Targeting Treatment of Soft Tissue Sarcomas (Cancer Treatment and Research)

TARGETING TREATMENT OF SOFT TISSUE SARCOMAS

Cancer Treatment and Research Steven T. Rosen, M.D., Series Editor Klastersky, J. (ed): Infectious Complications of Cancer. 1995. ISBN 0-7923-3598-8. Kurzrock, R., Talpaz, M. (eds): Cytokines: Interleukins and Their Receptors. 1995. ISBN 0-7923-3636-4. Sugarbaker, P. (ed): Peritoneal Carcinomatosis: Drugs and Diseases. 1995. ISBN 0-7923-3726-3. Sugarbaker, P. (ed): Peritoneal Carcinomatosis: Principles of Management. 1995. ISBN 0-7923-3727-1. Dickson, R.B., Lippman, M.E. (eds.): Mammary Tumor Cell Cycle, Differentiation and Metastasis. 1995. ISBN 0-7923-3905-3. Freireich, E.J, Kantarjian, H. (eds): Molecular Genetics and Therapy of Leukemia. 1995. ISBN 0-7923-3912-6. Cabanillas, F., Rodriguez, M.A. (eds): Advances in Lymphoma Research. 1996. ISBN 0-7923-3929-0. Miller, A.B. (ed.): Advances in Cancer Screening. 1996. ISBN 0-7923-4019-1. Hait, W.N. (ed.): Drug Resistance. 1996. ISBN 0-7923-4022-1. Pienta, K.J. (ed.): Diagnosis and Treatment of Genitourinary Malignancies. 1996. ISBN 0-7923-4164-3. Arnold, A.J. (ed.): Endocrine Neoplasms. 1997. ISBN 0-7923-4354-9. Pollock, R.E. (ed.): Surgical Oncology. 1997. ISBN 0-7923-9900-5. Verweij, J., Pinedo, H.M., Suit, H.D. (eds): Soft Tissue Sarcomas: Present Achievements and Future Prospects. 1997. ISBN 0-7923-9913-7. Walterhouse, D.O., Cohn, S. L. (eds.): Diagnostic and Therapeutic Advances in Pediatric Oncology. 1997. ISBN 0-7923-9978-1. Mittal, B.B., Purdy, J.A., Ang, K.K. (eds): Radiation Therapy. 1998. ISBN 0-7923-9981-1. Foon, K.A., Muss, H.B. (eds): Biological and Hormonal Therapies of Cancer. 1998. ISBN 0-7923-9997-8. Ozols, R.F. (ed.): Gynecologic Oncology. 1998. ISBN 0-7923-8070-3. Noskin, G. A. (ed.): Management of Infectious Complications in Cancer Patients. 1998. ISBN 0-7923-8150-5. Bennett, C. L. (ed.): Cancer Policy. 1998. ISBN 0-7923-8203-X. Benson, A. B. (ed.): Gastrointestinal Oncology. 1998. ISBN 0-7923-8205-6. Tallman, M.S., Gordon, L.I. (eds): Diagnostic and Therapeutic Advances in Hematologic Malignancies. 1998. ISBN 0-7923-8206-4. von Gunten, C.F. (ed): Palliative Care and Rehabilitation of Cancer Patients. 1999. ISBN 0-7923-8525-X Burt, R.K., Brush, M.M. (eds): Advances in Allogeneic Hematopoietic Stem Cell Transplantation. 1999. ISBN 0-7923-7714-1. Angelos, P. (ed.): Ethical Issues in Cancer Patient Care 2000. ISBN 0-7923-7726-5. Gradishar, W.J., Wood, W.C. (eds): Advances in Breast Cancer Management. 2000. ISBN 0-7923-7890-3. Sparano, Joseph A. (ed.): HIV & HTLV-I Associated Malignancies. 2001. ISBN 0-7923-7220-4. Ettinger, David S. (ed.): Thoracic Oncology. 2001. ISBN 0-7923-7248-4. Bergan, Raymond C. (ed.): Cancer Chemoprevention. 2001. ISBN 0-7923-7259-X. Raza, A., Mundle, S.D. (eds): Myelodysplastic Syndromes & Secondary Acute Myelogenous Leukemia 2001. ISBN: 0-7923-7396. Talamonti, Mark S. (ed.): Liver Directed Therapy for Primary and Metastatic Liver Tumors. 2001. ISBN 0-7923-7523-8. Stack, M.S., Fishman, D.A. (eds): Ovarian Cancer. 2001. ISBN 0-7923-7530-0. Bashey, A., Ball, E.D. (eds): Non-Myeloablative Allogeneic Transplantation. 2002. ISBN 0-7923-7646-3. Leong, Stanley P.L. (ed.): Atlas of Selective Sentinel Lymphadenectomy for Melanoma, Breast Cancer and Colon Cancer. 2002. ISBN 1-4020-7013-6. Andersson , B., Murray D. (eds): Clinically Relevant Resistance in Cancer Chemotherapy. 2002. ISBN 1-4020-7200-7. Beam, C. (ed.): Biostatistical Applications in Cancer Research. 2002. ISBN 1 -4020-7226-0. Brockstein, B., Masters, G. (eds): Head and Neck Cancer. 2003. ISBN 1-4020-7336-4. Frank, D.A. (ed.): Signal Transduction in Cancer. 2003. ISBN 1-4020-7340-2. Figlin, Robert A. (ed.): Kidney Cancer. 2003. ISBN 1-4020-7457-3. Kirsch, Matthias; Black, Peter McL. (ed.): Angiogenesis in Brain Tumors. 2003. ISBN 1-4020-7704-1. Keller, E.T., Chung, L.W.K. (eds): The Biology of Skeletal Metastases. 2004. ISBN 1-4020-7749-1. Kumar, Rakesh (ed.): Molecular Targeting and Signal Transduction. 2004. ISBN 1-4020-7822-6. Verweij, J., Pinedo, H.M. (eds): Targeting Treatment of Soft Tissue Sarcomas. 2004. ISBN 1-4020-7808-0. Finn, W.G., Peterson, L.C. (eds.): Hematopathology in Oncology. 2004. ISBN 1-4020-7919-2.

