome, 34 with stage 2 and 31 with stage 3 disease. The

5-year disease-free survival in the radiotherapy group was 53.1% and 60.6% in the observation only group. This absence of benefit is in line with earlier series.34,35 Furthermore, recent analysis of adjuvant radiotherapy compared with historical controls confirms a lack of benefit. Makarewicz et al retrospectively analysed 186 patients who had been nephrectomized for locally advanced disease;36 114 patients also received postoperative radiotherapy of 50 Gy to the renal bed. The difference in 5-year overall and disease-free

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ADJUVANT THERAPY IN RENAL CANCER

Table 12.3

155

Studies of adjuvant and neoadjuvant radiotherapy in renal cell cancer 5-year DFS (%)

Investigator(s)

Regimen

Kjaer et al, 198733

50 Gy in 20 fractions to renal bed, ipsi- and contralateral LN; observation 50 Gy to renal bed; observation 46 Gy to the renal bed and adjacent LN 33 Gy neoadjuvant radiotherapy; observation

Makarewicz et al, 199836 Gez et al, 200237 Juusela et al, 197738

Patients evaluated

Treated group

Untreated group

p value

65

53.1

60.6

NS

186 86

29.5 40a

31.3 –

NS N/A

88

47b

63b

NS

DFS, disease-free survival; LN, lymphnodes. a disease-free 10-year survival. b 5-year overall survival Randomized studies in bold.

survival between the group of patients treated with postoperative radiotherapy and without was 37.9% versus 35.5% and 29.5% versus 31.3%, respectively, which was not statistically significant. Two-thirds of relapses were metastatic, while local relapse was equally distributed between the groups. Gez et al treated 86 patients with various stages of disease by nephrectomy and 46 Gy of adjuvant radiotherapy to the renal bed.37 The 10-year disease-free survival was 40%, which the authors state was similar to historic controls. A single randomized trial of neoadjuvant radiotherapy was reported by Juusela et al who treated 38 patients with 33 Gy preoperative radiotherapy followed by nephrectomy, and 50 patients with nephrectomy alone.38 The survival rate after 5 years follow-up was 47% in the radiotherapy group and 63% in those treated by surgery alone, this difference was not statistically significant. These data indicate that there is no role for either neoadjuvant or adjuvant radiotherapy in renal carcinoma (Table 12.3).

ADJUVANT IMMUNOTHERAPY AND CHEMO-IMMUNOTHERAPY The current standard therapy for stage 4 renal cancer is immunotherapy with interferon α (IFNα), either alone or in combination with interleukin 2 (IL-2) and 5-fluorouracil (5-FU). Despite the only modest improvement in

outcomes in stage 4 disease, most studies have focused on these agents as the prime candidates in the adjuvant setting.

Interferon α Gotoh et al reported a benefit of adjuvant IFNα following radical nephrectomy when comparing 88 Japanese patients with historical controls.39 Most patients had early stage disease, although the population was heterogeneous and included some patients with stage 3 disease. Following surgery, patients received 5 mega-units (MU) IFNα at least five times per week for 4 weeks, and then at least two times per week for up to a year. The disease-free survival was 81% and overall survival was 90% at 5 years of follow-up. The authors commented that in the Japanese population, the expected 5-year disease-free survival would be 65%. Pizzocaro et al also investigated the role of adjuvant IFNα in a randomized trial of stage 2 and 3 patients,40 although about 10% of the patients treated would be reclassified as stage 4 in the current American Joint Committee on Cancer (AJCC) staging system on grounds of a N2 lymph node status.41 A total of 247 patients were allocated to either treatment with IFNα (6 MU three times per week for 6 months by intramuscular injection) following radical nephrectomy and lymphadenectomy or observation. The overall and disease-free survival were 66.0% and 56.7%, respectively,

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Table 12.4

Studies of adjuvant immunotherapy and chemo-immunotherapy in renal cell cancer 5-year DFS (%)

Investigator(s)

Regimens

Gotoh et al, 200439

IFNα: 5 MU 5 ×/week for 4 weeks, then 2 ×/week for a year IFNα: 6 MU 3 ×/week for 6 months; observation IFNα: 12 cycles of 3 MU/m2 D1, 5 MU/m2 D2, 20 MU/m2 D3–5; observation IFNα, vinblastine; observation IFNα, vinblastine; IFNα; observation IL-2: 600 000 U/kg every 8 hours D1–5, D15–19; observation IFNa: 5 MU/m2 D1 week 1 + 4, D1,3,5 week 2 + 3; 10 MU/m2 D1,3,5 week 5-8, IL-2: 10 MU/m2 twice daily D3-5 week 1 + 4, 5 MU/m2 D1,3,5 week 2 + 3, 5-FU 1000 mg/m2 D1 week 5–8; observation

Pizzocaro et al, 200140 Messing et al, 200342

Migliari et al, 199546 Jeon et al, 199947 Clark et al, 200354

Atzpodien et al, 200555

Patients evaluated

Treated group

Untreated group

p value

88

81

–

N/A

247

56.7

67.1%

NS

283

37

41

NS

62 18

82.1a 51b

51.6a 63

NS NS

44

23.8c

34.8c

NS

203

42

49

NS

DFS, disease-free survival; D, day; MU, mega-units. a Approximate 5-year DFS; bresults for both treatment regimens combined; cDFS at interim analysis, when trial was stopped due to lack of efficacy. Randomized studies in bold.

for the treated group and 66.5% and 67.1%, respectively, for controls at 5 years of followup. The differences were not statistically significant, but the authors noted a protective effect of adjuvant IFNα in a small group (n = 13) of IFNα-treated pN2/pN3 patients (equivalent to N2 and stage 4 in the current AJCC classification) compared with stagematched controls (n = 13). Messing et al randomized 283 patients with stage 3 or 4 disease (pT3-4a and/or node-positive, no distant metastasis) to either observation or up to 12 cycles of IFNα.42 All patients underwent radical nephrectomy and lymph node dissection. IFNα was given by intramuscular injection every three weeks, 3 MU/m2 on day 1, 5 MU/m2 on day 2, and 20 MU/m2 on day 3–5. The median follow-up was 10.4 years, and the 5-year disease-free survival was 37% in the interferon arm and 41% in the

observation arm. The 5-year overall survival was 51% in the treatment arm and 62% in the observation arm. These differences were not statistically significant and, importantly, failed to demonstrate a benefit for adjuvant single agent IFNα in very-high-risk patients, unlike the trial reported by Pizzocaro and colleagues40. These findings are consistent with published earlier studies,43–45 all of which fail to show a benefit in outcome of adjuvant IFNα in resected, high-risk renal cell cancer.

Interferon α combined with chemotherapy Two studies have investigated adding vinblastine chemotherapy to IFNα. In the first, by Migliari et al, 30 patients with pT2-T3 N0 M0 renal cell carcinoma received IFNα and vinblastine following radical nephrectomy and

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Table 12.5

157

Trials of novel therapies in renal cell cancer (adjuvant setting) 5-year DFS (%)

Investigator Galligioni et al, 1996

Regimens 59

Kirchner et al, 199560

Repmann et al, 200361 Jocham et al, 200462 Antigenics press release63

7

Adjuvant ASI: 10 tumour cells and 107 BCG × 3; observation Autologous virus modified tumour vaccine; low dose IL-2 and IFNα Autologous tumour cell lysate vaccine × 6; observation Autologous tumour cell lysate vaccine × 6; observation Vitespen every 2 weeks

Patients evaluated

Treated group

Untreated group

p value

120

63

72

NS

208

82.1a

–

N/A

112b

68.2

19.4

< 0.001

379

77.4

67.8

0.0204

604c

89.7

92.8

NS

DFS, disease-free survival; ASI, active specific immunotherapy. a In 56 patients with median follow-up of 39 months; bonly patients with T3 N0 M0 disease; coverall survival January 2006. Randomized studies in bold.

extended lymphadenectomy.46 The results were compared with a control group of 32 patients who underwent surgery alone. The median follow-up was just over 5 years for both groups; 82.1% of treated patients were alive without evidence of disease at the time of publication compared to only 51.6% of patients in the control group. However, this difference was not statistically significant. In a study by Jeon et al, 10 patients with pT3 N0 M0 disease randomly received either IFNα or IFNα with vinblastine following radical surgery.47 The outcome was compared with local historical controls of the same stage (n = 8). In this small study, the authors could not find any benefit from either regimen (Table 12.4). To date, there is no evidence to suggest that adding a cytotoxic agent to immunotherapy improves the disappointing results achieved with IFNα alone.

Interleukin-2 based therapy IL-2 has not been associated with a significant improvement of response in the metastatic setting when compared to IFNα,48–50 although some non-randomized51 and more recently randomized52,104 data suggest that there may be a small subgroup of long-term survivors when high-dose intravenous boluses are used.

In addition, there are data to suggest increased efficacy when it is used in combination with IFNα and 5-FU in patients with metastatic disease.53 There have therefore been a number of trials of IL-2 based therapy in the adjuvant setting. Clark et al randomized 44 patients with pT3b-4 or N1/N2 disease to either IL-2 or observation following nephrectomy.54 The intervention arm received intravenous IL-2 at 600 000 U/kg every 8 hours on days 1–5 and days 15–19 to a maximum of 28 doses. The trial closed early after an interim analysis failed to show any benefit for the IL-2 group with 76.2% of patients relapsing, compared to 65.2% in the observation arm. Atzpodien et al randomized 203 patients with high-risk renal cancer to IL-2, IFNα and 5-FU or observation following radical nephrectomy.55 Combination chemo-immunotherapy was administered according to the previously published regimen in advanced renal cancer by the same group,56 namely subcutaneous IFNα 5 MU/m2 on day 1, weeks 1 + 4 and days 1, 3, and 5, weeks 2 + 3; 10 MU/m2 on days 1, 3, and 5, weeks 5–8; subcutaneous IL-2 10 MU/m2 twice daily days 3–5, weeks 1 + 4 and 5 MU/m2, days 1, 3, and 5, weeks 2 + 3; and intravenous 5-FU 1000 mg/m2 day 1, weeks 5–8. The 2-, 5-, and 8-year survival rates after a median follow-up of 4.3 years were 81%, 58%, and 58%, respectively, in the treatment arm, and

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91%, 76%, and 66% in the observation arm. The survival advantage in the observation arm was statistically significant. The 2-, 5-, and 8-year disease-free survival rates were 54%, 42%, and 39% in the treatment arm, and 62%, 49%, and 49% in the observation arm. These differences were not statistically significant. In addition, subgroup analysis by high-risk T stage (pT3bpT4 and N0 M0), high-risk N stage (N1–2), and resected solitary metastasis did not show any clinical benefit for treatment. Presently in the UK, the HYDRA trial – the continuation of the EORTC 30955 trial – is investigating combination chemoimmunotherapy with IFNα, IL-2, and 5-FU compared to observation only.57 The target accrual is 308 patients, and it aims to close recruitment in late 2006. Several randomized trials have thus addressed the issue of adjuvant immunotherapy for renal cancer, either with IFNα, IL-2, or in combination with chemotherapy. None of these studies demonstrated a clinical benefit to justify the routine use of immuno- or immuno-chemotherapy in the non-metastatic setting in the nephrectomized patient (Table 12.4). Therefore, these patients should not be exposed to the significant toxicities associated with these regimens unless in the setting of a clinical trial.

FUTURE APPROACHES Several novel treatment strategies are showing promise in early clinical trials in patients with advanced renal cancer. Some of these treatments are already finding their way into adjuvant trials in the hope that, finally, we will develop an adjuvant therapy which improves on the outlook for those patients with resected RCC who are at high-risk of relapse.

Cancer vaccines Cancer vaccines are an attractive strategy for adjuvant therapy of any cancer as they are not usually associated with significant toxicity. Cancer antigens have been found in other solid tumours but have proved more elusive in RCC.58 Therefore, in renal cancer, most

vaccine strategies utilized autologous tumour cell preparations (Table 12.5). Galligioni et al randomized 120 patients to receive either ‘active specific immunotherapy’ (ASI) or follow-up post nephrectomy.59 ASI consisted of three intradermal injections of 107 autologous irradiated, devitalized tumour cells mixed with 107 bacillus Calmette-Guèrin (BCG) in the first two vaccinations, and alone for the last. The 5-year disease-free survival was 63% for treated patients and 72% for control patients after a median follow-up of 61 months. The 5-year overall survival was 69% and 78%, respectively. These differences were not statistically significant. Kirchner et al in a similar study compared the outcomes of 208 patients vaccinated with virus-modified tumour vaccines with historical controls and found that the outcome appeared better in the vaccinated group; in a sub-group of 56 patients who were followed up for 2 years or more, the 5-year disease-free survival was 82.1%.60 While these results did not prove a benefit, they nonetheless provided the justification for continued interest in the principle of cancer vaccination in renal cancer.

Autologous tumour cell lysate vaccine (Reinale) In a phase II trial, Repmann et al compared the outcomes of 148 patients post nephrectomy when treated with autologous tumour cell lysate vaccine with 88 patients who did not receive the vaccine.61 The vaccine was prepared by incubating patient’s own tumour cells with IFNγ to increase antigenicity and subsequent devitalization by repeated rapid freezing at −82°C without cryoprotection. It was then given intradermally as six doses at 4weekly intervals. The 5-year overall survival of patients in the vaccine group with stage T3 N0 M0 was 77.5% versus 25% in the control group, and the 5-year disease-free survival was 68.2% in the vaccine group versus 19.4% in the control group. The differences were statistically significant, as they were in T2 N0 M0 patients, although the differences were smaller.

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This was not a randomized trial but based on an interim analysis in 1997,64 these investigators instigated a phase III trial of the same vaccine which reported in 2004.62 The latter randomized 558 patients pre-nephrectomy with T2 3N0 3M0 renal cell tumours, although only 177 patients received vaccine. There were 202 patients in the control group and 179 patients were excluded from the outcome analysis. The primary endpoint was a reduction in the combination of progression and death. The combined rate for tumour progression and tumour-related death was 26% in the vaccine group and 39% in the control group at 5-year follow-up. The 5-year progression-free survival was 77.4% in the vaccine group and 67.8% in the control group. The difference for both endpoints was statistically significant. In a subgroup analysis, the vaccine had a statistically significant benefit in patients with T3 tumours, but not in those with T2 tumours. Despite the very promising results, there are several criticisms of this trial: firstly, the survival analysis in 379 patients was not a true intention-to-treat analysis (ITT), secondly, the authors reported an unusual combined measure of disease progression and death (rather than overall survival), and thirdly, toxicities were reported in a safety population of 553 patients who underwent surgery, therefore efficacy and safety data do not apply to the same cohort of patients. The loss of patients to analysis post nephrectomy with 558 patients randomized but only 379 evaluated is the most serious criticism, particularly since it affected the treatment arm more than the control arm (99 versus 75 excluded, and 5 patients withdrawing consent before surgery). This attrition of patients post randomization could have introduced serious bias to the result.65 A further 36 patients did not receive vaccine as per protocol but were included in the ITT analysis. It has been calculated that, if all randomized patients had been included in the final analysis (but excluding those who had a non-RCC histology), then the progression and death rate would be 30% in the vaccine arm and 39% in the control arm. In

159

response to these criticisms, the authors updated the ITT analysis at the 27th German Cancer Meeting (27. Deutscher Krebskongress) in 2006:66 in this analysis, 477 patients were included: 233 randomized to vaccine (with 134 patients receiving vaccine) and 244 randomized to the control group. Progression-free survival remained significantly better in the vaccine group, but overall survival was not statistically significant between the two groups. However, if analysis was restricted to those patients who actually received vaccine as per protocol, the improvement in overall survival was statistically significant in the vaccine group. Further trials of this vaccine are planned.67

Vitespen (HSPPPC-96, Oncophage) Phase 2 data of vitespen, an autologous tumour derived heat-shock protein polyvalent, in the metastatic setting produced promising results,68 with disease stabilization in a third of patients and a 2-year survival of 30%. Wood et al in 2004 presented feasibility data from an adjuvant phase 3 trial of the 644 patients with M0 renal tumours randomized at that time to either vitespen or observation. It was possible to produce vaccine in 92% of cases and endpoints are disease-free and overall survival.69 So far, outcome data has only been reported in a manufacturer’s press release: of the 728 patients entered into the study, 124 were found to have post-operative residual disease and were excluded from further survival analysis. In the remaining 604 patients, there was a trend towards better disease-free survival and worse overall survival, while in a subgroup analysis of 361 patients at low risk of relapse (stages 1 [high-grade], 2 [high-grade], and stage 3 T1, T2, and T3a [low-grade]), there was a statistically significant improvement in disease-free survival.63 These results are encouraging but need to be subjected to the appropriate peerreview before licensing and routine use in clinical practice can be recommended. Clearly, there remains scope for further definition of the role of vaccination in the adjuvant setting utilizing the above autologous tumour cell lysate vaccine and vitespen, and also other

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Table 12.6

Trials of novel therapies in renal cell cancer (metastatic setting) Progression free survival

Investigator

Regimens

Ratain et al, 200679

Sorafenib 400 mg twice daily; placebo Sorafenib 400 mg twice daily; placebo Sunitinib 50 mg daily for 4 weeks, 2 weeks break Sunitinib 50 mg daily for 4 weeks, 2 weeks break Bevacizumab 10 mg/kg; placebo 50 mg WX-G250 every 1 week for 20 weeks; 50 mg WX-G250 every 1 week × 12

Escudier et al, 200580 Motzer et al, 200685 Motzer et al, 200681 Yang et al, 200382 Mala et al, 200583

Patients evaluated

Treated group

Untreated group

p value

65

23 weeks

6 weeks

< 0.001

769

24 weeks

12 weeks

< 0.001

63

8.7 months

–

NA

106

8.3 months

–

NA

79a

4.8 months

2.5 months

< 0.001

36b

39 months

10 months

0.01

a

Data for 37 patients receiving low-dose bevacizumab not shown; bfour patients had progressive disease before treatment, 32 patients received 12 weeks of treatment, only responders at that point received a further 8 weeks of treatment and constitute the treatment group. Randomized studies in bold.

strategies such as autologous lymphocyte therapy,70 and HLA-A2- and HLA-A3-binding peptide vaccine.71 These treatments may also prove useful in patients with metastatic disease.72–74

Targeted therapies A number of targeted therapies try to exploit specific cellular abnormalities which have been identified as a result of a better understanding of the molecular mechanisms of cancer. Examples include inhibition of the tyrosine kinase c-kit in GIST,75 and Epidermal Growth Factor Receptor (EGFR)-family inhibition in colorectal,76 breast,77 and lung cancer.78 Several of these strategies are finding their way into the management of metastatic RCC (Table 12.6), and it is only a matter of time before they will also be trialled in the adjuvant setting (for a comprehensive review in advanced RCC see Chapter 14).