TARGETING TREATMENT OF SOFT TISSUE SARCOMAS

edited by

Jaap Verweij Department of Medical Oncology Erasmus University Medical Center Rotterdam, The Netherlands and

Herbert M. Pinedo Department of Medical Oncology Free University Medical Center Amsterdam, The Netherlands

KLUWER ACADEMIC PUBLISHERS NEW YORK, BOSTON, DORDRECHT, LONDON, MOSCOW

eBook ISBN: Print ISBN:

1-4020-7856-0 1-4020-7808-0

©2004 Kluwer Academic Publishers New York, Boston, Dordrecht, London, Moscow Print ©2004 Kluwer Academic Publishers Boston All rights reserved No part of this eBook may be reproduced or transmitted in any form or by any means, electronic, mechanical, recording, or otherwise, without written consent from the Publisher Created in the United States of America Visit Kluwer Online at: and Kluwer's eBookstore at:

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Table of Contents 1.

2.

Targeted therapy: Ready for prime time? C. Seynaeve and J. Verweij, Erasmus University Medical Center, Rotterdam, The Netherlands Volume-based radiotherapy targeting in soft tissue sarcoma Iain Ward, Tara Haycocks, Michael Sharpe, Anthony Griffin, Charles Catton, David Jaffray, Brian O’Sullivan, Princess Margaret Hospital, University of Toronto, Toronto, Canada

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3.

Preoperative therapy for soft tissue sarcoma 43 Janice N. Cormier, Howard N. Langstein, Peter W. T. Pisters, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

4.

TNF-based isolated limb perfusion: A decade of experience with antivascular therapy in the management of locally advanced extremity soft tissue sarcomas Dirk J Grünhagen, Flavia Brunstein, Timo L.M. ten Hagen, Albertus N. van Geel, Johannes H.W. de Wilt, and Alexander M.M. Eggermont, Erasmus University Medical Center, Rotterdam, The Netherlands

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5.

Pitfalls in pathology of soft tissue sarcomas Judith V.M.G. Bovée and Pancras C.W. Hogendoorn, Leiden Universtiy Medical Center, Leiden, The Netherlands

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Molecular biology and cytogenetics of soft tissue sarcomas: Relevance for targeted therapies Jonathan Fletcher, Brighams’ and Womens Hospital, Boston, MA, USA KIT and PDGF as targets Jaap Verweij, Erasmus University Medical Center, Rotterdam, The Netherlands Targeting mutant kinases in gastrointestinal stromal tumors: A paradigm for molecular therapy of other sarcomas Mike C. Heinrich, Christopher L. Corless, Portland, OR, USA Targeting other abnormal signalling pathways in sarcoma: EGFR in synovial sarcomas, in liposarcoma Jean-Yves Blay, Isabelle Ray-Coquard, Laurent Alberti, Dominique Ranchere, Hospital Edouard Herriot, Lyon, France Angiogenesis: A potential target for therapy of soft tissue sarcomas K. Hoekman and H.M. Pinedo, Free University Medical Center, Amsterdam, The Netherlands

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Index

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Preface The last decade we have witnessed a major change in the development of new techniques and agents for the treatment of cancer in general, and for soft tissue sarcomas in particular. The important achievements of molecular biology research have changed the landscape markedly. Increasingly subtypes of soft tissue sarcomas are shown to be related to changes in cellular growth factors in the cell signaling pathways. This in theory enabled to development of agents with specific activity against these factors. The presence of the KIT receptor at the surface of the gastrointestinal stroma tumor cell, and the constitutive activation by mutations, has lead to the discovery of the specific KIT tyrosine kinase inhibitor Imatinib, an agent with impressive activity in this disease. Before the era of Imatinib, GIST was an untreatable disease once metastasized. Imatinib clearly is a breakthrough in the approach of soft tissue sarcomas, and will likely serve as a role model for the development of other agents acting towards other receptors. Likewise, soft tissue sarcomas with their specific molecular characteristics, will likely serve as role model diseases for targeted treatment approaches. Whether the future lies in drugs with selective inhibition of only one receptor and one pathway, or multiple receptors and multiple pathways is currently a matter of debate, and again soft tissue sarcomas serve as role model. Fully in line with the more targeted approach in drug use, the changes in the field of radiation therapy and surgery basically also focus on a better targeting of the disease, albeit not based on the molecular characteristics yet. The present volume of this series reflects all of the above mentioned changes. World wide renowned experts have been willing to contribute to this book, and we would like to thank all of them for their efforts. Hopefully this book will contribute to a better understanding of the changes in the field, and will serve our patients in helping getting a better future. Jaap Verweij Herbert M. Pinedo Editors

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Chapter 1 Targeted therapy: Ready for prime time?

Caroline Seynaeve and Jaap Verweij

Dept. of Medical Oncology, Erasmus University Medical Centre-Daniel den Hoed Cancer Centre, Rotterdam, the Netherlands

Correspondence to: Caroline Seynaeve, MD, PhD Dept. of Medical Oncology, Erasmus University Medical Centre-Daniel den Hoed Cancer Centre, Groene Hilledijk 301 3075 EA Rotterdam, the Netherlands

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INTRODUCTION

Soft tissue tumours are a heterogeneous group of rare neoplasm’s with several histiotypes that all share a putative common mesenchymal origin, and account for only 1% of all adult malignancies. Variation in pathological definition has made it difficult to obtain exact numbers of patients with sarcomas. Based on the Surveillance, Epidemiology, and End Results (SEER) database, approximately 8,000 new cases of soft tissue sarcoma (STS) are diagnosed each year in the United States, while 4000 (50%) are dying per annum due to advanced or metastatic disease. This is a 10 times greater mortality that that of testicular cancer or Hodgkin’s disease, diseases with a similar or lower incidence (Stojadinovic et al, 2002). Since metastatic disease is only amenable to curative therapy in very selected cases (Blay et al, 2003) and very few drugs are available with meaningful activity, the search for effective systemic agents remains extremely important in order to improve the outcome and decrease mortality. Progress has long been modest and slow because of the rarity of the disease, the lack of systematic referral of adult patients to specialised centres also being influenced by the advanced age the disease mostly occurs (> 50 years), and the insufficient tumour selectivity of therapies. Further, research in the field of soft tissue sarcoma (STS) has been hampered by the wide range of histological appearances, with overlapping architectural and cytological characteristics, within which at this moment more than 50-100 different entities have been described (Weiss/Goldblum, 2001). Still new entities are being defined by means of improvement in light and electron microscopical appearances, immunohistochemical and molecular biological tools. While it has longer been recognised that many of the subtypes are associated with distinctive clinical and prognostic features, until recently a “onesize-fits-all” approach has been pursued because of the lack of truly targeted therapies. Being aware that this will change in the near future, results of randomised clinical trials on the efficacy of systemic therapy incorporating different subtypes are already difficult to interpret to day, and unfortunately probably will become even less informative in the future. Nevertheless, progress in diagnosis and therapy of adult STS over the last decades of the past century has been achieved resulting from improvement in pathological definition, imaging techniques, staging, surgical operating procedures and advances in limb preservation, the use of radiotherapy as an adjunct to other treatment modalities, a better delineation of the activity of the available chemotherapeutic agents doxorubicin and ifosfamide, and the search for new active drugs. Not to forget, advance has been obtained by the concerted action of the different specialists involved in the care of sarcoma patients working together in a multidisciplinary setting, while the efforts of co-operative

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groups facilitating cross-talk with respect to the communication of trial results and the initiation of new ideas for further studies greatly contributed. The start of this new century is characterised by exciting developments in all of the above as well as in genetic profiling of tumour specimens linking some sarcoma subtypes with distinct histopathological differences to each other and resulting in clarification of the classification of different sarcoma subtypes, and the molecular identification of oncogenes and protein products that will enable the development of targeted therapies. While the administered chemotherapy in the last century seemed independent of the subtype of STS, we are entering an era shifting towards targeted therapy for a specific subtype which hopefully will yield more benefit for both the patient and the scientific research group. As said, clinical trial design will also undergo change to reflect the nature of these therapies. However, since this strategy is not yet to-days practice, attempts to refine the currently available therapeutic armamentarium to maximise the therapeutic index by means of dose intensification and the identification of new agents with certain activity also remain of paramount importance. On the way to a new approach and further advance in systemic therapy in STS, various issues may be of importance which we will address in the following paragraphs: optimal use of systemic therapy at the beginning of the century, new and pipeline agents, molecular targets and signal transduction pathways, and changing methodology on testing new agents for activity.

2 CENTURY

CHEMOTHERAPY AT THE BEGINNING OF THE

Although over the last decades several known and new compounds have been tested for activity in STS, only doxorubicin and ifosfamide have meaningful activity. For both drugs a dose-response curve in STS has been identified, with higher response rates for doxorubicin administered at a cycle dose of and ifosfamide at a cycle dose of or more. Reported single agent response rates vary between 16-36%. Dacarbazine, while yielding some activity, has only shown short lasting responses of limited value (Seynaeve/Verweij, 1999; O’Sullivan et al, 2002). The value of these drugs has been studied in neo-adjuvant, adjuvant and metastatic setting.

2.1

(Neo-)Adjuvant Chemotherapy

The value of neo-adjuvant or adjuvant chemotherapy continues to be a matter of debate. Although the only randomised study investigating the value of neo-adjuvant therapy, by means of standard doses of adriamycin/ifosfamide, conducted by the EORTC failed to show any benefit in disease free and overall

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survival (Gortzak et al, 2001), the question remains actual since other groups have suggested impressive response rates using more dose-intensive regimens (Patel et al, 1998; Patel, 2002). The discussion has recently been stirred up by the results of the study by Delaney et al. reporting on the activity of MAID (mesna, adriamycin, ifosfamide and dacarbazine) interdigitated with radiotherapy and followed by surgery and postoperative chemotherapy in a subset of STS at very high risk of distant metastasis (Delaney et al, 2003, O’Sullivan/Bell, 2003). In comparison with a cohort of historical controls, the MAID regimen resulted in a dramatic improvement of distant disease free, disease-free and overall survival being 75% and 44%, 70 and 42%, and 87% and 58% respectively, all being statistically significant. As appealing these data may seem however, they have to be interpreted with great caution since all results come from non-randomised studies, while this approach should be investigated in randomised studies to avoid for bias in the comparative groups before it can be incorporated as standard of care. A similar discussion is ongoing with respect to the role of adjuvant therapy in STS (Verweij/Seynaeve, 1999). The most powerful evaluation of the value of chemotherapy (doxorubicin-based, standard doses versus control) originated from the Sarcoma Meta-Analysis Collaboration (SMAC) and showed a statistically significant improvement in local relapse-free survival (6%), distant metastasis-free (10%) and disease-free survival (10%) for treated patients, but only a trend toward an increased overall survival (4%) after a median follow-up of 9.4 years (SMAC, 1997). In 2001, the Italian Sarcoma Group reported that an intensified chemotherapy regimen consisting of epirubicin/ifosfamide in comparison with a control group, resulted in a significant increase of disease-free (48 versus 16 months, p=.04) and overall survival (75 versus 46 months, p=.03) in high-risk STS after a follow up of 59 months. Although this study was prematurely closed because of the interim results in favour of the chemotherapy group, it has to be noticed that where fewer metastatic events were seen at 2 years in the chemotherapy group (28% vs. 45%), identical metastatic rates were observed at the 4-year time point (Frustaci et al, 2001). Long term follow-up data from this study are therefore crucial, especially, where two other small studies using intensive anthracycline/ifosfamide regimens failed to confirm a benefit (O’Sulllivan/Bell, 2003). Further, the data of the ongoing EORTC study investigating the value of doxorubicin versus controls will hopefully add relevant information on this issue

2.2

Metastatic disease

In contrast with above-mentioned settings, the aim of systemic therapy in metastatic disease is disease control, symptom palliation and prolonged survival. As there are only modest gains in survival with the use of known chemotherapeutic agents, studies in the last decades of the century have focused on schedule optimisation and/or dose intensification (Bramwell et al,

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2000; Seynaeve/Verweij, 2002). Conclusions from these studies are that combination chemotherapy regimens produced higher response rates and more toxicity, but did not improve the complete response rate, the time to failure or overall survival. Some recent studies investigating more dose-intensive anthracyclin/ifosfamide regimens show unexpectedly high response rates, and resulted in a higher complete response percentage that may be important aiming at improved survival in selected individuals (Patel et al, 1998; Blay et al, 2003). However, these regimens have not yet been tested in a randomised setting. Therefore, the recently activated international world-wide EORTC-lead study, realised through the global co-operation of different collaborative groups, in which patients are randomised between doxorubicin (control) and a dose-intensified regimen (doxorubicin plus ifosfamide with G-CSF support) is warmly welcomed, while results are eagerly awaited and hopefully will bring an answer to a long-lasting question.