Sorafenib (BAY 43-9006) Sorafenib was initially developed as a selective inhibitor of the kinase B-raf for the treatment of malignant melanoma. The single agent results in melanoma have disappointed, but

data in metastatic renal cancer have been more promising. Ratain et al treated 202 stage 4 patients in a randomized discontinuation trial where all patients received sorafenib 400 mg twice daily orally for 12 weeks.79 At that point, those with stable disease (n = 65) were randomized to either placebo or continuation of therapy with sorafenib for another 12 weeks, while responders continued open-label sorafenib. In the randomized patients, progression-free survival was significantly longer in the sorafenib treated group (23 weeks) compared to those in the placebo arm (6 weeks) after a total of 24 weeks of treatment. Escudier et al randomized 769 patients with metastatic RCC who had progressed after first line treatment to either sorafenib 400 mg twice orally or placebo.80 The progression-free survival in the treated group was 24 weeks and 12 weeks in the placebo group, which again was statistically significant. Since mutations in B-raf have not been identified in renal cancer it is thought that the activity of sorafenib is explained by its inhibition of kinases such as vascular endothelical growth factor (VEGF) receptor 2 and 3 (VEGFR 2 and 3), FLT-3, and platelet-derived growth factor receptor (PDGFR).

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An adjuvant phase III trial of sorafenib versus placebo in patients with resected primary renal cell carcinoma at high or intermediate risk of relapse (SORCE) is being planned by the NRCI/MRC in the UK.84 This trial aims to randomize over 1500 patients post radical surgery to either sorafenib for 3 years, sorafenib for 1 year or placebo. The endpoints of this trial are disease-free and RCCspecific overall survival (Dr Tim Eisen, personal communication).

Sunitinib (Sutent, SU011248) Two reports suggesting activity in the metastatic setting have recently been published for another orally available multitargeted tyrosinekinase inhibitor, sunitinib. Like sorafenib, it is thought to act through inhibition of PDGFR, VEGFR, and FLT-3. Motzer et al treated 63 patients with advanced predominantly clear cell disease after failure of first line cytokine therapy with cycles of sunitinib 50 mg daily for 4 weeks followed by a 2-week rest period.85 A partial response by RECIST criteria86 was seen in 40% of patients, with stable disease in 27% of patients. The median time-to-progression was 8.7 months, with a median survival of 16 months. The same group conducted a further phase II trial with 106 patients with exclusively clear cell histology but otherwise identical clinical characteristics.81 A partial response was seen in 34% of patients, and 29% of patients had stable disease, the median time-to-progression was 8.3 months, while the median overall survival had not been reached at publication. Sunitinib is currently being trialled in the first line, stage 4 setting in a randomized phase III study comparing it to IFNα.87 The study aims to recruit 690 patients, the primary endpoint is time-to-progression. Should this study confirm the activity of sunitinib, it is likely that it will soon make the leap into the adjuvant trial setting.

Bevacizumab (Avastin) The recent discovery of the role of the von Hippel–Lindau (VHL) tumour suppressor gene and its mutations in renal cancer has led to the

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development of new treatments targeting the downstream abnormalities: the gene product of VHL regulates the breakdown of hypoxiainducible factor (HIF), which, if not broken down, upregulates downstream targets such as VEGF, transforming growth factor and PDGF, and erythropoietin. This paracrine loop causes endothelial cell proliferation, neo-angiogenesis and hypervascularity.88,89 Yang et al reported a trial of bevacizumab, a neutralizing monoclonal antibody against VEGF, in metastatic renal cancer.82 In a randomised phase II trial, 116 patients received either bevacizumab at a dose of 10 mg/kg (n = 39), bevacizumab at 3 mg/kg (n = 37), or placebo (n = 40). Treatment was administered every 2 weeks. There was a significant prolongation of progression-free survival in the high-dose-antibody group (4.8 months) as compared to those receiving placebo (2.5 months). This was not found when the lowdose antibody treatment group was compared to those receiving placebo; 70%, 86%, and 95% of patients had progressed in the highdose, low-dose, and placebo groups, respectively, at 8 months follow-up. These results are clearly encouraging, and while the role of bevacizumab is still being defined in the metastatic setting,90–96 it is already finding its way into adjuvant studies in colon cancer97,98 and will undoubtedly do so in renal cancer in the future.

WX-G250 (Rencarex) Immunization of mice with human renal cell carcinoma homogenates has identified MN/CA IX/G250, an antigen expressed on the surface of RCC cell. This is a transmembrane carbonic anhydrase(CA) which may play a role in the regulation of cell proliferation in response to hypoxic conditions and therefore may also be involved in tumourigenesis and progression. CA-IX is induced constitutively in about 85% of RCC99 but it is absent in most normal tissues with the exception of epithelial cells of the gastric mucosa.100 It is upregulated in RCC-cells incubated with IFN in vitro,101 although its expression seems to decrease with increasing tumour grade and

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stage.102 WX-250 is a human-mouse chimeric monoclonal antibody to CA-IX. In a phase II trial in metastatic RCC, 36 patients were treated weekly with 50 mg WX-G250 for 12 weeks.83 Those patients who responded (n = 10) received a further 8 weeks of treatment. In the responders, the median survival was 39 months, whereas non-responders had a median survival of 10 months. Based on these results, a phase III trial has been started assessing the use WX-G250 in the adjuvant setting.103 This trial aims to recruit 612 patients who have undergone radical nephrectomy plus lymphnode dissection and have no evidence of metastatic spread, and randomizes them to receive either WX-G250 once weekly for 24 weeks or placebo. The endpoints are disease-free and overall survival.

6.

7.

8. 9.

10.

11.

CONCLUSION There are still no adjuvant therapies in routine clinical use which impact disease-free and overall survival in renal cancer. However, there are a number of promising developments that involve vaccination strategies and targeted therapies. The latter in particular appear to be active in patients with metastatic disease and if these initial observations are confirmed in large randomized controlled trials then they will undoubtedly find their way into the adjuvant setting.

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52. McDermott DF, Regan MM, Clark JI et al. Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol 2005; 23: 133–41. Erratum in: J Clin Oncol 2005; 23: 2877. 53. Atzpodien J, Kirchner H, Illiger HJ et al. IL-2 in combination with IFN-alpha and 5-FU versus tamoxifen in metastatic renal cell carcinoma: longterm results of a controlled randomized clinical trial. Br J Cancer 2001; 85: 1130–6. 54. Clark JI, Atkins MB, Urba WJ et al. Adjuvant high-dose bolus interleukin-2 for patients with high-risk renal cell carcinoma: a cytokine working group randomized trial. J Clin Oncol 2003; 21: 3133–40. 55. Atzpodien J, Schmitt E, Gertenbach U et al. Adjuvant treatment with interleukin-2- and interferon-alpha2a-based chemoimmunotherapy in renal cell carcinoma post tumour nephrectomy: results of a prospectively randomised trial of the German Co-operative Renal Carcinoma Chemoimmunotherapy Group (DGCIN). Br J Cancer 2005; 92: 843–6. 56. Atzpodien J, Kirchner H, Jonas U et al. Interleukin2- and interferon alfa-2a-based immunochemotherapy in advanced renal cell carcinoma: a Prospectively Randomised Trial of the German Co-operative Renal Carcinoma Chemoimmunotherapy Group (DGCIN). J Clin Oncol 2004; 22: 1188–94. 57. HYDRA Adjuvant Interleukin-2, Interferon-Alpha and 5-Fluorouracil for Patients with high risk of relapse after surgical treatment for Renal Cell Carcinoma. ISRCTN 16387614; http://www.ncrn. org.uk/portfolio/data.asp?ID=672, accessed 4 July 2006. 58. Michael A, Pandha HS. Renal-cell carcinoma: tumour markers, T-cell epitopes, and potential for new therapies. Lancet Oncol 2002; 4: 215–23. 59. Galligioni E, Quaia M, Merlo A et al. Adjuvant immunotherapy treatment of renal carcinoma patients with autologous tumor cells and bacillus Calmette-Guerin: five-year results of a prospective randomized study. Cancer 1996; 77: 2560–6. 60. Kirchner HH, Anton P, Atzpodien J. Adjuvant treatment of locally advanced renal cancer with autologous virus-modified tumor vaccines. World J Urol 1995; 13: 171–3. 61. Repmann R, Goldschmidt AJ, Richter A. Adjuvant therapy of renal cell carcinoma patients with an autologous tumor cell lysate vaccine: a 5-year follow-up analysis. Anticancer Res 2003; 23: 969–74; Erratum in: Anticancer Res 2003; 23: 5370. 62. Jocham D, Richter A, Hoffmann L et al. Adjuvant autologous renal tumour cell vaccine and risk of tumour progression in patients with renal-cell carcinoma after radical nephrectomy: phase III, randomised controlled trial. Lancet 2004; 363: 594–9.

63. Antigenics announces results from in-depth analysis of phase 3 data of oncophage in kidney cancer and provides regulatory update, 7 June 2006; http://www.antigenics.com/news/2006/0607.phtml, accessed 5 July 2006. 64. Repmann R, Wagner S, Richter A. Adjuvant therapy of renal cell carcinoma with active-specificimmunotherapy (ASI) using autologous tumor vaccine. Anticancer Res 1997; 17: 2879–82. 65. Schulz KF, Grimes DA. Sample size slippages in randomised trials: exclusions and the lost and wayward. Lancet 2002; 359: 781–5. 66. Doehn C, Richter A, Theodor RA et al. Prolongation of progression-free and overall survival following an adjuvant vaccination with Reniale® in patients with non-metastatic renal cell carcinoma: Secondary analysis of a multicenter phase-III trial. http://www .egms.de/en/meetings/dkk2006/06dkk395.shtml# Abstract, accessed 5 July 2006. 67. LipoNova company website, http://www.liponova. de/_f/02_forschung/03_studien.php?country=, accessed 5 July 2006. 68. Assikis J, Daliani D, Pagliaro L et al. Phase II study of an autologous tumor derived heat shock proteinpeptide complex vaccine (HSPPC-96) for patients with metastatic renal cell carcinoma (mRCC). Proc Am Soc Clin Oncol 2003; 22: 386. 69. Wood CG, Escudier B, Gorelov S et al. A multicenter randomized study of adjuvant heat-shock protein peptide-complex 96 (HSPPC-96) vaccine in patients with high-risk of recurrence after nephrectomy for renal cell carcinoma (RCC) – a preliminary report. J Clin Oncol ASCO Annual Meeting Proceedings (Post-Meeting Edition) 2004; 22: 2618. 70. Phase II study of adjuvant autologous lymphocyte therapy in patients with high-risk renal cell carcinoma; http://clinicaltrials.gov/ct/gui/show/ NCT00002589?order=3, accessed 5 July 2006. 71. Phase II study of vaccine comprising HLA-A2- and HLA-A3-binding peptides from fibroblast growth factor-5 emulsified in montanide ISA-51 in patients with stage III or IV clear cell renal cell carcinoma; http: //www.clinicaltrials.gov/ct/gui/show/NCT00091403? order=3, accessed 5 July 2006. 72. Phase II study of b7-1 gene-modified autologous tumor cell vaccine and interleukin-2 in patients with stage IV renal cell carcinoma; http://www.clinicaltrials.gov/ct/gui/show/NCT00031564?order=4, accessed 5 July 2006. 73. Phase II pilot randomized study of vaccination comprising autologous dendritic cells loaded with autologous tumor lysate and keyhole limpet hemocyanin with or without non-myeloablative fludarabine in patients with stage IV renal cell carcinoma; http://www.clinicaltrials.gov/ct/gui/show/NCT00 093522? order=6, accessed 5 July 2006. 74. A randomized phase II study investigating the route of administration of oncophage (HSPPC-96) in

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99. Vissers JL, De Vries IJ, Schreurs MW et al. The renal cell carcinoma-associated antigen G250 encodes a human leukocyte antigen (HLA)-A2.1-restricted epitope recognized by cytotoxic T lymphocytes. Cancer Res 1999; 59: 5554–9. 100. Lam JS, Pantuck AJ, Belldegrun AS et al. G250: A carbonic anhydrase ix monoclonal antibody. Curr Oncol Rep 2005; 7: 109–15. 101. Brouwers AH, Frielink C, Oosterwijk E et al. Interferons can upregulate the expression of the tumor associated antigen G250-MN/CA IX, a potential target for (radio)immunotherapy of renal cell carcinoma. Cancer Biother Radiopharm 2003; 18: 539–47.

102. Uemura H, Nakagawa Y, Yoshida K et al. MN/CA IX/G250 as a potential target for immunotherapy of renal cell carcinomas. Br J Cancer 1999; 81: 741–6. 103. Phase III randomized study of adjuvant chimeric monoclonal antibody cG250 (Rencarex®) versus placebo in patients with primary non-metastatic clear cell renal cell carcinoma at high risk for recurrence after nephrectomy (‘ARISER’ study); http://www.clinicaltrials.gov/ct/show/NCT000870 22?order=1, accessed 5 July 2006. 104. Yang JC, Sherry RM, Steinberg SM et al. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol 2003; 21: 3127–32.

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Current systemic medical therapies for metastatic disease

13

Bernard Escudier, Martin Gore

INTRODUCTION The management of patients with renal cell carcinoma has made considerable progress in recent years, as demonstrated in the other chapters of this book. Early diagnosis has greatly improved due to new imaging techniques such as spiral computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET). The histopathological classification of renal cell carcinoma was reviewed in 2004 and new pathological entities described with the help of molecular markers. These markers will have to be incorporated into future staging systems and this has already been proposed by the University of California at Los Angeles (UCLA) group.1,2 Prognostic factors for both localized and metastatic disease are being refined, allowing for increasing accurate predictors of outcome. The management of patients with localized tumors continues to evolve with less morbid and extensive surgical techniques becoming common place. The treatments available for those with metastatic disease is also changing and there is a move away from cytokine therapy to the so-called targeted agents. In this chapter, we will focus on the current treatments available for patients with metastatic renal cell carcinoma (MRCC).

This practice is based on the results of two randomized trials which showed a statistically significant survival advantage for nephrectomy in those who received interferon for their metastatic disease.3,4 Nephrectomy should be offered to every patient with a good European Cooperative Oncology Group (ECOG) performance status who is to receive immunotherapy. However, some have reported that nephrectomy should not be offered if the metastatic tumour burden is high while that of the primary tumour is relatively low. This suggestion is based on the observation that some patients with their primary tumour in situ can have a good outcome when treated with high-dose interleukin 2 (IL-2).5 Furthermore, the role of cytoreductive surgery in the context of the new targeted therapies needs to be formally assessed. Surgery also plays an important role in MRCC in three other circumstances: • patients with single or localized metastasis in whom surgery can be associated with long-term survival and even cure • patients who have responded to medical treatment and can then obtain a surgical complete response6 • Palliative treatment to improve quality of life, e.g. renal bed recurrence and at some metastatic sites such as bone and brain.7

SURGERY IN MRCC The role of nephrectomy in patients with MRCC has been debated over many past years. Recently, nephrectomy in this situation (cytoreductive surgery) has become the standard of care before systemic treatment is started.

PROGNOSTIC FACTORS Prognostic factors for RCC have been extensively studied in the past decade, and many models for predicting outcome of both localized and metastatic disease have been described.

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Most of these models use histopathological, clinical, and biological variables to allow for the better stratification of patients. The first large prognostic factor study in MRCC was that of Elson and colleagues,8 and since then several groups have described other models.9–11 In all these models three prognostic groups are identified: good, intermediate, and poor, with corresponding survival rates. Prognostic factors for patients with MRCC are currently being studied by an international group, sponsored by the Kidney Cancer Association.12 This new staging system is likely to be available soon and should result in an international consensus on this important topic. However, these prognostic factors are being formulated from patient data derived from the cytokine era and whether the same factors will be applicable to those treated with the new targeted agents remains to be determined. Incorporation of new biomarkers into a new staging system is ongoing. Preliminary data from UCLA suggest that some of these markers such as carbonic anhydrase (CA)-IX and circulating endothelial cells may be relevant.1,2,13 However, the use of these sophisticated factors may be unhelpful to routine practice in the immediate future due to the lack of appropriate, simple to perform, and reproducible assays. In a number of large institutions, tremendous efforts are being made to find biomarkers that accurately reflect clinical outcomes. It will be a number of years before we know whether these efforts are successful.