3 SYSTEMIC THERAPY – OLD DRUGS IN A NEW JACKET / NEW DRUGS Over the last decades of clinical research it has been recognised that many of the STS subtypes are associated with distinctive clinical and prognostic features. Therefore, it has already longer been questioned whether the “one-sizefits-all-approach” with respect to chemotherapy as has been applied till now is still appropriate. An analysis of the Soft Tissue and Bone Sarcoma Group Study (STBSG) of the EORTC into prognostic factors for the outcome of chemotherapy in advanced STS reported in univariate analysis an increased overall survival (OS) in lipo- and synovial sarcoma (SS), a decreased survival time in malignant fibrous histiocytoma (MFH), a lower response rate in leiomyosarcoma (LMS), and a higher response rate in liposarcoma (p 50% in synovial and liposarcoma, and in LMS and MFH (see figure 1) (van Glabbeke et al, 2002). This is in accordance with the clinical observation that SS is more chemo-sensitive. Whether this chemosensitivity indeed especially

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concerns high-dose ifosfamide as has been reported in small series (Rosen et al, 1994, Spillane et al, 2000), remains to be proven in larger studies. However, the above mentioned may partly explain why some investigators report impressive results of a certain agent in a specific STS subtype, albeit that this was never observed in properly designed studies allowing inclusion of a variety of subtypes. Paxlitaxel has been studied in patients after or without prior exposure to first line chemotherapy showing response rates between 0% and 12,5% (Blacerzak et al, 1995; Patel et al, 1997; Casper et al, 1998). Despite the lack of meaningful activity of paclitaxel for the whole STS group, responses in two of these studies were seen in patients with an angiosarcoma (Blacerzak et al, 1995; Casper et al, 1998). Based on these observations, Fata et al. reviewed their institutional experience with paclitaxel (different schedules) in nine patients with an angiosarcoma of the scalp/face, and found an impressive response rate of 89% with a median duration of 5 months (Fata et al, 1999). Attempts are being undertaken to try to investigate this further in a global study. Fewer studies have investigated docetaxel. In an initial phase II study conducted by the EORTC activity was seen in 18% of the patients. In a subsequent randomised study by the same EORTC group with doxorubicin as the control agent, docetaxel did not show any activity in 34 patients including 3 patients with an angiosarcoma, while a response was seen in 1/3 angiosarcoma patients in the doxorubicin arm (Verweij et al, 2000). In the EORTC analyses, LMS was reported to be less chemo-sensitive. One has to be aware that these data certainly are influenced by the fact that some of the LMS nowadays would be classified as GIST, known to be chemo-resistant. Investigating the value of gemcitabine in STS in small phase II studies some activity has been observed, with a pharmacological advantage being suggested with a 150-minute infusion. Responses to gemcitabine were particularly seen in uterine leiomyosarcoma whereas none were noted in gastrointestinal LMS (Spath-Swalbe et al, 2000; Patel et al, 2001; Svancarova et al, 2002; Okuno et al, 2002 and 2003). Interestingly, the combination of gemcitabine and docetaxel showed an impressive response rate of 53% in a nonrandomised phase II study in chemotherapy-naive or pretreated LMS, being 55% in uterine and 40% in other LMS, respectively. The performed pharmacokinetic evaluation in this study demonstrated that the 90-minute infusion time resulted in approximately 50% longer period of time above the gemcitabine concentration threshold of which may be important for greater DNA incorporation of gemcitabine affecting cell kill (Hensley et al, 2002). Although it is difficult to assess from this small study whether the high response rate is caused by the chemo-sensitivity of uterine LMS, which also has been suggested by others (Leyvraz et al, 2001; Pautier et al, 2002), the longer infusion schedule of gemcitabine or the synergistic activity of the chemotherapy combination, or just chance, these results are interesting enough to warrant further investigation into this issue.

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ET-743 (Trabectedin), a cytotoxic tetrahydroisoquinolone alkaloid isolated from a murine organism that binds to DNA and causes single strand breaks resulting in cell death, has over the last years been studied as novel antitumor agent in STS, because it had shown potent antiproliferative activity in vitro (Delaloge et al, 2001). While objective response rates in second line therapy for the whole group were modest, ranging between 6% and 8%, better response rates were seen in LMS and liposarcoma (14% and 16%) and the response duration was months (le Cesne, 2002). Even more important, in all studies performed in Europe and the United States impressive long-lasting major responders as well as a high number of durable stable diseases (+/- 50%) were seen. Overall survival at 12 months was consistently between 45-55%, for a category of patients being refractory to first line therapy and starting on the drug at documented progression (Demetri, 2002; Brain, 2002). The observation of a long durable response and stable disease, associated with clinical benefit in symptomatic disease, resulted in reconsideration of the optimal way of response assessment of novel antitumor agents in STS, as we will comment on later.

4 MOLECULAR TARGETS AND SIGNAL TRANSDUCTION PATHWAYS IN SOFT TISSUE SARCOMA

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The success of imatinib mesylate in treatment of GIST has led to a better appreciation of how studies of STS can enhance the understanding of cancer biology and development of targeted therapies. It also has taught us that expression of a target may not be enough to build a targeted clinical trial upon, but that it may be relevant to conduct model studies on the functional relevance of the target for tumour growth. Once this is established there is a justification to perform clinical studies directed towards this target. If functional relevance can not be proven because of the lack of appropriate assays, one has to be aware that the pragmatism of nevertheless studying the target in a clinical setting may be useful and may yield relevant information. The identification of new and relevant targets being involved in STS is one of the crucial steps. Microarray analysis allowing for the determination of gene expression profiles in sarcoma specimens may prove to be most useful hereby. Nielsen et al. recently reported data from a set of 41 sarcomas and described characteristic expression profiles for GIST (with kit being the discriminator gene), monophasic synovial sarcomas involving the retinoic-acid pathway and the epidermal-growth-factor receptor (EGF), subgroups of LMS (calponin-positive and –negative), while MFH and liposarcoma exhibited considerable heterogeneity (Nielsen et al, 2003). Lee et al., studying gene expression profiles in SS, LMS and MFH (n=9 in each group), also found a distinct pattern in SS, and identified a subset of MFH, but did not distinguish two separate LMS groups (Lee et al, 2003). Unfortunately, there was very little overlap between the identified genes in the two SS clusters, on one hand because other gene sets have been studied and selected, on the other hand possibly influenced by the subtype of SS studied which is not specified in the study of Lee et al. Further, these findings reflect that it is necessary to study large enough sarcoma samples before coming to conclusions. However, the observation that EGF is expressed in monophasic SS, while erb-B2 expression has been demonstrated in the epithelial component of biphasic SS (Nielsen et al, 2003; Borden et al, 2003) opens avenues to test the value of EGF-inhibitors or herceptin in this disease, which is further addressed in chapter 9. In addition, in vitro studies have shown that epithelioid sarcoma cells overexpressing EGFR1 respond to EGFR1-antibody therapy, lending support to test these inhibitors in epithelioid sarcoma. In inflammatory myofibroblastic tumours (IMT’s) composed of spindled mesenchymal cells admixed with a striking inflammatory infiltrate predominantly consisting of plasma cells and lymphocytes, the neoplastic nature became apparent by the observation that translocations and other rearrangements in the short arm of chromosome 2 occurred in the IMT spindle cells. These aberrations create fusion oncogenes that encode activated forms of the ALK receptor tyrosine kinase. ALK fusion oncoproteins are also characteristic for many anaplastic large cell lymphomas (Tuveson/Fletcher, 2001). Specific antagonists of these proteins may be effective in this type of diseases, but are not yet available.

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Most dermatofibrosarcoma protuberans tumours contain a translocation of chromosomes 17 and 22, resulting in oncogenic juxtaposition of the COL1A1 and platelet-derived growth factor beta genes. Since imatinib mesylate

is also an inhibitor of and it is assumable that glivec may be effective in this disease. Activity of glivec in this entity, indeed, has been reported in two case reports, underscoring this assumption (Schuetze et al, 2002; Labropoulos et al, 2003). Likely, most desmoplastic round cell tumours (DRCT’s) express an EWS-WT1 fusion oncogene resulting from a translocation of chromosomes 11 and 22. The oncoprotein EWS-WT1 is a transcriptional regulator inducing expression of which binds and activates both PDGFreceptors and (Tuveson/Fletcher, 2001). Since DRCT’s are quite chemotherapy-resistant it certainly is worthwhile to study the activity of glivec in this entity as well. This topic is further highlighted in chapter 9. The use of farnesyl transferase inhibitors (FTI) to target the oncogenic ras protein may be applicable in sarcomas overexpressing the ras protein, as is the case in the neurofibromatosis syndrome 1, which can predispose to malignant peripheral nerve sheath tumours (MPNST). FTIs can inhibit the trafficking of ras protein to the cell membrane by inhibition of the farnesylation of this protein (Scappaticci/Marina, 2001). Liposarcomas tend to be of low grade and generally have a better survival than many other STS subtypes. There is some laboratory evidence that the heterodimeric complex of peroxisome proliferator-activated receptor-gamma and the retinoid acid receptor (RAR) alpha functions as a central regulator or adipocyte differentiation, while it has been demonstrated that human liposarcoma cells can be induced to undergo terminal differentiation by treatment

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by PPAR ligand pioglitazone. Demetri et al. have used troglitazone, an analogue drug mediating differentiation, to attempt differentiation in poorly differentiated subtypes of liposarcoma (Scappaticci/Marina, 2001). This is further addressed in chapter 9. Finally, angiogenesis inhibitors are of great interest in STS, on one hand because of the important involvement of vessels in vascular sarcomas e.g. angiosarcomas and hemangioendotheliomas, and on the other hand because it may give us yet another mechanism to attack STS. In chapter 10 an overview is provided.

5 CHANGING METHODOLOGY ON TESTING NEW AGENTS FOR ACTIVITY Although phase II studies performed in a small group of patients suffer from biases with respect to random and prognostic variables (age, performance status, disease free interval, histotype....) or other unknown variables, they remain useful as screening studies to evaluate whether a new agent has biological activity (rather than therapeutic benefit) in the intended cohort of patients. If the results of the phase II trial are consistent with activity as expected from an active drug, the new agent deserves further testing. If results are consistent with the level of activity from an inactive drug, then the experimental agent is rejected from further investigation. Sample size is computed to ensure that these 2 decision rules are mutually exclusive. The statistical design to use by preference remains the two steps optimal and minimax design as proposed by Simon (van Glabbeke et al, 2002) Response to therapy, based on a measured decrease in the size of objective lesions, is considered the most effective end-point to document biological activity of cytotoxic agents. However, for non-cytoreductive anticancer drugs, as for example for signal transduction inhibitors and angiogenesis inhibitors, biological activity is frequently not expected to translate into a diminution of lesions, but rather in slowing down or arrest the growth acceleration. This still may result in clinical benefit (decrease of symptoms, improved quality of life, increase of progression free survival). The benefit of static disease (long term SD) during a certain therapy has since long been recognised for breast cancer, showing that survival in patients with durable SD (> 6 months) was similar to the survival in patients achieving an objective response for both first- and second-line endocrine therapies (Robertson et al, 1997 and 1999). However, these observations have been obtained in randomised studies, while data on stable disease rate in most phase II studies are lacking. Nevertheless, the data on ET-743 in STS suggest that stable disease induced by a cytotoxic agent may be worthwhile and actually underestimated in this entity. This is further substantiated by a recent retrospective literature review on a large number of cytotoxic agents tested in STS (Verweij/van Glabbeke, 2003).