MEDICAL TREATMENT OF METASTATIC DISEASE

IL-2 therapy despite the great enthusiasm generated by the initial reports from Rosenberg and colleagues.14 In contrast, two randomized trials have demonstrated that IFN improves survival when compared with medroxyprogesterone acetate15 or vinblastine alone.16 A Cochrane review also supports the use of IFN.17 Based on these studies, IFN has became the standard comparator for the evaluation of new treatments in MRCC, even in the USA where only high-dose IL-2 has been approved. In the past decade, various studies have been performed to determine whether a combination of IFN with IL-2 and/or chemotherapy can improve outcomes. Some important studies have been reported on these strategies: • The French group reported that a combination of IL-2 and IFN improves response rates and progression-free survival (PFS) over IL-2 or IFN alone18 and that switching from one cytokine to the other is not useful.19 • The German Group have reported that a triplet combination of IL-2, IFN, and 5-fluorouracil (5-FU) is very active.20 They reported that this combination improves survival versus tamoxifen in one study and IFN plus vinblastine in another.21, 22 • The Cytokine Working Group has run two different randomized studies with highdose IL-2 but neither demonstrated an improvement in overall survival, despite the fact that the response rate and PFS was significantly better with high-dose IL-2.5, 23

Cytokine-based therapy

However, recent studies have been reported which might change the way patients will be offered these treatments.

IL-2 and interferon (IFN) remained the standard treatment for patients with MRCC in 2005. These treatments are still the only approved drugs in most countries although schedule and dosage of these agents may vary. The efficacy of these two drugs, which have now been used for more than 20 years in MRCC, is still controversial. There are no randomized trials that demonstrate an improvement in overall survival with

• Bolus IV IL-2 is the gold standard in the USA. This treatment, despite its toxicity and lack of overall survival benefit in randomized trials, results in longlasting complete remissions in 5–10% of patients.5,23 Based on these considerations, IL-2 should be reserved for patients with a good performance status (PS) and who have other good prognostic features. Recent studies from the

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Cytokine Working Group show that high expression of CA-IX is a good predictor of response to IL-2.13 The same group has also described some pathological features which could further help determine those patients who are likely to benefit from this treatment. A specific study aiming to validate these predictive factors of response will start soon in the USA and might help define a patient group for which high-dose IL-2 is appropriate standard therapy. • A recent study reported at American Society of Clinical Oncology (ASCO) 2005 by the French group24 has studied the role of IL-2 and IFN in the intermediate prognostic group of patients, as defined by these authors.11,18 In this trial, the Percy Quattro study, patients were randomized between medroxyprogesterone acetate, IL-2, IFN, and a combination of both cytokines. This study has failed to demonstrate any survival benefit for treatment with IL-2 and/or IFN over medroxyprogesterone. Thus, continuing to treat this group of patients with cytokines becomes questionable and should be carefully considered on a case by case basis only. • The triple regimen IL2–IFN–5-FU (so called Atzpodien regimen) is still under investigation, because its benefits have not been confirmed by other investigators. A large study is currently ongoing in Europe through the Medical Research Council (MRC) and European Organisation for Research and Treatment of Cancer (EORTC), comparing this triple regimen to IFN alone. If this study shows an overall survival benefit for the triple regimen, then its place as standard of care will need to be considered. If not, then it is unlikely to play any further role in the management of patients. There is general consensus on the use of cytokines in patients with MRCC: • These drugs should not be given to patients with poor prognosis (bad PS, poor risk groups). In these patients, new therapies should be given as first line or they should receive palliative care only.

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• In patients with good prognostic factors, cytokine-based regimens remain the standard of care, either high-dose IL-2 or subcutaneous IL-2 or IFN. • In patients with an intermediate prognosis, the results of the French Percy Quattro study suggest that the new targeted therapies may be appropriate as first-line therapy; however, this proposition needs to be tested. The above consensus might change during 2006/7 with the emerging results from the randomized trials comparing the new targeted agents with cytokine-based therapies in first-line.

Targeted agents Better understanding of the physiology of clear cell carcinoma has led in the past years to a new generation of drugs, aimed at targeting the vascular endothelial growth factor (VEGF) hypoxia-inducible factor (HIF) pathway. These drugs block angiogenesis through their interaction with the VEGF pathway, and can induce either tumour shrinkage, stasis, and/or necrosis, leading to delays in tumour progression. Decreases in tumour vascularization have been observed in patients receiving these compounds, by different radiological techniques including Doppler ultrasound25 and dynamic CT.26 Results from second-line studies with these new agents have been recently reported and they offer new options for patients with MRCC. • Sorafenib (BAY 43-9006) is a multitarget tyrosine kinase inhibitor which interacts with many receptors on the VEGF pathway, mainly VEGF R2 and platelet-derived growth factor (PDGF). This oral drug has shown promising activity and a good safety profile in MRCC in phase I/II. Recently, Escudier et al27 reported the results of a large randomized study in patients in whom a first-line treatment had failed. In this study, 903 patients were randomized between sorafenib and placebo. Tumour shrinkage has been observed in a large majority of patients (> 70%) and PFS was significantly

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improved, from 3 to 6 months (p < 0.0001). Survival data show that patients treated with sorafenib have a 39% increase in overall survival compared with placebo.28 Sunitinib is another multitargeted tyrosine kinase inhibitor which has activity in MRCC. Motzer and colleagues29 reported at ASCO 2005 the results from two consecutive phase II studies in more than 160 patients with MRCC. The patients had failed first-line cytokine based therapy. High response rates (approximately 40%) have been observed in these trials and the median survival is about 16 months. The activity of this promising drug will need to be confirmed through a large phase III trial comparing sunitinib to IFN in untreated patients, and such a trial has already accrued. The results are awaited. Rini and colleagues30 reported at ASCO 2005 on a phase 2 trial of AG013736. This agent produced a response rate of 46% in 52 patients. As with sorafenib and sunitinib, this is a multitargeted oral kinase inhibitor with actions very similar to sunitinib. It also has a good safety profile. The activity of this drug needs to be confirmed in larger randomized studies. Bevacizumab (avastin) is an antibody against VEGF. This drug significantly improves PFS,31 and is currently being tested in combination with IFN in two large randomized studies in patients with untreated MRCC. The combination of bevacizumab and gefitinib (Tarceva) initially resulted in promising data32 but recently a randomized study has been reported as failing to show benefit over bevacizumab alone (Genentech press release, 18 October 2005 on line). Thus, the role of this antibody in MRCC remains to be determined. Temsilorimus (CCI 779) is a mTOR inhibitor, acting directly on HIF production, a driver for the VEGF pathway. Activity of this drug has been reported by Atkins and colleagues in 200433 and has to be confirmed in a large phase III of patients with poor prognosis MRCC which is currently in progress.

CONCLUSIONS The current standard first-line treatment for patients with MRCC remains cytokine based. However, it is anticipated that the new targeted agents will play a significant role in the management of these patients and may even displace the use of cytokines. Should this be the case then it remains to be determined which one will be the preferred agent in this context. Combining these agents, either together or with cytokines, has a strong rationale and many studies are currently investigating such strategies. It is expected that there will be further drugs developed that target other receptors and peptides along the VEGF/HIF pathway and this all adds to the general air of optimism that currently pervades experimental therapeutics as it relates to MRCC.

REFERENCES 1. Kim HL, Seligson D, Liu X et al. Using tumor markers to predict the survival of patients with metastatic renal cell carcinoma. J Urol 2005; 173: 1496–501. 2. Lam JS, Pantuck AJ, Belldegrun AS, Figlin RA. G250: a carbonic anhydrase IX monoclonal antibody. Curr Oncol Rep 2005; 7(2): 109–15. 3. Flanigan RC, Salmon SE, Blumenstein BA et al. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med 2001; 345(23): 1655–9. 4. Mickisch GH, Garin A, van Poppel H, de Prijck L, Sylvester R. European Organisation for Research and Treatment of Cancer (EORTC) Genitourinary Group. Radical nephrectomy plus interferon-alfabased immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet 2001; 358(9286): 966–70. 5. McDermott DF, Regan MM, Clark JI et al. Randomized phase III trial of high-dose interleukin2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol 2005; 23: 133–141. 6. Kavolius JP, Mastorokos DP, Pavlovich C et al. Resection of metastatic renal cell carcinoma. J Clin Oncol 1998; 16(6): 2261–6. 7. Kollender Y, Bickels J, Price WM et al. Metastatic renal cell carcinoma of bone: indications and technique of surgical intervention. J Urol 2000; 164(5): 1505–8. 8. Elson PJ, Witte RS, Trump DL. Prognostic factors for survival in patients with recurrent or metastatic renal cell carcinoma. Cancer Res 1988, 48: 7310–13.

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9. Motzer RJ, Mazumdar M, Bacik J et al. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol 1999; 17(8): 2530–40. 10. Zisman A, Pantuck AJ, Dorey F et al. Mathematical model to predict individual survival for patients with renal cell carcinoma. J Clin Oncol 2002; 20(5): 1368–74. 11. Negrier S, Escudier B, Gomez F et al. Prognostic factors of survival and rapid progression in 782 patients with metastatic renal carcinomas treated by cytokines: a report from the Groupe Francais d’Immunotherapie. Ann Oncol 2002; 13(9): 1460–8. 12. Elson PJ, Manola JB, Mazumdar M et al, for the international kidney cancer working group. Prognostic factors for survival in patients with metastatic renal cell carcinoma: a study from the Kidney Cancer Association’s International Kidney Cancer Working Group (IKCWG). J Clin Oncol 2005; 23: 386s (abstract 4533). 13. Upton MP, Parker RA, Youmans A, McDermott DF, Atkins MB. Histologic predictors of renal cell carcinoma response to interleukin-2–based therapy. J Immunother 2005; 28(5): 488–95. 14. Rosenberg SA, Lotze MT, Muul LM et al. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Eng J Med 1985; 313: 1485–92. 15. MRC trial. Interferon-alpha and survival in metastatic renal carcinoma: early results of a randomised controlled trial. Medical Research Council Renal Cancer Collaborators. Lancet 1999; 353(9146): 14–17. 16. Pyrhonen S, Salminen E, Ruutu M et al. Prospective randomized trial of interferon alfa-2a plus vinblastine versus vinblastine alone in patients with advanced renal cell cancer. J Clin Oncol 1999; 17(9): 2859–67. 17. Coppin C, Porzsolt F, Kumpf J, Coldman A, Wilt T. Immunotherapy for advanced renal cell cancer. Cochrane Database Syst Rev 2005; 1: CD001425. [Review] 18. Negrier S, Escudier B, Lasset C et al. Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Francais d’Immunotherapie. N Engl J Med 1998; 338(18): 1272–8. 19. Escudier B, Chevreau C, Lasset C et al. Cytokines in metastatic renal cell carcinoma: is it useful to switch to interleukin-2 or interferon after failure of a first treatment? J Clin Oncol 1999; 17: 2039–43. 20. Lopez Hänninen E, Kirchner H, Atzpodien J. Interleukin-2 based home therapy of metastatic renal cell carcinoma: risks and benefits in 215 consecutive single institution patients. J Urol 1996; 155: 19–25. 21. Atzpodien J, Kirchner H, Illiger HJ et al. IL-2 in combination with IFN-alpha and 5-FU versus tamoxifen in metastatic renal cell carcinoma: long-term results

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of a controlled randomized clinical trial. Br J Cancer 2001; 85(8): 1130–6. Atzpodien J, Kirchner H, Jonas U et al. Interleukin-2and interferon alfa-2a-based immunochemotherapy in advanced renal cell carcinoma: a Prospectively Randomized Trial of the German Cooperative Renal Carcinoma Chemoimmunotherapy Group (DGCIN). J Clin Oncol 2004; 22(7): 1188–94. Yang JC, Sherry RM, Steinberg SM et al. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol 2003; 21(16): 3127–32. Négrier S, Perol D, Ravaud A et al. Do cytokines improve survival in patients with metastatic renal cell carcinoma (MRCC) of intermediate prognosis? Results of the prospective randomized PERCY Quattro trial. J Clin Oncol 2005; 23: 380s (abstract LBA4511). Lamuraglia M, Escudier B, Chami L et al. To predit progession-free survival and overall survival in metastatic renal cancer treated with sorafenib: Pilot study using dynamic contract-enhanced Doppler ultrasound. Eur J Cancer. 2006 Oct; 42(15): 2472–9. Rixe O, Meric J, Bloch J et al. Surrogate markers of activity of AG-013736, a multi-target tyrosine kinase receptor inhibitor, in metastatic renal cell cancer (RCC). ASCO Meeting Abstracts 1 June 2005: 3003. Escudier B, Eisen T, Stadler WM et al. A phase III trial of sorafenib for advanced clear-cell renal cell carcinoma. N Engl J Med, in press. Escudier B, Szczylik C, Eisen T et al. Randomized phase III trial of the multikinase inhibitor sorafenib (BAY43-9006) in patients with advanced renal cell carcinoma (RCC). Eur J Cancer 2005; 3: 226 (Abstract 794). Motzer RJ, Michaelson MD, Redman BG et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 2006, 24(1): 16–24. Rini B, Rixe O, Bukowski R et al. AG-013736, a multitarget tyrosine kinase receptor inhibitor, demonstrates anti-tumor activity in a Phase 2 study of cytokine-refractory, metastatic renal cell cancer (RCC). ASCO Meeting Abstracts 1 June 2005: 4509. Yang JC, Haworth L, Sherry RM et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003; 349(5): 427–34. Hainsworth JD, Sosman JA, Spigel DR et al. Treatment of metastatic renal cell carcinoma with a combination of bevacizumab and erlotinib. J Clin Oncol 2005; 23(31): 7889–96. Atkins MB, Hidalgo M, Stadler WM et al. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 2004; 22(5): 909–18.

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Novel systemic therapies for metastatic disease

14

James MG Larkin, Tim Eisen

INTRODUCTION Response rates to combination chemotherapy1 and to hormonal agents2 in metastatic renal cell carcinoma (RCC) are only 5–10%. It has been known for some time that the immune system has a role in the natural history of RCC. For example, spontaneous regressions are rare but well described3,4 and immunotherapy with interferon (IFN) in metastatic disease produces response rates in the range of 10–20% with median response durations of 3–16 months.5 Randomized controlled trials have shown a survival advantage to IFN compared to non-immunotherapy.6,7 Treatment with high-dose intravenous interleukin-2 (IL-2) causes substantial toxicity but in non-randomized trials approximately 9% of patients with metastatic RCC will have a complete response (CR) to treatment and in 70–80% of these patients the responses are prolonged.8 There may therefore be a role for high-dose IL-2 in selected patients with metastatic RCC and good performance status. In summary, immunotherapy for metastatic RCC has poor response rates and significant toxicity but offers the prospect of prolonged complete remission or cure. Careful patient selection for such therapy is critical: some data suggest that high tumour carbonic anhydrase IX9 expression is predictive of significantly prolonged median survival after IL-2 therapy and this antigen therefore may be a useful biomarker.

NOVEL AGENTS There is a need for better treatments for metastatic RCC given the modest efficacy and

potentially significant toxicity of standard treatments. Novel treatment approaches, including those which are immunotherapeutic, cytotoxic, anti-angiogenic, and kinase inhibitor targeted, will be reviewed here.

Immunotherapy The established role of immunotherapy in the treatment of metastatic renal cell carcinoma has led to the continued investigation of therapeutic strategies designed to augment anti-tumour immunity. Vaccination, allogeneic stem cell transplantation and anti-cytokine therapy will be reviewed here.

Vaccines The use of vaccines to generate an enhanced immune response against infectious diseases is arguably the greatest achievement of medicine in the 20th century. Vaccination against cancer is intuitively appealing but the identification of tumour-specific antigens and the generation of effective immune responses against such antigens has been difficult. A particular problem is that tumour antigens may vary both between different types of cancer and between patients with the same type of cancer. This problem may be circumvented in principle by vaccinating a patient with their own tumour after appropriate manipulation. Many vaccination strategies have used dendritic cells (DCs) to present tumour antigens to the immune system. DCs are potent antigen presenting cells that when manipulated to express tumour antigens have been shown in

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Allogeneic stem cell transplantation (allo-SCT) has a proven role in the treatment of some haematological malignancies, but its application remains experimental in the treatment of solid tumours. The efficacy of allo-SCT is due to T lymphocyte reactivity against tumour cells; T cell reactivity is also responsible for graft versus host disease (GVHD), a common outcome from allogeneic transplantation that is associated with significant morbidity. Six phase II trials of allo-SCT in metastatic renal cell carcinoma with response rates between zero and 56% and treatment-related mortality up to 33% have been reported.18–23 It should also be noted that any response to therapy is delayed so tumour growth may grow unchecked for several months. The complexity and toxicity of alloSCT mean that this approach remains confined to clinical trials in RCC at the current time.

and meningitis (n = 1). Steroids were used to treat autoimmune enteritis, and one patient underwent colectomy for perforation while in the others the condition resolved. Six partial responses to therapy were recorded (RR = 15%) of which 5/6 were in a higher dose cohort (n = 20 total) for a response rate of 25% (5/20) in that cohort and 5% (1/21) in a lower dose cohort. Interestingly, all six responding patients were among the 12 patients showing autoimmune manifestations with no responses in the other 29 patients (p = 0.0002). The authors conclude that CTLA4 blockade using the MDX-010 antibody can induce the regression of metastatic RCC and that these regressions are associated with clinical autoimmune events. A second anti-CTLA4 antibody, CP-675,206, has been studied in metastatic melanoma (n = 34 patients) and renal cell carcinoma (n = 4 patients) in a phase I trial.25 Although the primary objective of the trial was to determine the maximum-tolerated dose and the recommended phase II dose, there were two complete responses (maintained for 34+ and 25+ months), and two partial responses (26+ and 25+ months) among 29 patients with measurale melanoma but none among the patients with RCC. There had been no relapses after objective responses to therapy at the time the study was published. Doselimiting toxicities included panhypopituitarism, diarrhoea, dermatitis, vitiligo, and hyperthyroidism. Although no responses were noted in the patients with RCC, this study demonstrates the safety of this approach and the results of larger trials are awaited.