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Since in phase II screening studies of biological agents response rate is not always an appropriate endpoint, an alternative endpoint may be “progression free survival/rate” (PFR) or “time to progression”. This endpoint has properly been defined by the RECIST Working Group and was considered a valuable alternative to estimate the biological activity of this type of agents in phase II studies by the EORTC and also by others (Therasse et al, 2000; Korn et al, 2001). However, the appropriate time point of assessing PFR has not been clearly defined, partly because this may be disease- or agent-specific and therefore impossible to define in general. The purpose of the earlier mentioned analysis of the EORTC studying the PFR in STS obtained by an active or an inactive agent, in the assumption that doxorubicin, ifosfamide and dacarbazine (as generally accepted) are the only active agents, has exactly been set up to clarify this for STS (van Glabbeke et al, 2002). In pre-treated patients (n=380), which is the relevant group for the purpose of phase II screening studies, the 3- and 6- months progression free rates were respectively 39% and 14% for an active drug (n=234), and 21% and 8% for an inactive agent (n=146). For the whole cohort, the rates were 28% and 10%. The Kaplan-Meier estimate of the PFR in patients treated with an active of an inactive drug is shown in figure 2 (standard error approximately 5%). The selection of an appropriate time point for PFR is known to be a compromise between the need to avoid false-positive trials, and practical burdens coincided with a long period of observation. If the disease is slowly progressing, absence of objective progression at the first evaluation (generally 6-8 weeks after the start of therapy) may not reflect any substantial drug activity. In the EORTC study there was no major discrimination between active and inactive agents at this time point. On the other hand, a study requiring a long treatment and follow-up period in this setting, which possibly can extend over years (as in GIST), may logistically be difficult to conduct and is unattractive in view of the purpose of a phase II study, which is to screen new agents for activity. Therefore, the EORTC suggested evaluating the progression free status at 3 and 6 months after the start of therapy. Further, the EORTC proposed to consider a drug as active in first line therapy of STS if the PFR at 6 months is 30-55% (depending on histology). For second line therapy, a PFR at 3 months of 40% would suggest drug activity, and 20% would suggest inactivity (van Glabbeke et al, 2002; Verweij/van Glabbeke, 2003). Another way of looking at the data could be to take together objective response and stable disease rate, resulting in the determination of the rate of no progression. Although van Oosterom already in 1986 proposed to use “progression arrest” as an endpoint in phase II studies (van Oosterom, 1986), the idea was only recently picked up by the NCIC that developed a multinomial phase II stopping rule using response and early progression. They showed that this was more efficient as compared to the usually used stopping rules (Dent et al., JCO, 2001). These data certainly would gain strength if PFR or progression arrest rates could be assessed by means of the use of the EORTC database in

12

combination with those of other co-operative groups, possibly even resulting in the determination of subtype specific progression arrest rates. Further, this would provide strong suitable tools that could serve as reference for future phase II studies aiming at more efficient screening of new and old drugs for activity in STS.

6

CONCLUSION

The fast development and application of microscopic and new immunohistochemical tools, molecular and cytogenetic analytical methods results in a better identification of specific or clusters of subtypes in STS, and provides specific molecular targets to which selected agents are being developed. This allows for a further evaluation of the characteristics and chemo-sensitivity of these different subtypes to known agents, and necessitates the prospective screening of selected (old and new) drugs in subtype specific cohorts of patients. Further, the drugs aiming at targeting the identified molecular target also have to be tested in subtype specific studies. In order to make this process as efficient as possible the endpoints of phase II screening studies should be clearly selected. We propose to use the 3and 6- month PFR as a reference value in phase II screening studies, while progression arrest also may be of relevance. Moreover, performing these screening studies of molecular targeting agents in a cohort of patients expressing the specific target in a disease already rarely occurring will not be possible

13

without a joined effort and a global co-operation of the several co-operative groups. We hope that the topics in this book may contribute to a better understanding hereby, and stimulate the co-operation and participation into initiated screening studies.

7

REFERENCES

1. Balcerzak SB, Benedetti J, Weiss GR et al. (1995) A phase II trial of paclitaxel in patients with advanced soft tissue sarcomas. Cancer 76, 2248-2252 2. Blay J-Y, van Glabbeke M, Verweij J, et al. (2003) Advanced soft tissue sarcoma: a disease that is potentially curable for a subset of patients treated with chemotherapy. Eur J Cancer 39: 64-69 3. Borden EC, Baker LH, Bell RS et al. (2003) Soft tissue sarcomas of adults: state of the translational science. Clin Cancer Research 9: 1941-56 4. Brain EGC (2002) Safety and efficacy of ET-743: the French experience. Anti-cancer Drugs 13 (suppl 1): 11-14 5. Bramwell V, Anderson HC, Charette ML et al. (2000) Doxorubicin-based chemotherapy for the palliative treatment of adult patients with locally advanced or metastatic soft tissue sarcoma: a meta-analysis and clinical practice guidelines. Sarcoma, 4: 103-112 6. Casper ES, Waltzman RJ, Schwartz GK et al. (1998) Phase II trial f paclitaxel i patients with soft tissue sarcoma. Cancer Invest 16: 442-446 7. Delaloge S, Yovine A, Taamma A et al. (2001) Ecteinasidin-743: a marine derived compound in advanced, pretreated sarcoma patients – preliminary evidence of activity. J Clin Oncol 19: 12481255 8. Delaney TF, Spiro IJ, Suit HD et al. (2003) Neoadjuvant chemotherapy and radiotherapy for large extremity soft tissue sarcoma. Int J Radiat Oncol Biol Phys, 56: 1117-1127 9. Demetri GD (2002) ET-743: the US experience in sarcomas of soft tissues. Anti-cancer Drugs 13 (Suppl 1): 7-9 10. Dent S, Zee B, Dancey J et al. (2001) Application of a new multinomial phase II stopping rule using response and early progression. J Clin Oncol 19: 785-791 11. Fata F, O’Reilly E, Ilson D et al. (1999) Paclitaxel in the treatment of patients with angiosarcoma of the scalp or face. Cancer 86: 2034-2037 12. Frustaci S, Gherlinzoni F, de Paoli A, et al. (2001) Adjuvant chemotherapy for adult soft tissue sarcomas of the extremities and girdles : results of the Italian randomized cooperative trial. J Clin Oncol, 19: 1238-1247 13. Gortzak E, Azarelli A, Buesa J et al. (2001) A randomised phase II study on neo-adjuvant chemotherapy for “high-risk”adult soft tissue sarcoma. Eur J Cancer 37: 1096-1103 14. Hensley ML, Maki R, Venkatraman E et al. (2002) Gemcitabine and docetaxel with unresectable leiomyosarcoma: results of a phase II trial. J Clin Oncol 20: 2824-2831 15. Korn EL, Arbuck SG, Pluda JM et al. (2001) Clinical trial designs for cytostatic agents: are new approaches needed? J Clin Oncol 19: 265-272 16. Labropoulos SV, Papadopoulos S, Hadjiyiassemi L et al. (2003) Response of metastatic dermatofibrosarcoma protuberans to imatinib mesylate. Proceedings ASCO 2003, J Clin Oncol 22: 830 (#3334) 17. Le Cesne A. (2002) Improving efficacy in soft tissue sarcoma. Satellite symposium ESMO 2002, 18 October, Nice, France. 18. Lee Y-F, John M, Edwards S et al. (2003) Molecular classification of synovial sarcomas, leiomyosarcomas and malignant fibrous histiocytomas by gene expression profiling. Brit J Cancer 88: 510-515

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19. Leyvraz S, Jundt G, Lissoni A et al. (2001) High-dose Ifosfamide and doxorubicin for the treatment of gynaecological sarcomas. Proceedings ASCO 2001, J Clin Oncol 20 (part 1): 362a (#1443) 20. Nielsen TO, West RE, Linn SC et al. (2002) Molecular expression of soft tissue tumours: a gene expression study. Lancet 359: 1301-1307 21. Okuno S, Edmonson J, Mahoney M et al. (2002) Phase II trial of gemcitabine in advanced sarcoma. Cancer 94: 3225-3229 22. Okuno S, Ryan LM, Edmonson J et al. (2003) Phase II trial of gemcitabine in patients with advanced sarcomas. Cancer 97: 1969-1973 23. O’Sullivan B, Bell RS, Bramwell V (2002) Sarcoma of the soft tissue. In: Souhami R, Tannock I, Hohenberger P, and Horiot JC (eds): Oxford Textbook of Oncology. Oxford University Press, Oxford, UK, 2002, 2495-2523 24.O’Sullivan B, Bell RS (2003) Has “MAID” made it in the management of high-risk soft tissue sarcoma? Int J Radiat Oncol Biol Phys, 56: 915-916 25. Pautier P, Genestie C, Fizazi K et al. (2002) Cisplatin-based chemotherapy regimen (DECAV) for uterine sarcomas. Int J Gynaecol Cancer 12: 749-754 26. Patel SR, Linke KA, Burgess MA et al. (1997) Phase II study of paclitaxel in patients with soft tissue sarcomas. Sarcoma 1, 95-97 27. Patel SR, Vadhan-Rai S, Burgess MA, et al. (1998) Results of two consecutive trials of doseintensives chemotherapy with doxorubicin and ifosfamide in patients with sarcoma. Am J Clin Oncol 21: 317-321 28. Patel SR, Gandhi V, Jenkins J et al. (2001) Phase II clinical investigation of gencitaine in advanced soft tissue sarcomas and window evaluation of dose rate on gemcitabine triphosphate accumulation. J Clin Oncol 19: 3483-4389 29. Patel SR (2002) Systemic therapy for advanced soft tissue sarcoma. Curr Oncol Rep 4: 299304 30. Robertson JFR, Wilsher PC, Cheung KL et al. (1997) The clinical relevance of static disease category for 6 months on endocrine therapy in patients with breast cancer. Eur J Cancer 33: 17741779 31. Robertson JFR, Howell A, Buzdar A et al. (1999) Static disease on anastrozole provides similar benefit as objective response in patients with advanced breast cancer. Breast Ca Res & Treatm 58: 157-162 32. Rosen G, Forscher C, Lowenbraun S et al. (1994) Synovial sarcoma: uniform responsee of metastases to high-dose ifosfamide. Cancer 73: 2506-2511 33. Sarcoma Meta-Analysis Collaboration (1997) Adjuvant chemotherapy for localised respectable soft tissue sarcoma of adults: meta-analysis of individual data. Lancet 350: 1647-1654 34. Scappaticci FA, Marina N (2001) New molecular targets and biological therapies in sarcomas. Ca Treatm Reviews 27: 317-326 35. Schuetze SM, Rubin BP, Eary JF et al. (2002) Molecular targeting of PDGF beta by imatinib mesylate in dermatofibrosarcoma protuberans. Proceedings CTOS 2002, Sarcoma 6 (suppl 2): 71 (#25) 36. Seynaeve C, Verweij J (1999) High-dose chemotherapy in adult sarcomas: no standard yet. Semin Oncol, 26: 119-133 37. Seynaeve C, Verweij J. (2002) High dose chemotherapy in sarcomas: science, fiction or science fiction? In: Lorigan P, Vandenberghe E (eds): High dose chemotherapy, Principles and Practice. Dunitz Publishers, London, UK, 2002, 167-179, 38. Spath-Schwalbe E, Genvresse I, Koschuth A et al. (2000) Phase II trial of gemcitabine in patients with pretreated advanced soft tissue sarcoma. Anti-cancer drugs 11: 325-329 39. Spillane AJ, A’Hern R, Judson I et al. (2000) Synovial sarcoma: a clinicopathologic, staging, and prognostic assessment. J Clin Oncol, 16: 1794-3803 40. Stojadinovic A, Leung DHY, Allen P et al. (2002) Primary adult soft tissue sarcoma: Timedependent influence of prognostic variables. J Clin Oncol 20: 4344-4352