Anti-CTLA4

Anti-TNFα

The cytotoxic T lymphocyte-associated antigen 4 (CTLA4) is an inhibitory receptor, inactivation of which can cause lymphocyte activation and the augmentation of antitumour immunity. MDX-010, a human IgG1 antibody to CTLA4 has been studied in a phase II trial in metastatic renal cell carcinoma in which 41 patients were treated.24 Significant autoimmune toxicities were reported in 12 patients: enteritis (n = 9), hypophysitis (n = 2),

Tumour necrosis factor α (TNFα) is a proinflammatory cytokine that may have a role in the pathogenesis of metastatic RCC via autocrine and paracrine stimulation. Infliximab is a chimeric human/mouse monoclonal antibody against TNFα used in the treatment of inflammatory diseases such as Crohn’s disease and rheumatoid arthritis.26,27 Infliximab has been studied in a small phase II trial in metastatic RCC after failure of

preclinical models to induce anti-tumour immunity.10 Furthermore, safety and limited efficacy of DC-based vaccine strategies have been demonstrated in small phase I and II studies in metastatic renal cell carcinoma11–15 and phase III data are awaited with interest. The heat-shock protein-based vaccine HSPPC-96 is an autologous, polyvalent vaccine produced from resected cancer tissue. A phase II trial has shown the safety and tolerability of this approach16 and a phase III trial comparing HSPPC-96 versus observation in patients with renal cell carcinoma at high risk for recurrence after nephrectomy is currently recruiting.17

Allogeneic stem cell transplantation

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immunotherapy.28 Infliximab was administered intravenously at week 0, 2, 6, 14, 22, and 30 at a dose of 5 mg/kg. Fifteen patients were evaluable for toxicity and response at the time of reporting. Median follow-up was 172 days (range 29–269) and median age was 57 years. Two patients (12%) achieved a partial response (PR) at 14 and 30 weeks and 1 late response (15 weeks) was observed following initial progressive disease at 6 weeks. Median progression-free survival was 56 days (95% CI 37 to 75). The only significant toxicity was one episode of grade 3 hypersensitivity. The authors conclude that infliximab is safe and active in RCC.

Cytotoxic therapy Ixabepilone (BMS-247550) Ixabepilone is an epothilone, a novel class of cytotoxic agents with a similar mechanism of action to paclitaxel, but with the potential advantage of activity in taxane-resistant settings in preclinical models.29 Ixabepilone is administered intravenously in Cremophor (polyethoxylated castor oil) with prophylactic antihistamines to prevent hypersensitivity reactions. Daily, weekly, and three weekly dosing schedules of ixabepilone have been reported in peer-reviewed journals30–34 and in abstract form.35,36 Neuropathy, neutropenia, fatigue, myalgia/arthralgia, diarrhoea, and stomatitis were the most common toxicities reported. Neuropathy and neutropenia were the dose-limiting toxicities although neuropathy was less common on the daily schedules than the weekly or 3-weekly schedules. Ixabepilone has demonstrated relatively broad-spectrum anti-tumour activity in phase II trials including a response rate of 14% in advanced clear cell renal carcinoma.37 This result needs confirmation and suggests that there may be a role for epothilones in the therapy of renal cell carcinoma.

Antiangiogenic therapy Judah Folkman proposed antiangiogenesis in 1972 as a ‘new concept for therapy of solid

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tumours’.38 Without functional vasculature, tumours rely on diffusion for nutrients and waste product excretion and growth over 1–2 mm3 cannot occur. Tumour vasculature in principle constitutes an attractive therapeutic target for a number of reasons. First, it is a universal component of solid tumours. Second, effects on a relatively small number of vascular cells should lead to an amplification of effect on tumour cells as large numbers of tumour cells are generally reliant on a smaller number of vascular cells. Lastly, tumour vasculature is generally regarded as a genetically stable tissue conscripted by the release of proangiogenic factors such as VEGF (vascular endothelial growth factor) to support genetically unstable malignant tissue. The relative genetic stability of stromal tissue in comparison with tumour tissue may make the acquisition of resistance to treatment less common than is the case with tumour cells.39 Antiangiogenic treatments may also work by producing a morphologically and functionally ‘normalized’ vascular network, allowing easier access for other therapeutic agents.40,41 Many of the multitargeted kinase inhibitors may exert a therapeutic effect via antiangiogenesis and this class of drugs will be reviewed separately (see section below). Thalidomide and the anti-VEGF monoclonal antibody bevacizumab will be reviewed here.

Thalidomide Thalidomide has been investigated in the treatment of several different tumour types and exerts activity through a variety of mechanisms such as the inhibition of cytokines, the blocking of angiogenesis, the promotion of T cell responses and the modulation of cell adhesion molecule expression. When given at a low dose of 100 mg orally once a day in the treatment of metastatic RCC, thalidomide is relatively well tolerated with grade 1–2 fatigue as the main toxicity.42 Attempts to administer higher doses of thalidomide have been limited by significant constipation, fatigue, and peripheral neuropathy such that only 40% of 25 patients in one study were able to reach the

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target dose of 600 mg daily.43 At least nine phase II studies of thalidomide as a single agent in metastatic RCC have been reported44 with a median response rate of 7% (range 0–17%). Furthermore, a randomized phase II study in 60 patients compared medroxyprogesterone acetate at a dose of 300 mg per day with escalating doses of thalidomide from 100 mg to 400 mg per day.45 No objective responses to treatment were seen in either arm and no difference in median overall survival was reported between treatment arms. Toxicity was significant in the thalidomide arm and only 30.8% of patients reached a dose of 400 mg. Based on these data, thalidomide does not appear superior to medroxyprogesterone acetate in metastatic RCC and has significant toxicity. Thalidomide has been administered with other agents in the treatment of metastatic RCC. The addition of thalidomide to IFN-α does not result in improved response rate, progression-free or overall survival in comparison with IFN-α alone although toxicity in terms of fatigue, thromboembolic events and myelosuppression is greater.46 Thalidomide has also been combined with IL-2 and with capecitabine and 5-fluorouracil in phase II studies with limited efficacy but significant toxicity. The combination of thalidomide and low-dose bevacizumab does not result in any responses to therapy and progression-free survival is similar to that reported with bevacizumab alone.47

Bevacizumab Bevacizumab is a monoclonal antibody directed against (VEGF), an important regulator of the physiological and pathological formation of new blood vessels, i.e. angiogenesis.48,49 When administered intravenously in combination with irinotecan, 5-flourouracil, and leucovorin, bevacizumab results in a statistically significant, and clinically meaningful, prolongation in survival for patients with metastatic colorectal cancer from 15.6 to 20.3 months versus chemotherapy alone.50 Promising data have also been reported in other solid tumour

types.51–53 Bevacizumab has been evaluated in metastatic RCC as monotherapy in a randomized phase II trial in which doses of 3 mg/kg and 10 mg/kg every 2 weeks were compared with placebo.54 Response rate and time to progression (TTP) were the primary endpoints; an interim analysis after 110 patients were randomized showed a significant prolongation of TTP in the higher-dose group (4.8 versus 2.5 months, hazard ratio (HR) 2.55, p < 0.001). The trial was stopped early on the basis of this result although only four responses to treatment occurred (response rate 10%, all in the higher-dose arm) and no survival benefit was demonstrated. Bevacizumab was generally well tolerated with hypertension and asymptomatic proteinuria the principal side effects.

Kinase inhibitor therapy Kinase inhibitors are small molecule drugs that inhibit tyrosine kinases (TKs). Tyrosine kinases catalyse the transfer of γ-phosphate groups to tyrosine residues on target polypeptides or proteins from adenosine triphosphate (ATP). The phosphorylation of proteins such as signalling molecules is often an activating event that in tumours can cause increased cellular proliferation, prevent apoptosis, and promote metastasis and angiogenesis. Tyrosine kinases can be classified as receptorand non-receptor-kinases (Figure 14.1). Receptor TKs such as the epidermal growth factor receptor (EGFR/ERBB1) span the cell membrane and transduce signals from the exterior to the interior. Multiple intracellular downstream signalling pathways55 such as RAS/RAF/MEK/ERK (MEK, mitogen-activated protein kinase kinase; ERK, extracellular signal-related kinase), protein kinase C (PKC) and PI3K (phosphoinositol 3′-kinase) may be activated by ligand binding. Non-receptor TKs such as c-ABL relay intracellular signals and can be activated for example by phosphorylation by other kinases. TKs can be dysregulated in cancer in a number of ways. The classic example is BCRABL in chronic myelogenous leukaemia which occurs as a result of the balanced (9;22)

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Ligand

Receptor

c-KIT

Cell membrane

Effector/ adaptor

FIt-3 PDGFR

RAS BRAF V600E BRAF CRAF

VEGFR2 VEGFR3 Axitinib

Sorafenib

RAF

MEK

Sunitinib Sorafenib ERK

Proliferation, angiogenesis, metastasis Figure 14.1 Schematic representation of the action of selected tyrosine kinase inhibitors in renal cell carcinoma. Note that axitinib, sorafenib and sunitinib inhibit receptor tyrosine kinases and that sorafenib also inhibits RAF family non-receptor tyrosine kinases. See text for abbreviations.

chromosomal translocation. This translocation causes the production of the non-receptor TK BCR-ABL fusion protein: a domain in BCR overcomes the autoinhibition of ABL, causing constitutive TK activation. A second mechanism of TK dysfunction in malignant cells is via increased sensitivity of a receptor to a ligand, e.g. EGFR mutations in some non-small cell lung cancers that alter receptor signalling.56,57 A further mechanism is a result of the overexpression of a tyrosine kinase or its ligand, e.g. EGFR, VEGFR or platelet-derived growth factor receptor (PDGFR) in renal cell carcinoma.58–70 The use of the kinase inhibitors axitinib, sorafenib, sunitinib and temsirolimus for the treatment of metastatic RCC will be reviewed here.

Axitinib (AG-013736) Axitinib is an oral inhibitor of the receptor tyrosine kinases VEGFR1, VEGFR2, PDGFR and c-KIT (Table 14.1 and Figure 14.1) given

at a dose of 5 mg twice daily.71 Three partial responses to treatment were reported in a phase I trial, of which two were in patients with renal cell carcinoma. Interestingly, one of the responding patients stopped axitinib after a year of therapy to be considered for the surgical excision of lung metastases. Four weeks later, the disease had progressed to such an extent that surgery was no longer possible and axitinib was restarted, resulting in renewed tumour shrinkage. A phase II study of axitinib in metastatic renal cell carcinoma was recently reported in abstract form.72 Fifty-two patients entered the study; eligibility criteria included failure of one prior cytokinebased therapy. A partial response to treatment was reported in 21 patients (40%). With a median follow up of one year, only one patient with a PR had relapsed (after 232 days of therapy). Reported grade 1 or 2 toxicities were nausea (29%), fatigue (29%), diarrhoea (27%), hoarseness (19%), anorexia (17%), and weight loss (15%). Hypertension was

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Table 14.1

Tyrosine kinase inhibitors in clinical trials in renal cell carcinoma: Summary

Agent Axitinib (AG-013736) Sorafenib (BAY 43–9006) Sunitinib (SU011248) Temsirolimus (CCI-779)

Target

Trial phase

VEGFR1, VEGFR2, PDGFR, c-KIT

2

VEGFR2, VEGFR3, PDGFR, FLT-3, c-KIT, CRAF, wtBRAF, V600E BRAF

2, 3

VEGFR2, PDGFR, FLT-3, c-KIT

2, 3

mTOR

2, 3

See text for abbreviations.

reported in 17 patients (33%); 12% of patients had grade 3 or 4 hypertension and 6% of patients had aggravated hypertension.

Sorafenib (BAY 43-9006) Sorafenib was designed as an inhibitor of the non-receptor serine threonine kinases BRAF and CRAF. The BRAF and CRAF kinases are members of the RAF/MEK/ERK intracellular signalling cascade, a downstream effector of RAS, which can be activated in turn by cell surface receptor tyrosine kinases. Activation of the RAF/MEK/ERK cascade leads to changes in cellular metabolism, transcription and the intracellular cytoskeleton.73 This pathway is also known to be involved in the survival and proliferation of tumour cells and is a therapeutic target in cancer.74 It is not clear, though, if dysfunction of the RAF/MEK/ERK cascade is important in RCC, although there are some data to suggest that it may be relevant.75,76 Sorafenib also inhibits a number of receptor TKs in cell-free assays known to be involved in tumorigenesis and angiogenesis such as VEGFR2, VEGFR3, Flt-3, c-KIT, and PDGFR (Table 14.1 and Figure 14.1).77 Furthermore, sorafenib inhibits the BRAF mutant V600E which is present in greater than 50% of malignant melanomas78 but has not been reported in RCC.79 The recommended phase II dose of sorafenib was 400 mg twice daily continuously on the basis of four phase I studies in 163 patients.80–83 Seven patients with RCC were

treated in these studies; there was one partial response of 104 days duration82 and 5 patients had stable disease80 (including 1 patient for almost 2 years). The results of a multicentre phase II randomized discontinuation trial (RDT) of sorafenib in RCC were reported recently.84 All histological subtypes were eligible for trial entry and most patients received sorafenib as second-line (56%) or third-line (34%) therapy. All patients were of European Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1 and 56% had undergone nephrectomy. Sixty-five patients with stable disease (response between 25% tumour growth and 25% tumour reduction) after 12 weeks on sorafenib were randomized to sorafenib (n = 32) or placebo (n = 33). After 24 weeks, 16 patients (50%) on sorafenib were progression-free compared with 6 patients (18%) on placebo (p = 0.0077). Median progression-free survival (PFS) after randomization was greater with sorafenib than placebo (24 versus 6 weeks, p = 0.0087). Sorafenib was restarted in 28 patients who progressed on placebo after a median time of 7 weeks from randomization. Median PFS after restarting sorafenib in these patients was 24 weeks. The most common drug-related toxicities were fatigue, rash, and hand–foot skin reaction. The investigators concluded that sorafenib has a marked effect on progression-free survival in metastatic RCC with an acceptable toxicity profile. A randomized phase II trial comparing sorafenib with interferon in the first-line setting for metastatic is currently underway.85

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The interim results of a multicentre phase III randomized placebo-controlled doubleblind trial of sorafenib in advanced RCC in patients who had progressed after 1 prior systemic therapy have also been reported in abstract form.86 Subjects of PS 0 or 1 were randomized to receive sorafenib 400 mg twice daily or placebo and best supportive care. The co-primary endpoints of the trial were overall survival (OS) and progression-free survival. At the time of the progression-free survival analysis, 769 of the planned 884 patients had been randomized and 342 events had been reported. Baseline prognostic characteristics were similar between both groups; 93% of patients had undergone nephrectomy and 82% had received prior cytokine therapy. Median progression-free survival was 24 weeks for the sorafenib versus 12 weeks for the placebo arm (HR 0.44; p < 0.000001) and the 12-week progression-free rate was 79% for the sorafenib versus 50% for the placebo arm. Toxicities reported for sorafenib versus placebo were rash (34% versus 13%), diarrhoea (33% versus 10%), hand–foot skin reaction (27% versus 5%), fatigue (26% versus 23%) and hypertension (11% versus 1%). Grade 3 or 4 adverse events were reported in 30% of patients on sorafenib versus 22% of patients on placebo. Response data from the trial were updated in an oral presentation.87 Nine-hundred and three patients had been enrolled by the data cut-off of 31 May 2005. At this time, there had been one CR to treatment (in the sorafenib arm) and 51 PRs (43 (10%) in the sorafenib arm versus 8 (2%) in the placebo arm). Stable disease was reported in 333 patients on sorafenib versus 239 patients on placebo (74% versus 53%) and progressive disease in 56 patients on sorafenib versus 167 on placebo (12% versus 37%). Many patients with stable disease on sorafenib group had tumour shrinkage insufficient to meet the response evaluation criteria in solid tumours (RECIST) criteria for partial response and continued follow-up is needed to determine the significance of this observation. Preliminary OS data from a planned interim analysis were presented

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after 220 events. Median OS in the placebo group was 14.7 months and had not been reached in the sorafenib group (HR 0.72, p = 0.018). The threshold for statistical significance for this interim analysis was p < 0.0005. As of 31 May 2005, placebo patients were permitted to crossover to sorafenib treatment. By 30 November 2005, 216 of 452 patients88 on placebo had crossed over and there had been 367 deaths (171 in the sorafenib arm and 196 in the placebo arm). Median overall survival at this point was 15.9 months in the placebo and 19.3 months in the sorafenib arm (HR 0.77, p = 0.015). The threshold for statistical significance for this interim analysis was p < 0.0094 and as such the results are not yet statistically significant. It should also be noted that the increase in overall survival in the placebo arm between interim analyses is consistent with a treatment effect due to sorafenib in the intention-to-treat analysis. The final analysis of overall survival will be performed after 540 events.

Sunitinib (SU011248) Sunitinib is administered orally and inhibits the receptor tyrosine kinases VEGFR2, PDGFR, FLT-3, and c-KIT (Table 14.1 and Figure 14.1).89,90 Sunitinib has shown single agent activity in gastrointestinal stromal tumours (GISTs) after failure of imatinib therapy and in acute myeloid leukaemia.91,92 Two phase I studies have established a dose of 50 mg once a day for 4 weeks followed by a 2week break as the recommended phase II dose.92,93 Doses up to 59 mg/m2 have been administered with dose-limiting toxicities of grade 3 fatigue, grade 3 hypertension and grade 2 bullous skin toxicity. Hair discoloration and yellow coloration of the skin were also noted at higher doses. In one trial, only patients with acute myeloid leukaemia were treated.92 Two patients in this study (out of 15) experienced fatal bleeding from a concomitant non-small-cell lung cancer and from intracerebral bleeding. Both of these adverse events occurred at a dose of 50 mg and neither were explained completely by thrombocytopenia.

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In the other trial,93 there were 6 (out of 28) responses to treatment. Three of the responses occurred in patients with RCC. Two independent multicentre single arm phase II trials of sunitinib in metastatic RCC have been reported. The first trial94 recruited 63 patients and the second trial95 recruited 106 patients; eligibility for both trials included failure of one previous cytokine therapy. Twentythree patients (36%) in the first trial achieved a partial response and 17 (27%) had stable disease for at least 3 months. Twenty-two of the responding patients had clear cell histology (of 55 patients in the trial with clear cell histology) and one had papillary histology (of 4 patients in the trial with non-clear cell histology). Median time to progression in the 63 patients was 54 weeks. Fatigue was the commonest adverse event; 27% of patients had grade 2 and 11% of patients had grade 3 fatigue. All other grade 3 clinical adverse events had an incidence of less than 5% while grade 2 diarrhoea, nausea, constipation, dyspepsia, stomatitis, or vomiting was reported in approximately 10–20% of patients. Onehundred and five patients in the second trial were assessable for response at the time of reporting, 27 (25%) of whom had at least a 30% decrease in tumour size. The high response rates and generally manageable toxicity profile of sunitinib as second-line therapy reported in these trials have prompted a phase III trial of sunitinib versus interferon as first-line therapy for metastatic RCC.96 Seven-hundred and fifty patients were randomized to interferon or sunitinib in this phase III study. Patients received sunitinib at standard dose and schedule or interferon at a dose of 9 MU three times a week. The primary endpoint of the trial was progression-free survival and all patients had clear cell histology and PS 0 or 1. Over 90% of patients had favourable or good prognosis and 90% had had prior nephrectomy. The response rate to sunitinib was 31% and to interferon 6% (p < 0.000001) with a further 47% of patients on sunitinib undergoing disease stabilization in contrast to 57% on interferon. Progressive disease was reported in 16% of patients on

sunitinib and 34% of patients on interferon. The median progression-free survival was 11 months (95% CI 10 to 12) on sunitinib versus 5 months (95% CI 4 to 6) on interferon (HR 0.415, p < 0.000001). The median overall survival had not been reached at the time of reporting for either drug. Toxicity was similar in both groups except that 5–10% of patients in the sunitinib group had grade 3 or 4 hypertension, diarrhoea or hand–foot syndrome. Grade 3 or 4 neutropenia and thrombocytopenia were also more common in the sunitinib group, occurring in about 10% of patients. The authors conclude that sunitinib is a new reference standard for the firstline treatment of metastatic RCC and that mechanism-directed therapy based on tumourspecific molecular features is validated.

Temsirolimus (CCI-779) Temsirolimus (CCI-779) is an mTOR (mammalian target of rapamycin) inhibitor (Table 14.1). The mammalian target of rapamycin is a non-receptor tyrosine kinase; mTOR activation has various downstream effects including increasing hypoxia-inducible factor (HIF)-1α gene expression at the levels of both mRNA and protein.97 Furthermore, reduced PTEN (phosphatase and tensin homologue deleted on chromosome 10) expression has been demonstrated in a proportion of RCCs.98,99 Loss of PTEN function results in Akt phosphorylation with downstream effects on cell survival, growth, and proliferation that may be blocked using rapamycin derivatives100 in this specific subset of tumours. As a result, inhibition of mTOR activation is a rational therapeutic strategy in RCC. Temsirolimus was administered as a weekly intravenous infusion over 30 minutes at doses between 7.5 mg/m2 and 220 mg/m2 in a phase I study.101 Adverse events were manageable and reversible at all doses tested and a partial response to treatment was reported in one patient with clear cell renal carcinoma. Based on these results, but not on classical definitions of maximum-tolerated dose, temsirolimus has been evaluated in a phase II study in metastatic RCC

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in 111 patients who were randomly assigned to receive 25, 75 or 250 mg of the drug as a weekly intravenous infusion.102 Over 90% of patients had had prior systemic therapy. One complete response, 7 partial responses (response rate = 7%), and 29 minor responses (26%) to treatment were reported. Just over half of patients (51%) had a response to treatment or stable disease for over 24 weeks. The most frequent grade 3 or 4 toxicities were hyperglycaemia (17%), hypophosphataemia (13%), anaemia (9%), and hypertriglyceridaemia (6%). Neither toxicity nor efficacy was significantly influenced by temsirolimus dose level. The results of a randomized three-arm phase III study comparing temsirolimus, IFN and the combination of the two agents in the first-line treatment of poor risk patients with metastatic RCC were reported recently.103 Patients had a Karnofsky PS of 60 or greater and at least 3 of the following poor-risk features: lactate dehydrogenase (LDH) greater than 1.5 times the upper limit of normal, haemoglobin less than the lower limit of normal, corrected calcium > 10 mg/dL (> 2.50 mmol/L), time from diagnosis to first treatment < 1 year, Karnofsky PS of 60–70 and multiple organ sites of metastases. Six-hundred and twenty-six patients were treated in the study, over 80% of whom had a Karnofsky performance status of 60–70. IFN was administered at 18 MU three times a week as a single agent and temsirolimus at 25 mg/m2 once a week as a single agent. In the combination therapy arm, IFN was given at 6 MU three times a week and temsirolimus at 15 mg/m2. Response rates were similar in all three arms and ranged between 7% and 11% but overall survival was statistically significantly longer in the temsirolimus single agent arm in comparison with the other two arms (10.9 months for temsirolimus, 7.3 months for IFN and 8.4 months for the combination, HR 0.73, p = 0.0069 for single agent temsirolimus). Adverse events were generally similar in all three arms although 69% of patients treated with temsirolimus had any grade 3 or 4 toxicity compared with 85% on interferon and 87% with the combination (p < 0.001). The authors conclude that temsirolimus can be considered

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as first-line therapy for patients with poor risk features and that mTOR is an important therapeutic target in renal cell carcinoma. The importance of mTOR in renal cell carcinoma has been independently confirmed by the fact that the mTOR inhibitor RAD001 has recently been reported to have activity in renal cell carcinoma in a second-line setting.104 Twenty-eight patients were treated with RAD001 at a dose of 10 mg daily orally and partial responses were reported in 9 (36%). In assessing this trial some commentators have postulated that patients in the temsirolimus alone arm appeared to do better because such sick patients actually may have been harmed by IFN. However, the IFN alone arm did at least as well as expected and this does not therefore seem a likely explanation. This study is remarkable because temsirolimus clearly has activity in this very sick group of patients who have not yet been shown to benefit from any other treatment.

COMBINATION THERAPY There is interest in (‘horizontally’) combining active agents in metastatic RCC to investigate potential synergy and to maximize the chance of disease control. The only published report to date of possible synergy between agents in the treatment of metastatic RCC is between the EGFR tyrosine kinase inhibitor erlotinib and bevacizumab.105 Sixty-three patients with metastatic clear cell renal carcinoma were treated with bevacizumab 10 mg/kg intravenously every 2 weeks and erlotinib 150 mg orally daily in a phase II trial. Fifteen patients (25%) had objective responses (14 PRs and 1 CR). Thirty-six patients (61%) had stable disease and 13 of these patients had minor objective responses (10–30% decrease in tumour size). The median progression-free survival was 11 months and median survival had not been reached at the time of reporting. Toxicity was generally manageable although one episode of grade 4 toxicity was reported (a gastrointestinal bleed). Although the EGFR is overexpressed in approximately 70% of renal cell carcinomas (59), three phase II studies of the EGFR

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tyrosine kinase inhibitor gefitinib in metastatic RCC have been published106–108 in which 67 patients were treated without evidence of efficacy. The high response rate reported with the combination of erlotinib and bevacizumab was of interest given the lack of response to gefitinib and the low (10%) response rate to bevacizumab.54 However, this result has not been confirmed in a recently reported randomized phase II study comparing bevacizumab with the combination of bevacizumab and erlotinib.109 One-hundred and three systemictreatment-naïve patients were randomized in the study; there were no significant differences in progression-free or overall survival, response rate (13–14%) or disease stabilization rate (68%) between the two groups. Toxicity was also similar in both arms and the authors conclude that the addition of erlotinib to bevacizumab does not appear to enhance clinical benefit in metastatic RCC. Sorafenib has been administered in combination with bevacizumab in 2 phase I/II studies recently reported in abstract form.110,111 The combination of the two drugs appeared generally to increase sorafenib-associated toxicities and the administration of sorafenib at doses of over 200 mg/day often resulted in dose-limiting toxicity. Preliminary evidence of efficacy was noted despite the fact that only low doses of sorafenib could be administered and mature data are awaited. Sorafenib has also been administered in combination with interferon to 100 patients in two phase II studies.112,113 IFN was administered at a dose of 10 MU three times a week and sorafenib at 400 mg twice daily. IFN toxicity generally predominated and the majority of patients had dose reductions with grade 3 or 4 fatigue a particularly problematic side effect. Preliminary evidence of efficacy was again noted and the authors conclude that sorafenib can be combined with IFN and that further investigation of this combination is warranted.

UNRESOLVED QUESTIONS A number of questions concerning the use of novel systemic agents in RCC are unresolved.

First, the question of how systemic treatment might be sequenced (‘vertically’) is important. Preliminary data from 35 patients pretreated with antiangiogenic therapy (such as thalidomide, lenalidamide, bevacizumab, and axitinib) who subsequently received sorafenib or sunitinib114 show an overall response rate of 20% and disease stabilization in a further 43% of patients. Data have also been reported of the treatement of bevacizumab-refractory metastatic RCC with sunitinib.115 Sixty-one patients were treated, of whom 16% responded to treatment and 61% had stable disease with manageable toxicity. These data demonstrate both the feasibility of sequencing of anti-angiogenic therapy and evidence of efficacy in the second-line setting. There is a need in RCC for the identification of markers to allow the selection of patients for different types of therapy. Carbonic anhydrase IX expression has emerged as a predictor of outcome in patients with RCC receiving IL-2-based therapy9 and there is interest in the use of microarray technology for the classification of renal cell carcinomas.116,117 The use of such technology has generated considerable interest in other types of tumour118–125 but presents significant challenges.126 Second, there are few data on the treatment of non-clear cell renal carcinoma with novel agents. It is possible that antiangiogenic therapies have less efficacy for non-clear cell histology as von Hippel–Landau dysfunction is less common than in clear cell renal carcinoma but this has not been tested in clinical trials. A small number of patients with papillary RCC have been treated with sorafenib84 (n = 15) and sunitinib94 (n = 4) in phase II studies. Two PRs to treatment with sorafenib were reported and three other patients had tumour shrinkage between 25% and 49% (not sufficient to be deemed a PR using the World Health Organization [WHO] criteria) while one PR to sunitinib was reported. Third, the in vivo mechanism of action of many agents has not been established. Neoadjuvant therapy with biopsies both before and on treatment may allow this question to be addressed.127 Neoadjuvant therapy may also allow markers of response prediction to

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be identified and radiological changes to be correlated with pathological and molecular changes due to treatment.128 Fourth, a novel aspect of kinase inhibitor therapeutics has been reported in the treatment of gastrointestinal stromal tumours (GISTs) with imatinib. In the treatment of GISTs, imatinib dose can be increased on disease progression and approximately 25% of patients will experience renewed disease stabilization.129 Dose escalation of kinase inhibitors on disease progression has not been investigated in RCC although anecdotally, sorafenib toxicity can attenuate with prolonged therapy, allowing the dose to be increased. The mechanism of this reduction in toxicity is unknown. Interesting comparisons can be drawn between kinase inhibitors active in RCC. For example, sorafenib and sunitinib inhibit similar tyrosine kinases (although RAF kinases are not inhibited by sunitinib) but the toxicity profile of the drugs is different: skin toxicity is probably the most problematic side effect of sorafenib130 while sunitinib can cause significant myelosuppression.93,94 As kinase inhibitor therapy is often cytostatic, long-term treatment is likely in many cases and toxicity is therefore important in the selection of therapy. The efficacy of sorafenib and sunitinib is also different in advanced RCC: responses to treatment are relatively rare with sorafenib, but disease stabilization is often seen whereas responses to sunitinib treatment are more common.94 It is possible to speculate that the toxicity and efficacy profiles of these drugs in RCC are related to differences in the spectrum of kinases inhibited but there are currently no experimental data to support this view. Finally, novel agents are under investigation in renal cell carcinoma for adjuvant therapy. Although immunotherapy is efficacious in metastatic disease, this does not translate to the adjuvant setting131–133 and in fact inferior OS has been reported with immunotherapy in comparison with placebo.135 Given the activity of a number of novel agents in advanced disease, there is interest in the evaluation of these drugs in early stage disease to minimize the likelihood of relapse after surgery.

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CONCLUSIONS Immunotherapy results in a small overall survival advantage in metastatic RCC but there is a need for better systemic therapies. Agents that interfere with pathological angiogenesis such as the anti-VEGF monoclonal antibody bevacizumab have demonstrated efficacy in phase II studies in advanced disease. A number of other novel systemic agents are under evaluation in metastatic RCC and the kinase inhibitors have shown particular promise. Axitinib, sorafenib, and sunitinib inhibit VEGF, PDGF and c-KIT receptor tyrosine kinases while temsirolimus inhibits mTOR. These drugs generally are administered orally and have demonstrated significant activity with manageable toxicity in phase II studies in metastatic RCC in generally immunotherapyrefractory patients. Sunitinib has demonstrated prolonged progression-free survival and temsirolimus prolonged overall survival, the latter in patients with poor risk features, in first-line phase III studies in comparison with interferon. Sorafenib has demonstrated prolonged progression-free survival in a second-line phase III study in comparison with placebo. Further survival data from these trials are awaited as are data from trials combining kinase inhibitors with other systemic treatments in RCC. Given the activity of kinase inhibitors in advanced RCC, these agents are likely to be investigated in the adjuvant setting to attempt to minimize the risk of disease recurrence and in the neoadjuvant setting to identify biomarkers of response to therapy, to investigate mechanisms of drug action in vivo and potentially to downstage tumours prior to surgery.

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Radiotherapy and supportive care

15

Vincent Khoo and Lynda Pyle

INTRODUCTION In the primary management of renal cancer, radiotherapy has a limited role. However, irradiation has been utilized in the adjuvant and postoperative residual disease scenarios as well as in the unresectable and metastatic disease settings. The rationale and merit for each of these situations will be reviewed in the first half of this chapter. Another crucial and important aspect of renal management is the adequate provision of prompt and appropriate supportive care. This aspect of management may often be neglected until late in the management of this disease. Supportive care covers many aspects of patient management and is best managed within a multidisciplinary team. The principles, organization, and range of supportive care will be discussed in the latter half of this chapter.

RADIOTHERAPY Although renal cancer has been considered as a relatively radio-resistant tumour, clinical experience using radiotherapy has demonstrated that a reasonable proportion of renal tumours can respond to irradiation. Radiotherapy has been utilized in many different clinical situations including the preoperative and adjuvant settings, for postoperative residual disease, in local recurrence, and for unresectable primary and metastatic disease. Its value in each of these settings will be reviewed in the following sections.

Preoperative and adjuvant radiotherapy In this setting, some early retrospective studies1–4 using adjuvant radiotherapy have

suggested a survival benefit, but these studies were not randomized, had small numbers with a large variation in clinical demographics, radiation dose and techniques were not consistent, and follow-up arrangements were uncontrolled. These factors limit the value of the reported outcomes. Subsequent later retrospective studies suggested mainly a benefit in local control rates using adjuvant radiotherapy. Rafla5 reported a significant improvement in local control from 79% to 91% with the addition of radiotherapy in 190 patients but details of irradiation were not provided. In this non-randomized study, a survival benefit from 37% to 56% at 5 years with postoperative radiotherapy was noted only in those patients with renal pelvis and capsular involvement. More recently, Stein et al6 reported on a retrospective non-randomized cohort of 123 patients treated with either surgery alone or surgery with adjuvant radiotherapy. They found no significant differences between the groups for either overall survival or local control rates. These studies led to the randomized evaluation for the role of either preoperative or adjuvant radiotherapy. Four prospective randomized studies were conducted with two in the preoperative setting and two in the adjuvant setting.

Preoperative radiotherapy Van der Werf-Messing7 and Juusela et al8 reported on the use of preoperative irradiation using a total dose of 30 Gy in 126 and 88 patients, respectively. Both of these studies were randomized and did not report any difference

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in 5-year overall survival rates. Limitations of both these studies included small patient numbers, the use of subtherapeutic irradiation doses even for microscopic disease, and non-discriminating inclusion of all disease stages into the trial such as early stage T1 N0 disease where additional local therapy is unlikely to provide a benefit. In addition, there is no information provided on local control rates which is an important aspect of the use of this treatment strategy.

Adjuvant radiotherapy The two randomized trials in this setting were published by Finney9 and Kjaer et al.10,11 The earlier trial9 recruited 100 patients treated to a total dose of 55 Gy while the later trial11 recruited 65 patients treated to a dose of 50 Gy. Despite this adequate dose, there was no 5-year overall survival benefit for adjuvant irradiation. The 5-year survival rates reported by Finney9 was 47% with surgery alone compared to 36% with the addition of radiotherapy and by Kjaer et al11 was 64% with surgery alone compared to 38% with combined therapy. It is interesting to note that both trials were reported twice in the same year in two different journals. In the Finney study9 survival was reported using crude rather than actuarial results and different results were published in each report making evaluation of this study difficult. This trial also suffered from the same non-discriminating inclusion of all disease stages. In the smaller study by Kjaer et al,11 4 of 32 patients (12.5%) in the adjuvant radiation arm were not irradiated and follow-up was not undertaken in one patient. Of note in both trials was the high level of radiation related toxicity. In the Finney trial, there were four deaths from right-sided irradiation (8%).9 In the Kjaer trial, significant abdominal complications were reported in 12/27 (44%) of irradiated cases in which 5/27 (19%) contributed to the patient’s death.11 The Kjaer study was heavily criticized for treating a large volume of bowel within the treatment field using higher than standard fraction sizes (i.e. 2.5 Gy per fraction compared to 1.8–2.0 Gy per fraction) to doses that are considered to

have exceeded the tolerance of small bowel with the radiation technique used. Another interesting observation is that the reported local failure rates of 3–12% were much lower than the 21–25% reported in previous studies.5,6 This may be related to improved surgical technique or perhaps the inappropriate inclusion of more early-stage disease cases could have contributed to the excellent local control rates. The Kjaer study11 was the only study to utilize computed tomography (CT) staging and was able to exclude patients with early-stage disease and metastatic disease from entry into the trial. CT evaluation is an important staging tool and permits the exclusion of early metastatic disease that can have an impact on the outcome of such studies if these inappropriate metastatic patients are included.

Summary All four randomized trials failed to demonstrate a survival benefit for preoperative or adjuvant irradiation. Despite being randomized trials, there are several major limitations in trial design and methodology which are outlined above and included inappropriate case selection and inadequate patient numbers. Furthermore, treatment morbidity was substantially high and the radiotherapy techniques used then will now be superseded by improved irradiation methods. New radiotherapy methods include threedimensional (3D) CT planning for conformal designed treatments and/or intensity modulated delivery with acceptable dose-fractionation schemes that may permit higher tumoricidal doses and reduced treatment side effects. Despite the severe limitations of these randomized studies, it is unlikely that future radiotherapy trials in this setting will be undertaken even if they are well designed using modern radiotherapy techniques.

Radiotherapy for unresectable primary disease, postoperative residual disease and local recurrence There are no randomized data to support the use of radiotherapy in the settings of unresectable primary disease, postoperative residual

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RADIOTHERAPY AND SUPPORTIVE CARE

disease, and local recurrence following surgery. However, based on previous retrospective data,12–16 it is reasonable to consider the use of radiotherapy in these settings depending on the intended rationale for its application. For patients in whom surgery is contraindicated due to the poor performance status or unsuitable clinical condition of the patient, radiotherapy may be used as an alternative if other local therapies such as radioablation are not appropriate either. One small series of nine non-metastatic unresectable patients reported 44% alive at a median follow-up of 27 months.17 Survivors in this small study were reported to have tumour sizes < 3.5 cm, negative nodes and no extension into the renal vein or invasion of Gerota’s fascia. In addition, if there is extensive disease, then radiotherapy may be used as primary therapy for palliation or growth restraint to prevent unabated progression of disease into surrounding normal tissues or critical normal structures. Radiotherapy may also be considered for cases of local recurrence that are unresectable; recurrences that have occurred following a second resection or are not amenable to other local treatments, with the same intention of preventing severe or troublesome local symptoms from uncontrolled local tumour invasion. There is controversy surrounding the use of postoperative irradiation in cases where there is a high likelihood of residual disease or clear evidence of residual disease following surgery. An argument may be mounted for the use of radiotherapy in these situations, particularly with residual macroscopic disease, if this remains the only known site of disease, the patient’s performance status is good, and the development of local recurrence is likely to result in substantial deterioration of the patient’s quality of life from symptoms of local invasion. This argument may gain more credence with the use of modern radiotherapy methods that can now deliver reasonable doses using techniques that can substantially limit treatment-related side effects.

Modern radiotherapy techniques If irradiation is to be used, then radiotherapy treatment volumes need to be designed based

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Figure 15.1 An example of conformal radiotherapy treatment fields for a patient suffering a tumour recurrence in the postoperative renal bed site. The target volume (near cylindrical shape) is located centrally and is denoted by the pink outline. Note that each treatment beam has been shaped to the profile of the target volume in the direction of beam delivery, which is then projected onto an outline of the axial skeleton for further illustration of the conformal field shapes. (See Colour Plate Section).

on the 3D shape of the tumour mass or target volume. In this manner, the 3D spatial relationship of the radiotherapy treatment beams can be assessed in relation to the normal tissues/organs surrounding the tumour mass which will limit the dose that can be safely delivered to the target volume. The potential side effects on surrounding normal tissues or organs can then be objectively estimated to ensure safe delivery of the prescribed dose. Each predetermined treatment field in the radiotherapy plan can then be shaped to the profile of the target volume within the beam’s-eye-view in a technique called conformal radiotherapy (Figure 15.1). Conformal radiotherapy permits tailoring of the radiotherapy fields to the individual patient and can substantially reduce dose to surrounding normal tissues. A further advance in the delivery of conformal radiotherapy is the use of intensity modulation of the conformally shaped radiotherapy beams. Intensity-modulated radiotherapy (IMRT) is a technique whereby the dose fluence delivered from each treatment beam can be substantially varied in dose intensity across the individual treatment beam field. By combining several intensity modulated treatment beams, high doses can be ‘painted’ to selected regions of the tumour with the effect

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Table 15.1

Normal structures to be considered in renal radiotherapy

Structure and clinical endpoint

Tolerance dose per volume (TD 5/5)

Dose* (Gy)

Contralateral kidney for clinical nephritis and renal failure

1/3 renal volume 2/3 renal volume 3/3 renal volume 5–10 cm length > 10 cm length

50 30 23 50 45–47 40–50 Gy

1/3 liver volume 2/3 liver volume 3/3 liver volume

50 35 30

Spinal cord for myelitis or necrosis Small bowel for obstruction, perforation or fistula Liver for hepatic failure

*Dose is based on the use of conventional fractionated treatments using between 1.8 and 2.0 Gy per fraction delivered once per day and 5 days per week. TD 5/5 is the estimation of the probability of organ dysfunction of 5% at 5 years from a given dose delivered to a given organ volume. (Modified from Emami et al. Int J Radiat Oncol Biol Phys 1991; 21: 109–22.13)

of conforming the delivered dose to very irregular or concave shapes much easier than other external beam techniques. In this manner, the dose to nearby critical structures can also be substantially reduced and permits conformal avoidance of normal organs to reduce the likelihood of both acute and late radiation complications. Normal structures that need to be considered in the radiotherapy treatment of renal masses or renal bed recurrences are listed in Table 15.1 together with their dose tolerances.13,18 The dose tolerances described for each organ are based on conventional dosefractionation schemes and take into account simplistic volume effect considerations. One example of a dose-fractionation scheme for treatment in the clinical situation of either unresectable disease or local recurrence is a target volume that may include microscopic disease to a dose of between 44 Gy and 46 Gy in 1.8–2 Gy per fraction with consideration of a boost for macroscopic disease to a total dose of up to 50–60 Gy if the dose-volume constraints listed in Table 15.1 are met. An example of a conformal plan dose distribution is shown in Figure 15.2. Another recent advance in radiotherapy technique is the application of image-guided radiotherapy where online radiotherapy imaging tools and equipment are used to provide 3D spatial localization of the target volume at

the time of irradiation as treatment verification for adaptive dose delivery or to track and gate the delivery of radiotherapy to the renal mass that will be displaced by respiration. In this manner, image-guided radiotherapy can further improve the accuracy and reliability of radiotherapy which in turn can permit a reduction of unnecessary dose to the surrounding normal tissues.

Radiotherapy for metastasis Radiotherapy is an effective therapy for palliation of local and symptomatic metastatic disease or to prevent the progression of metastatic disease in critical sites. It is used commonly to prevent or limit neurological involvement such as in spinal cord compression and nerve/plexus invasion, to improve the pressure effects of brain metastasis and to alleviate pain from bony metastasis or to prevent skeletal related complications such as pathological fractures. Radiotherapy can either be used alone or in combination with surgery. The choice of a radiotherapy dosefraction schedule will depend on the patient’s expected survival time, the site being treated, and normal tissue constraints. Some examples include a single fraction of 8 Gy, 16 Gy in two fractions, 20 Gy in five daily fractions or 30 Gy in 10 daily fractions. These patients are best managed in a multidisciplinary team setting

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a

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b

c

Figure 15.2 An example of a high-dose co-planar conformal radiotherapy plan to treat a local renal cancer recurrence. (A) The transverse dose distribution through the isocentre of the treatment plan. The isodoses are listed by colour on the right hand side of the diagram. The orientation angles of the three treatment beams are also shown. (B) The sagittal dose distribution. (C). The coronal dose distribution in the same patient as in (A) and (B). (See Colour Plate Section).

where the management plan can be fully discussed and coordinated between all members of the renal team. Although radiotherapy has been reported to provide palliation relief in 67–77% of patients suffering from symptomatic bony metastasis,19,20 there are few prospective reports of studies evaluating bony metastasis from renal cancer using modern measures of pain assessment and benefit such as quality of life. A recent prospective non-randomized study of 25 patients reported a decrease in site-specific pain in 83% of cases, significant pain decrease in 48% of cases, and complete response in 13%.21 These responses were based on patient questionnaires. The median duration of response was 3 months. Quality of life measures were improved in 33% for up to a median duration of two months but 46% reported deterioration in quality of life, deemed to be related to systemic disease progression. Up to 10–11% of renal cancer patients will develop brain metastasis during the course of their illness. The prognosis of these patients is dependent on factors such as the number of brain metastasis (single versus multiple),

whether they are surgically resectable or not, the presence of other metastasis, the rate of disease progression and the patient’s performance status. Untreated, these patients have a poor prognosis with a median survival time of approximately one month. Radiotherapy can improve the quality of life, local control, and median survival time for these patients. The therapy choice depends on the prognostic factors previously mentioned. Whole-brain radiotherapy is usually given for palliation. Stereotactic radiosurgery can be delivered to multiple lesions in patients with better prognostic features and has been reported to provide comparable results to surgical series. In a single institution series, stereotactic radiosurgery was delivered to 35 patients with 52 brain metastasis with local control rates of approximately 90% and a median survival time of 14 months.22 In this study, favourable prognostic factors in multivariate testing were age < 55 years, lack of active systemic disease, and use of immunotherapy and/or chemotherapy after stereotactic radiosurgery. There are no randomized trials comparing surgical brain metastasectomy with stereotactic radiosurgery.

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Summary

SUPPORTIVE CARE

FO NL Y

The role of radiotherapy in the primary management of renal disease is limited. There is no evidence for the use of adjuvant irradiation in resected primary renal disease. However, radiotherapy may be considered for other clinical situations such as unresectable primary disease, postoperative residual disease and local recurrence with the primary aim of restraining local tumour progression and preventing uncontrolled local tumour invasion of surrounding normal tissues. Modern radiotherapy techniques can now deliver higher doses with an acceptable level of side effects to achieve this aim. Further advances using intensity modulated and image-guided radiotherapy may improve the therapeutic ratio of irradiation. There is a definite role for radiotherapy in metastatic disease to provide symptom palliation, prevent neurological catastrophies, and improve quality of life. The application of radiotherapy for the individual patient is best discussed within a multidisciplinary team setting.

as cytokine therapy can continue for many months. Patients tend to tolerate treatment better if they know what to expect. Educating them before the start of treatment will give them the confidence to self-administer their medication at home. With low-dose cytokine regimens this is usually by subcutaneous injection three times a week. Asking patients to inject themselves and observe for side effects can add extra stress to the existing problems of living with cancer. For those who cannot give themselves injections relatives can be taught or the support of the primary care team can be sought. The most common acute side effects of interferon α treatment are fevers, chills, sweating, fatigue, headache, and anorexia. Less common side effects include nausea and vomiting, diarrhoea, cough, myalgia, anaemia, leucopenia and thrombocytopenia. Depression can be severe especially in patients with a previous history of depression. Men can become impotent, so it is important when talking to the patient about their side effects that this is discussed as many men are too embarrassed to disclose this side effect themselves. Rarer side effects from interferon are dizziness, tingling in the hands, visual disturbances and seizures. Subcutaneous interleukin-2 can have all of the above side effects but also has other toxicities worth noting. Local skin reaction at the site of the injection and general skin reaction are more severe with interleukin-2 than with interferon and can be distressing. Nightmares may be experienced. Oedema can occur even at low-dose regimens. Hypotension can also be a problem. In higher doses, usually administered in hospital interleukin-2 can cause capillary leak syndrome, which can also be associated with pulmonary oedema and respiratory distress. If not treated promptly this could be fatal. Detection of signs and symptoms of this syndrome should be carefully monitored. This includes daily weight, fluid balance chart, and observation for signs of dyspnoea. The management of this and other toxicities is shown in Tables 15.2 and 15.3. Fatigue is the most frequently reported side effect. Patients find this the most difficult one to cope with as there are no effective counter-measures.

PR

OO

This section will look at supportive issues arising during the systemic therapy of renal cell cancer. The article will focus on cytokine therapy and the new multitargeted kinase inhibitors. Immunotherapy for metastatic renal cancer has been used for many years with some effect at the expense of significant toxicity. More recently the emergence of multitargeted kinase inhibitors has widened treatments options for patients in the first- and second-line setting. It is vital that patients are given education and support while taking these drugs as many of the side effects are unique.

Immunotherapy Interferon α is the usual cytokine used in patients with metastatic renal cancer in Europe, while interleukin-2 is the cytokine of choice in the USA. Combination of these two drugs with or without chemotherapy agents increases treatment toxicity.23 Managing the side effects effectively is particularly important

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For most of these side effects if they become intolerable a dose reduction or a ‘drug holiday’ will usually result in an improvement within a few days.

Multitargeted kinase inhibitors Sorafenib and sunitinib are multitargeted kinase inhibitors and have recently become available for the treatment of metastatic renal cell cancer. Both are tablets and patients take them at home. Therefore patients need to be taught to recognize early symptoms of side effects and how to manage them. A good relationship with the oncology nurse is important as they are usually the person the patient will first contact for help and advice. Many of the side effects are well known but there are also unique side effects to these drugs. Fatigue is very commonly seen and patients need to be told that this is to be expected as some will associate this with worsening of their disease. Encourage them to rest and reserve their energy for doing things which are important. It is important that bloods are checked for anaemia as low haemoglobin will increase fatigue and discourage the patient. Nausea can be an upsetting side effect for patients as this makes them feel unwell. This discourages the patient from eating and therefore causes weight loss, another symptom often associated with disease progression. Supporting patients to take regular antiemetics and dietary advice such as eating ‘little and often’ and avoiding fatty spicy food will help. Mucositis is commonly seen with these drugs and can be painful and cause difficulty in swallowing. Encourage oral hygiene and modifying diet to exclude hot and spicy food. Tobacco and alcohol should be discouraged as this can cause irritation to the mouth. Regular toothpaste can also cause discomfort, changing to children’s toothpaste may help. Topical anaesthetic mouthwashes or gels can be used. Abdominal discomfort may occur with or without diarrhoea. Diarrhoea can occur and if not treated can lead to dehydration. Patients need to be educated in recognizing the symptoms early and to use antidiarrhoeal agents.

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Encourage patients to increase their fluid intake. Anorexia – not wanting to eat due to lack of appetite can be made worse by any of the above side effects and patient may need referral to a dietician for advice and support. Weight should be monitored regularly. Hypertension can occur and is usually seen soon after the start of therapy. This is usually mild to moderate and is treated with standard antihypertensive drugs. Blood pressure should be monitored at all outpatient visits, and may require visits to the general practitioner. In the USA it is recommended that patients attend for weekly measurement of blood pressure. Skin change – many patients on kinase inhibitors have cutaneous reactions. Folliculitis can be distressing and may require antibiotics, but this is not thought to be caused by an infection.23 Facial erythematous rashes are seen with sorafenib, and periocular oedema can be seen with sunitinib, but neither usually needs specific treatment. Patients need reassurance that this is reversible. Sunitinib can cause skin pigmentation and patients appear to have a yellow tinge to their skin. Urine can also turn very yellow. The most important skin toxicity is hand–foot syndrome. It is important that this is recognized and treated early. Patients on sunitinib or sorafenib commonly experience hand–foot syndrome or palmar plantar erythrodysaesthesia. This is different from the hand–foot syndrome associated with cytotoxic agents.23 Commonly patients will describe pain and tingling in their feet before the hyperkeratotic lesions appear. This usually occurs after 2–4 weeks of treatment. Although the existing common toxicity criteria were developed for cytotoxic agents, it is still important to use them when describing the toxicity of multitargeted kinase inhibitors as this standardizes communication among medical teams.24 Grading for skin reaction:25 • Grade I: mild redness, swelling or altered sensation (tingling, numbness), but skin is intact; no interference with activities of daily living (ADL)

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Table 15.2

Management of interferon α-related side effects

Toxicity

Intervention

Comments

Fever

Paracetamol, 500 mg, 30 minutes pre-injection and 2 hours post injection; then as required Where fever persists, exclude infection When fever no longer appears to be a side effect, paracetamol may be omitted for a trial period

High temperature with or without chills and rigors seen with the first injection; generally decreases with subsequent injections

Rigors

Apply blankets If rigors progress beyond mild shivering, pethidine, 12.5–25 mg im/iv may help Doses up to a maximum of 100 mg have been used Reassure the patient that the rigors are self-limiting

Often seen with the first injection or second administration of doses of > 5 million IU

Malaise

Advise patients that these symptoms may occur and that they will improve with time If there is no improvement consider changing interferon α dose

Usually occurs 12–24 hours after injection and improves throughout treatment

Fatigue

Teach patients energy-saving strategies and ways of maximizing periods of greater energy. Refer to occupational therapist for specialist advice

May develop after 1–2 weeks of treatment and may worsen throughout the course of treatment

Headache

If not controlled with paracetamol (as for fever), contact doctor to rule out other causes and/or need for additional analgesics

Tends to be frontal and persistent; usually responds well to simple analgesics

Anorexia

Advise the patient about taking small, frequent meals and the use of supplements; refer to a dietician as appropriate Steroids should not be used to stimulate appetite as they may interfere with the effectiveness of interferon α

Not seen in all patients, but often persistent

• Grade II: hands and feet are swollen and painful, making ADLs more difficult, but the skin remains intact • Grade III: pain is severe and interferes significantly with ADLs; skin breakdown is evident (cracking, peeling, blistering) Educating the patients about this skin reaction before they start therapy can help prevent the skin reaction becoming severe. Supportive measures should be introduced at the first signs of this skin reaction to try to prevent worsening of the symptoms. Patients should modify normal activities to reduce friction, avoid tight clothing and manmade fibres.

Moisturizing the skin and using padded insoles will also reduce discomfort. Avoiding exposure to heat and hot water is important as this will exacerbate the condition. Although most commonly found on the hands and feet, it is seen on other parts of the body especially pressure points. The hand–foot syndrome will resolve when the drugs are stopped. Hair changes have been seen both with sunitinib and sorafenib. This can be in texture and in colour. This can be seen especially in sunitinib which causes hair depigmentation while patients are taking the drug but this is reversed during their two week break.

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Table 15.3

199

Management of interleukin-2-related side effects

Toxicity

Intervention

Comments

Fever, malaise

Reassure the patient that this is normal and encourage rest Can be helped by paracetamol (1 g) or NSAIDs A fan may be used to cool the patient

Occurs within hours to days of the initiation of treatment

Rigors

If persisting for 20 minutes or longer, pethidine 12.5 mg iv or im, may be given to a maximum dose of 100 mg within 1 hour

Observe for respiratory depression when using pethidine

Erythema, pruritus, dry desquamation

Advise the patient to wear loose, non-restrictive clothing Keep the skin cool to reduce pruritus Calamine lotion or aqueous cream with menthol may be used to soothe the skin. If this is ineffective, an oral antihistamine such as chlorphenamine maleate, 4–8 mg t.d.s., may be used The skin must be kept constantly moisturized using emollient

Develops in most patients. Is associated with perivascular infiltration by T-lymphocytes. Care must be taken not to mask any signs of neurotoxicity by using antihistamines

Pain and induration at injection site

Use lidocaine gel sparingly Topical NSAID gel

Anorexia

Encourage patients to take small, frequent meals, and to maintain an adequate fluid intake. If appriopriate, please refer patient to a dietician

Anorexia is characteristic of interleukin-2 therapy. The use of steroids as stimulants should be avoided

Capillary leak syndrome

For detection, the patient should be weighed daily. If body weight increases by > 5%, human serum albumin should be given with or without diuretics A strict fluid balance chart must be kept If the patient exhibits any signs of dyspnoea, contact medical staff at once. Treatment may have to be stopped and supportive measures initiated Dopamine hydrochloride may be required to maintain renal perfusion

May be associated with pulmonary oedema and respiratory distress. May be fatal

Hypotension associated with capillary leak syndrome

If systolic blood pressure drops below 100 mmHg, inform medical staff It may be necessary to use plasma expanders to maintain blood pressure If hypotension is prolonged and severe, or the patient is symptomatic, interleukin should be temporarily (or sometimes permanently) discontinued Vasopressors may be required to support blood pressure

Usually resolves once therapy is discontinued

NSAID, non-steroidal anti-inflammatory drug.

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Table 15.4

Selected cytochrome P450-CYP-3A4 substrates, inhibitors, and inducers

Substrates

Inhibitors

Inducers

Amiodarone Alprazolam Buspirone Cisapride Ciclosporin Diltiazem Erythromycin Felodipine Indinavir Midazolam Nifedipine Pimozide Pioglitazone Quinidine Ritonavir Sertraline Sidenafil Simvastatin TAO R-warfarin Tacrolimus Triazolam Verapamil Zolpidem

Clarithromycin Ciclosporin Delavirdine Erythromycin Fluconazole Grapefruit juice Indinavir Itraconazole Ketoconazole Miconazole TAO Nefazodone Ritonavir Verapamil

Barbiturates Carbamazepine Griseofulvin Nevirapine Phenytoin Rifampin St John’s wort

Haematological changes – anaemia, neutropenia, and thrombocytopenia can occur and patients should be taught to observe for fatigue, symptoms of infection, and bruising or bleeding. Patients should receive clear instructions about what to do if they experience symptoms. Drug interactions may occur and is important when prescribing other medication that the manufacturer’s guidelines are reviewed. In particular, caution should be used when a patient is taking a drug that is either metabolized by or induces the cytochrome enzyme CYP-3A4 (Table 15.4).

Summary Both cytokine and multitargeted kinase inhibitor treatment may go on for long periods. Early intervention is important to prevent side effects worsening and preventing prolonged drug interruption. Education and communication is the key to supporting patients through treatments which can be difficult to tolerate

but given the right information can be well tolerated and beneficial to the patient.

REFERENCES 1. Riches EW, Griffiths IH, Thackray AC. New growths of the kidney and ureter. Br J Urol 1951; 23(4): 297–356. 2. Flocks RH, Kadesky MC. Malignant neoplasms of the kidney; an analysis of 353 patients followed five years or more. J Urol 1958; 79(2): 196–201. 3. Bratherton DG. The place of radiotherapy in the treatment of hypernephroma. Br J Radiol 1969; 42(504): 949. 4. Peeling WB, Mantell BS, Shepheard BG. postoperative irradiation in the treatment of renal cell carcinoma. Br J Urol 1969; 41(1): 23–31. 5. Rafla S. Renal cell carcinoma. Natural history and results of treatment. Cancer 1970; 25(1): 26–40. 6. Stein M, Kuten A, Halpern J et al. The value of postoperative irradiation in renal cell cancer. Radiother Oncol 1992; 24(1): 41–4. 7. van der Werf-Messing B. Proceedings: carcinoma of the kidney. Cancer 1973; 32(5): 1056–61. 8. Juusela H, Malmio K, Alfthan O, Oravisto KJ. Preoperative irradiation in the treatment of renal adenocarcinoma. Scand J Urol Nephrol 1977; 11(3): 277–81.

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9. Finney R. The value of radiotherapy in the treatment of hypernephroma – a clinical trial. Br J Urol 1973; 45(3): 258–69. 10. Kjaer M, Iversen P, Hvidt V et al. A randomized trial of postoperative radiotherapy versus observation in stage II and III renal adenocarcinoma. A study by the Copenhagen Renal Cancer Study Group. Scand J Urol Nephrol 1987; 21(4): 285–9. 11. Kjaer M, Frederiksen PL, Engelholm SA. Postoperative radiotherapy in stage II and III renal adenocarcinoma. A randomized trial by the Copenhagen Renal Cancer Study Group. Int J Radiat Oncol Biol Phys 1987; 13(5): 665–72. 12. Bratherton DG. The place of radiotherapy in the treatment of hypernephroma. Br J Radiol 1969; 42: 949. 13. Sandeman TF. The radiotherapy of malignant disease of the kidney and ureter. Australas Radiol 1970; 14: 285–93. 14. Finney R. The value of radiotherapy in the treatment of hypernephroma – a clinical trial. Br J Urol. 1973; 45: 258–69. 15. Malkin RB. Regression of renal carcinoma following radiation therapy. J Urol. 1975; 114: 782–3. 16. Brady LW Jr. Carcinoma of the kidney – the role for radiation therapy. Semin Oncol 1983; 10: 417–21. 17. Beitler JJ, Makara D, Silverman P, Lederman G. Definitive, high-dose-per-fraction, conformal, stereotactic external radiation for renal cell carcinoma. Am J Clin Oncol 2004; 27(6): 646–8.

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18. Emami B, Lyman J, Brown A et al. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 1991; 21(1): 109–22. 19. Halperin EC, Harisiadis L. The role of radiation therapy in the management of metastatic renal cell carcinoma. Cancer 1983; 51(4): 614–17. 20. Onufrey V, Mohiuddin M. Radiation therapy in the treatment of metastatic renal cell carcinoma. Int J Radiat Oncol Biol Phys 1985; 11(11): 2007–9. 21. Lee J, Hodgson D, Chow E et al. A phase II trial of palliative radiotherapy for metastatic renal cell carcinoma. Cancer 2005; 104(9): 1894–900. 22. Mori Y, Kondziolka D, Flickinger JC, Logan T, Lunsford LD. Stereotactic radiosurgery for brain metastasis from renal cell carcinoma. Cancer 1998; 83(2): 344–53. 23. Van Spronsen DJ, Mulders PFA, De Mulder PHM. Novel treatments for metastatic renal carcinoma. Crit Rev Oncol Hematol 2005; 55: 177–91. 24. Robert CS, Soria J-C, Spatz A et al. Cutaneous sideeffects of kinase inhibitors and blocking antibodies. Lancet Oncol 2005; 6: 491–500. 25. Manchen B. Nursing management of patients undergoing treatment for renal cell carcinoma. Advances in the treatment of renal carcinoma 2006. 26. Mrozek-Orlowski ME, Frye DK, Sanborn HM. Capecitabine: nursing implications of a new oral chemotherapy agent. Oncol Nurse Forum 1999; 26: 753–62.

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Index

acetabulum, surgery for metastatic RCC 145–6, 146 adjuvant therapy cancer vaccines 158–60, 173–4 chemotherapy 153–4 future approaches 158–62 immunotherapy and chemo-immunotherapy 155–8, 196–7, 198, 199 neoadjuvant therapy 182–3 radiotherapy 154–5 targeted therapies 160–2 RCC trials 160 unresolved questions 183 alcohol 3–4 allogeneic stem cell transplantation 174 analgesics 12, 15 angiogenesis, thalidomide 35 ankle, metastatic RCC 146–7, 147 anorexia, treatment 198–9 antiangiogenic medical therapy 175–6, 182 anti-CTLA4 174 antihypertensives 12, 15 anti-TNFα 174–5 asbestos 13 autologous tumor cell lysate vaccine 158–9 Avastin see bevacizumab axitinib (AG-013736), kinase inhibitor therapy 177–8, 177, 178 BAY 43-9006 see sorafenib benign renal epithelial tumors 56–7 metanephric adenoma 56 papillary adenoma 56 renal oncocytoma 31–3, 56–7 benzidine 14 bevacizumab 34, 35, 160, 161, 170, 176 combination therapy with erlotinib 181–2 with sorafenib 182 BHD 24, 31–3 Birt–Hogg–Dubé syndrome 31–3 bone metastases biomechanical factors 145 embolization 90–2, 92 osteosyntheses, failure 148–9, 149 RFA 99 surgery 143–52 diaphyseal lesions 147–8, 147, 148

hip and proximal femur 146, 146 knee and ankle 146–7, 147 orthopedic management 149 patient classification 150 pelvis and acetabulum 145–6, 146 risk assessment of fracture 145 shoulder girdle 147, 148 spinal metastases 149–50, 151 survival 144 bortezomib 34, 35 Bosniak cyst classification 81 brain metastases 195 bronchial metastases 139–40 c-MET 30, 35 cadmium 14 calcium 7 cancer vaccines 158–60, 173–4 autologous tumor cell lysate vaccine 158–9 metastatic RCC trials 157 vitespen (HSPPPC-96) 159–60, 174 capillary leak syndrome 199 carbonic anhydrase CA II 69–71 CA IX 32, 35, 69–70, 71, 161–2, 173 carcinoid tumors of kidney 54–5 CCI-779 see temsirolimus cetuximab 34, 35 chemotherapy, adjuvant 153–4 agents trialled in metastatic RCC 154 chromophobe RCC 27, 31–3, 51–2 chromosome abnormalities 24 chromosome-3 23–5, 24 constitutional balanced translocations 33–4 loss in clear cell RCCs 49 other candidate genes 24–5 von Hippel–Landau tumor suppressor 23–4 chromosome-14, non-papillary RCCs 69 classifications bony metastases 150 Bosniak (cysts) 81 clear cell RCC 24 malignant renal epithelial tumors 24 WHO 48 papillary RCC 24 clear cell RCC 23–7, 47–9, 48 alveolar architecture 48 classification 24


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INDEX

clinical presentation 41–3 familial, with no known genetic abnormality 34 gene/product 24 histology 48–9, 48 Fuhrman nuclear grading 49, 49 pigmentation 50 oncogenes and growth factors 26 other candidate regions/genes 24–5 pathological appearance 47–9 VHL 23–4, 30, 49, 61, 161 see also renal cell carcinoma (RCC) clinical presentation of RCC 41–3 changing patterns 41 classical presentation 41–2 local effects 42 metastases 42, 43, 61–74 paraneoplastic effects 42–3 ‘too late’ triad 41 coal/coke/asphalt/tar products 15 coffee and tea 7–8 collecting duct carcinoma 27 chromosome abnormalities 24 histology 51 low-grade variant 52–3, 53 computed tomography (CT) 76–8 left renal mass lesion 80 multislice CT: advantages/disadvantages 76, 77 normal pelvicalyceal opacification 77 with percutaneous biopsy 87–9 pulmonary metastasectomy 131–2, 133 renal cell carcinoma (stage T1) 77 staging 82–3 CP-675206 174 cysts, classification 81 cytochrome P450–CYP-3A4 substrates, inhibitors and inducers 200 cytokeratins 54 cytokine-based therapy of metastatic disease 168–9 consensus on use 169 cytotoxic medical therapy 175 cytotoxic T lymphocyte-associated antigen-4 (CTLA4) 174 Denver pleuroperitoneal shunt 140 diabetes mellitus 11–12 diaphyseal lesions, metastatic RCC 147–8, 147, 148 diesel/gasoline engine exhaust 13 diet in etiology of RPC 4–10 diuretics 12, 15 Doppler ultrasound 75–6 drinking water solutes 8 DRR1 25

ECOG score, metastatic RCC 62, 63–5 EGFR 26, 32, 34, 176–9, 181–2 embolization osseous metastases 90–2, 92 for palliation 89–90, 90, 91 renal cancer 89–92 vs nephrectomy 89 endobronchial disease 139–40 presentation 139 treatment 140 epidemiology of renal cell cancer (RCC) 1 incidence rates females 3, 5, 7 males 2, 4, 6 epidemiology of renal pelvic cancer (RPC) 14 incidence rates females 7, 9, 11 males 6, 8, 10 erlotinib, with bevacizumab 181–2 etiology of renal cell cancer (RCC) 1–14 alcohol 3–4 analgesics 12 antihypertensive medications 12 asbestos 13 benzidine 14 cadmium 14 coffee and tea 7–8 diabetes mellitus 11–12 diesel and gasoline engine exhaust 13 diet 4–10 diuretics 12 drinking water solutes 8 genetic susceptibility 14 herbicides/insecticides 14 hypertension 11 hysterectomy 12 lead 14 obesity 8–9 occupational exposures 12–13 oophorectomy 12 physical activity 10 polycyclic aromatic hydrocarbons 13 radiation 12 reproductive factors and hormones 10–11 solvents 13 tobacco 1–3 urinary tract diseases 12 vinyl chloride 14 etiology of renal pelvic cancer (RPC) 14–15 Ewing’s sarcoma 55 18

F-deoxyglucose PET, assessment pre pulmonary metastasectomy 132–3, 133 fatigue 197, 198


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fats, dietary, and RCC 6–7 femur solitary bone metastases, radiographs 144 surgery for bone metastases 146, 146 fever, treatment 198–9 FHIT 24 fibronectin 26 FLT-3 160, 161 folliculin 33 Fuhrman nuclear grading of renal carcinoma 49 gefitinib 34, 35, 182 geldenamycin 34 gene expression, profiling in metastatic RCC 69–70 genetics 23–34 inherited RCC and biochemical pathways 24, 27–34 molecular genetics 23–40 susceptibility 14 Glut1 glucose transporter 29 hand-foot syndrome 197 hematuria, classical presentation of RCC 41–2 hepatic disease, Stauffer syndrome 43 herbicides/insecticides 14 hereditary leiomyomatosis renal cell cancer (HLRCC) 31 gene/product 24 hereditary papillary renal cell carcinoma (HRPC) 30–1 gene/product 24 Xp-translocated papillary RCC 28 see also papillary renal cell carcinoma high-intensity focused ultrasound (HIFU) 92 hip and proximal femur, metastatic RCC 146, 146 histological appearance of tumors 47–59 hormone-related factors 10–11 HSPPPC-96 (vitespen) 159–60, 174 humeral prosthesis 148 hypertension 11 hypotension 199 hypoxia-inducible factor alpha (HIFα) pathway 28–9, 30, 32–3, 34 downregulation 34 downstream targets 34–5 targeted by VHL 30, 49, 161 tumorigenesis 49 hysterectomy 12 IGF-1 9 image-guided ablation 92–9 see also radiofrequency ablation (RFA) imaging 75–85 computed tomography (CT) 76–8

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detection and characterization of renal tumors 80–1 magnetic resonance imaging (MRI) 78–9 positron emission tomography (PET) 79–80 ultrasound 75–6 imatinib 183 immunological factors, prognostic factors in metastatic RCC 68–9 immunotherapy 173–5, 196–7, 198, 199 active specific immunotherapy 158 anti-CTLA4 174 anti-TNFα 174–5 and chemo-immunotherapy 155–8 with interferon alpha 156–7, 156, 168–9, 173 interleukin-2 based therapy 156, 157–8, 167, 168–9, 173 vaccines 158-60, 173–4 inflammatory markers of metastatic RCC 66 infliximab 174–5 inherited RCC and biochemical pathways 24, 27–34 Birt–Hogg–Dubé syndrome, chromophobic and oncocytic renal carcinomas 31–3, 56–7 germline constitutional chromosome 3 translocations 34–5 other hereditary renal cancers 33 VHL gene effects 30 interferon alpha 155–6, 168–9, 173 combined with sorafenib 182 combined with chemotherapy 156–7 side effects 196–7, 198 interleukins IL-2 based therapy 156, 157–8, 167, 168–9, 173 prognostic value in metastatic RCC 68–9 response to therapy in metastatic RCC 70–1 side effects 196, 199 skin reactions 196–8 and thalidomide 176 interventional radiology 87–101 embolization osseous metastases 90–2, 92 for palliation 89–90, 90, 91 in renal cancer 89–92 image-guided ablation 92–9 percutaneous biopsy 87–9 irradiation see radiotherapy ixabepilone (BMS-247550) 175 kinase inhibitor therapy 176–81, 177 unresolved questions 183 see also sorafenib; sunitinib


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knee, metastatic RCC 146–7, 147 Knudsen 2-hit hypothesis 28, 29 lactate dehydrogenase (LDH) 66, 181 laparoscopic partial nephrectomy 121–5 complications 123–5 indications/contraindications 121–2, 122 oncologic outcomes 125 series 124 technique 122–3 warm ischemia vs cold ischemia 123 laparoscopic radical nephrectomy 117–21 advantages and outcomes 118–19, 119, 121 indications 117–18 safety 119, 120–1 technique and surgery 119–20 vs open radical nephrectomy 120 oncological outcome 118 survival 118 lead 14 leiomyomatosis renal cell cancer, gene/ product 24 lung function, spirometry 134 MAD2B 25–6 magnetic resonance imaging (MRI) 78–9 indeterminate lesions 81 left upper pole RCC 79 with percutaneous biopsy 87–9 staging 82–3 malignant pleural effusion 140–1 malignant renal epithelial tumors 47–56 associated with neuroblastoma 53 chromophobe RCC 51–2 classification 24 collecting duct carcinoma 51, 52 Fuhrman nuclear grading of renal carcinoma 49 low-grade collecting duct carcinoma 52–3, 53 mixed epithelial and stromal tumor of kidney 55–6 multilocular cystic RCC 49 neuroepithelial and neuroendocrine tumors 54–5, 55 papillary RCC 50–1 pigmented RCC 50 renal carcinoma associated with Xp11.2 translocation 53 with rhabdoid features 49–50, 50 sarcomatoid RCC 56 unclassifiable 56 WHO classification 48 see also clear cell RCC MCC 25 MDX-010 174

metanephric adenoma 56 metastatic RCC 42, 43, 61–74 classification of bony metastases 150 clinical factors 62–8 demographics 62 disease-related factors 67 performance status (PS) 62 presenting symptoms 62–7 prior treatment 67–8 clinical presentation 42, 43, 61–74 location of metastases 43 multivariable analyses 63–5 natural history 130 osseous see bone metastases prognostic factors for outcome 61–74 cytogenetics 69 gene expression 69–70 genetic factors 69–70 immunological factors 68–9 pathology 68 response to therapy 70–1 survival 62–70 propagation by tumor thrombus 42 relapse pattern of RCC 129–30 frequency of metastases 129 natural history 130 timing of metastases 129 site of metastases 129–30 nodal spread 130 pleural disease 130 pulmonary disease 129–30, 130 spontaneous regression 130 surgery, bone metastases 143–52 see also pulmonary metastasectomy; thoracic RCC methyl methacrylate, osseous metastases, RFA 99 microarrays, profiling in metastatic RCC 69–70 mixed epithelial and stromal tumor of kidney 55–6 molecular genetics 23–40 biochemical pathways 27–34 pathogenesis of RCC 34–5 sporadic RCC 23–7 see also clear cell RCC mTOR, inhibition by temsirolimus 170, 178, 180–1 mTOR pathway, rapamycin 34, 35 mucinous tubular and spindle cell carcinoma 54, 54 multilocular cystic RCC 49 nephrectomy laparoscopic partial 45, 121–5 laparoscopic radical 117–21


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in metastatic disease 167 and nodal dissection 45 open vs laparoscopic radical nephrectomy oncological outcome 118 safety 120 survival 118 radical 44–5 vs embolization 89 neuroblastoma, and RCC 53 neuroepithelial and neuroendocrine tumors 54–5, 55 nm23 25 nodal dissection 45 NRC-1, NRC-2 24 nuclear grading (Fuhrman) 49, 49 obesity 8–9 occupational exposures 12–13 oestrogens 9, 10 OGG1 25 oncocytic renal carcinoma 31–3 oncocytoma 31–3, 56–7 oncogenes, sporadic RCC 26 oophorectomy 12 orthopedic management, metastatic RCC 149 osseous metastases see bone metastases p53 25 palliation embolization 89–90, 90, 91 radiofrequency ablation 99 radiotherapy 195 VATS talc pleurodesis 140–1 papillary adenoma 56 papillary RCC 50–1 classification 24 gene/product 24 histology 50–1 variants (types 1 and 2) 26, 50-1, 51 Xp loss 26 Xp-translocated papillary RCC 28 paraneoplastic syndromes 42–3 parathormone-related peptide 42 pathogenesis of RCC 34–5 new treatment strategies 35 pathological appearance of tumors 47–59 benign renal epithelial tumors 56–7 malignant renal epithelial tumors 47–56 prognostic factors in metastatic RCC 68 PDGFR 34–5, 160, 161, 177–9 pelvis, surgery for metastatic RCC 145–6, 146 percutaneous biopsy 87–9 performance status (PS), metastatic RCC 62 phosphatase and tensin homolog (PTEN) 69

207

physical activity 10 pigmented RCC 50 pleural biopsy, VATS 140 pleural effusions 140–1 diagnosis 140 treatment 140 pleural metastases, relapse pattern of RCC 130 pleuroperitoneal shunt 140 PNET, small round cell tumors 55 polycyclic aromatic hydrocarbons 13 positron emission tomography (PET) 79–80 PET-CT study, recurrent RCC 80 18 F-deoxyglucose PET in pulmonary metastasectomy 132–3, 133 presentation of RCC see clinical presentation of RCC prognostic factors, current systemic medical therapies 167–8 proteasome inhibitors 35 protein kinase C 30 protein and RCC 6–7 pulmonary function tests, spirometry 134 pulmonary metastasectomy 130–9 assessment 131–4 CT and 18F-deoxyglucose PET 132–3, 133 fitness for surgery 133–4 with extrapulmonary metastatic disease 139 historical note 130–1 principles 131 relapse patterns 139 repeat metastasectomy 139 results 137–9 operative mortality and morbidity 137 survival, complete vs incomplete metastasectomy 137–9, 138 surgical approach 136–7 double lumen endotracheal tube 134 incisions 134–6 lateral thoracotomy 135 systematic nodal dissection 137 video-assisted thoracoscopic surgery (VATS) 135 pulmonary metastases cannon-ball deposits 130 relapse pattern 129–30 radiation exposure 12 radiofrequency ablation (RFA) 92–9 circuit arrangement 93 effect on surrounding normal kidney 94 follow-up 96–7 long-term results 97–9 moditoring during treatment 96 in other situations 99 RF probes 94


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success factors 93–4, 95, 96, 97 technique 94–6, 98 radiotherapy 154–5, 191–6 adjuvant/neoadjuvant 154–5, 192 local recurrence 193 metastasis 194–5, 195 palliation 195 postoperative residual disease 193 preoperative radiotherapy 191–2 structures to be considered 194 studies 155 techniques 193–4, 193, 194 unresectable primary disease 192–3 rapamycin, mTOR pathway 29, 32, 34, 35 Ras/Raf/MEK mitogen-activated (MAPK) pathway 32 RASSF1A 25 RB 25 renal cell carcinoma (RCC) associated with neuroblastoma 53 papillary RCC 50–1 pigmented RCC 50 rhabdoid RCC 49–50, 50 unclassifiable 56 see also clear cell RCC renal medullary cancer, sickle cell trait/disease 34 renal oncocytoma 31–3, 56–7 renal pelvic cancer (RPC) 14–15 reproductive factors and hormones 10–11 rigors, treatment 198–9 sarcomatoid RCC 56 shoulder girdle, metastatic RCC 147, 148 sickle cell trait/disease, renal medullary cancer 34 skin reactions 196–8 small round cell tumors 55 smoking 1–3, 14–15 International Agency for Research on Cancer (IARC) 1 solitary kidney, laparoscopic partial nephrectomy 122 solvents 13 sorafenib 34, 35, 160–1, 160, 169–70, 177, 178–9, 178 combined with interferon 182 unresolved questions 182–3 spinal metastases embolization 90–2, 92 RFA 99 surgery 149–50, 151 spindle cell carcinoma 54, 54 spirometry, lung function 134 sporadic renal cell carcinoma (RCC) 23–7 staging of RCC 43–4, 57–8

areas of controversy/future modification 43–4 CT or MRI 82–3 histological sampling of RCC 57 necrosis 57–8 TNM staging 57 2002 system 44 tumor, nodes, metastases 82–3 Stauffer syndrome 43 stem cell transplantation 174 sunitinib 34, 35, 61, 160, 161, 170, 177, 178, 179–80 unresolved questions 182–3 supportive care 196–200 immunotherapy 196–7, 198, 199 multitargeted kinase inhibitors 176–81, 177, 197–200, 200 systematic nodal dissection (SND), in pulmonary metastasectomy 137 systemic medical therapies (current) 167–71 cytokine-based therapy 168–9 immunotherapy 196–7, 198, 199 prognostic factors 167–8 supportive care 196–200 surgery 167 targeted agents 169–70 systemic medical therapies (novel) 173–81 antiangiogenic medical therapy 175–6, 182 combination therapy 181–2 cytotoxic medical therapy 175 immunotherapy 173–5 allogeneic stem cell transplantation 174 kinase inhibitor therapy 176–81, 177, 197–200, 200 unresolved questions 182–3 temsirolimus, kinase inhibitor therapy 170, 178, 180–1 TGF-β 25 thalidomide 35, 175–6 thoracic RCC 129–42 non-pulmonary thoracic metastases 139–41 endobronchial disease 139–40 malignant pleural effusion 140–1 pulmonary metastasectomy 130–9 TNM see staging tobacco 1–3, 14–15 ‘too late’ triad of symptoms 41 tumor necrosis factor (TNF α) 174–5 tumor thrombus, RCC propagation 42 tyrosine kinases, therapy 176–81, 177 ultrasound 75–6 HIFU 92 urinary tract diseases 12


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vaccines 158–60, 173–4 vitespen (HSPPPC-96) 159–60, 174 varicocele, IVC involvement 42 VEGF 176 VEGFR 29, 34, 161, 169, 177–9 metastatic RCC 61 VEGFR-2 and -3 160, 177–9 VHL 23–4, 30, 49, 61, 161 hypoxia-inducible factor α (HIF α) pathway 28–9, 30, 32–3, 34 metastatic RCC 61 tumorigenesis 49 VHL protein complexes 32–3 targets 33 video-assisted thoracoscopic surgery (VATS) pulmonary metastasectomy 135 talc pleurodesis 140–1 vinyl chloride 14 vitamins 6–7

vitespen (HSPPPC-96) 159–60, 174 von Hippel–Landau disease 28–30 clear cell RCC main protein targets of VHL protein 33 VHL effects 23–4, 30, 49, 61, 161 gene/protein product 24 tumor suppressor, chr-3 changes 23–4 WHO classification, malignant renal epithelial tumors 48 Wilms tumor 55 WT1 25 WX-G250 160, 161–2 Xp loss 26 Xp-translocated RCC 11.2 translocation 53 papillary RCC 28

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Clinical Progress in Renal Cancer

Renal Cancer. Methods and Protocols

Renal Cancer Methods And Protocols

Progress in Anti-Cancer Chemotherapy

Gene Therapy in the Treatment of Cancer: Progress and Prospects (Cancer: Clinical Science in Practice)

Cancer neurology in clinical practice

Cancer Chemotherapy in Clinical Practice

Thyroid Cancer in Clinical Practice

Thyroid Cancer in Clinical Practice

Renal Cell Cancer: Diagnosis and Therapy

Renal Cancer: Methods and Protocols (Methods in Molecular Medicine)

Renal Cancer: Methods and Protocols (Methods in Molecular Medicine)

Clinical Cancer Prevention (Recent Results in Cancer Research, Volume 188)

Cancer Neurology in Clinical Practice (Current clinical Oncology)

Renal Disease in Dogs and Cats: Comparative and Clinical Aspects

Cancer: A Comprehensive Clinical Guide

Advances in Targeted Cancer Therapy (Progress in Drug Research)

Renal Physiology

Tumor Budding In Colorectal Cancer: Recent Progress In Colorectal Cancer Research

Autologous And Cancer Stem Cell Gene Therapy (Progress in Gene Therapy) (Progress in Gene Therapy)

Core Concepts in Renal Transplantation

Core Concepts in Renal Transplantation

Prostate and Renal Cancer, Benign Prostatic Hyperplasia, Erectile Dysfunction and Basic Research: An Update (Progress & Controversies in Oncological Urology)

Cancer Clinical Trials: Proactive Strategies (Cancer Treatment and Research)

Methods of Cancer Diagnosis, Therapy and Prognosis, Volume 6: Ovarian Cancer, Renal Cancer, Urogenitary tract Cancer, Urinary Bladder Cancer, Cervical Uterine Cancer

Drug Resistance in the Treatment of Cancer (Cancer: Clinical Science in Practice)

Optical Imaging of Cancer: Clinical Applications

Cancer: Basic Science and Clinical Aspects

Prostate Cancer-Science and Clinical Practice

Optical Imaging of Cancer: Clinical Applications

Clinical Progress in Renal Cancer

Renal Cancer. Methods and Protocols

Renal Cancer Methods And Protocols

Progress in Anti-Cancer Chemotherapy

Gene Therapy in the Treatment of Cancer: Progress and Prospects (Cancer: Clinical Science in Practice)

Cancer neurology in clinical practice

Cancer Chemotherapy in Clinical Practice

Thyroid Cancer in Clinical Practice

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Renal Cell Cancer: Diagnosis and Therapy

Renal Cancer: Methods and Protocols (Methods in Molecular Medicine)

Renal Cancer: Methods and Protocols (Methods in Molecular Medicine)

Clinical Cancer Prevention (Recent Results in Cancer Research, Volume 188)

Cancer Neurology in Clinical Practice (Current clinical Oncology)

Renal Disease in Dogs and Cats: Comparative and Clinical Aspects

Cancer: A Comprehensive Clinical Guide

Advances in Targeted Cancer Therapy (Progress in Drug Research)

Renal Physiology

Tumor Budding In Colorectal Cancer: Recent Progress In Colorectal Cancer Research

Autologous And Cancer Stem Cell Gene Therapy (Progress in Gene Therapy) (Progress in Gene Therapy)

Core Concepts in Renal Transplantation

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Prostate and Renal Cancer, Benign Prostatic Hyperplasia, Erectile Dysfunction and Basic Research: An Update (Progress & Controversies in Oncological Urology)

Cancer Clinical Trials: Proactive Strategies (Cancer Treatment and Research)

Methods of Cancer Diagnosis, Therapy and Prognosis, Volume 6: Ovarian Cancer, Renal Cancer, Urogenitary tract Cancer, Urinary Bladder Cancer, Cervical Uterine Cancer

Drug Resistance in the Treatment of Cancer (Cancer: Clinical Science in Practice)

Optical Imaging of Cancer: Clinical Applications

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