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41. Svancarova L, Blay J-Y, Judson I et al. (2002) Gemcitabine in advanced adult soft tissue sarcomas. A phase II study of the EORTC soft tissue and bone sarcoma group. Eur J Cancer 38: 556-559 42. Therasse P, Arbuck GA, Eisenhauer EA et al. (2000) New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92: 205-216 43. Tuveson DA, Fletcher JA (2001) Signal transduction pathways in sarcoma as targets for therapeutic intervention. Curr Opin Oncol 13: 249-255 44. Van Glabbeke M, van Oosterom AT, Oosterhuis JW et al. (1999) Prognostic factors for the outcome of chemotherapy in advanced soft tissue sarcoma: an analysis of 2,185 patients treated with anthracycline-containing first line regimens – an EORTC soft tissue and bone sarcoma group study. J Clin Oncol 17: 150-157 45. Van Glabbeke M, Verweij J, Judson I et al. (2002) Progression-free rate as the principal endpoint for phase II trials in soft-tissue sarcomas. Eur J Cancer 38: 543-549 46. Van Oosterom AT (1986) Phase II new drug trials in soft tissue sarcomas. In: Pinedo H and Verweij J (eds): Clinical management of soft tissue sarcomas. Boston, MA, Martinus Nijhoff Publishers, 131-138 47. Verweij J, Seynaeve C. (1999) The reason for confining the use of adjuvant chemotherapy in soft tissue sarcoma to the investigational setting. Semin in Radiation Oncology, 9: 352-359 48. Verweij J, Lee SM, Ruka W et al. (2000) Randomized phase II study of docetaxel versus doxorubicin in first- and second-line chemotherapy fr locally advanced or metastatic soft tissue sarcoma in adults: a study of the EORTC soft tissue and bone sarcoma group. J Clin Oncol 18: 2081-2086 49. Verweij J, van Glabbeke M (2003) Translating targets into treatment: changes in trial methodology and treatment approaches for soft tissue sarcomas. In: Educational book, ASCO 2003, 522-530 50. Weiss SW, Goldblum JR (2001) In: Weiss SW, Goldblum JR (eds): Enzinger and Weiss’s Soft Tissue Tumors. Mosby Inc, St Louis, Missouri, 2001: 1-19

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Chapter 2 Volume-based radiotherapy targeting in soft tissue sarcoma Iain Ward1 ,Tara Haycocks2, Michael Sharpe3, Anthony Griffin4, Charles Catton1, David Jaffray3, Brian O’Sullivan1

Departments of Radiation Oncology1, Radiation Therapy2, Medical Physics3, and Surgical Oncology4, Princess Margaret Hospital, University of Toronto, Toronto, Canada.

Correspondence: Brian O’Sullivan Department of Radiation Oncology Princess Margaret Hospital University of Toronto 610 University Avenue Toronto, Ontario Canada, M5G 2M9 Tel: 416 946 2123 Fax: 416 946 6556 Email: [email protected]

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1

INTRODUCTION

Although a highly effective adjuvant therapy, traditional radiotherapy (RT) target volumes used for STS have largely been constrained by available technology and are not ideal in some situations; this includes inadequate dose administration because of normal tissue constraints and/or the necessity for excessive volume coverage of normal tissue to encompass the tumor region. The advent of very precise treatment planning and delivery systems, including three dimensional conformal radiotherapy (3D CRT) and intensity modulated radiotherapy (IMRT), means it is now possible to select target volumes that more closely approach the optimum. Consequently, these new approaches provide great opportunity for treatment enhancement in the future. In this chapter, the principles of RT will be discussed as they relate to current or potential uses in the management of soft-tissue sarcoma (STS). Specific examples of situations in STS that lend themselves to volumetric-based RT planning approaches will be depicted to illustrate theses concepts and detailed background to the use of such approaches will be provided.

2

DEFINING TARGETS FOR RADIOTHERAPY OF STS

2.1

Tissues at risk

The choice of RT volumes in STS is profoundly influenced by the appreciation of the existence of a zone that may contain sub-clinical disease in proximity to the presenting site of the primary tumour. The size and extent of the putative ‘risk zone’ depends on a number of factors, and appreciating this will effect the target volume chosen for radiotherapy. Also, perhaps more than most cancers, the pathway to appropriate treatment may already have been declared by events that have taken place prior to referral. For example, the type of biopsy that may have already been performed, or a prior inappropriate excision may jeopardize the form and outcome of local treatment thereafter. 1

2.2

Local patterns of spread

In broad terms, soft tissue sarcomas tend to spread in a longitudinal direction within the muscle groups of the extremity. They generally respect barriers to tumor spread in the axial plane of the extremity such as bone, interosseous membrane, major fascial planes, etc. Thus the margins of radiation therapy must be wide in the cephalo-caudal direction but in the cross section there may be much greater security in defining non-target structures. For nonextremity lesions (e.g. head and and neck and torso lesions), the direction of sarcoma growth is also along the involved musculature but care must be taken to

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ensure that the fascial planes are appropriately recognized and encompassed in the radiation target volume. 2

2.3

Regional lymphatic pathways of spread

Regional lymph node involvement in STS is unusual and for most histological sub-types the nodal areas are not ordinarily treated electively. Important exceptions to this generalization include epithelioid sarcoma, clear cell sarcoma, angiosarcoma, and embryonal rhabdomyosarcoma.2 However the presence of overt regional lymph node disease generally prompts their inclusion, if the patient is being considered for curative management, although we recognize that institutional preference may vary in this regard. In targeting the lymphatic drainage areas, it is usual to treat the chain along the vascular supply to eventually reach the terminal group of lymph nodes that are at risk. 2

2.4

Paucity of available evidence

Unfortunately, with one exception,3 no formal assessment of target volumes in STS has been undertaken using contemporary hypothesis solving techniques such as comparative clinical trials. Also, problems in defining the gross tumor volume (GTV) will persist until resolution of dilemmas surrounding imaging characteristics occurs, at least when considering pre-operative radiotherapy where the volumes are most selectiveFor example, one obvious problem concerns the significance of peritumoral edema evident on magnetic resonance imaging4 and whether such areas should be considered part of the GTV (see figure 1).

2.5

Extracompartmental sarcoma

Certain anatomic areas are potential spaces without good definition from the standpoint of tumour containment and in such situations it is usual to design the radiotherapy target volume to encompass the extreme limits of the structure or region in question (generally determined by where the fascial reflections eventually merge). Areas such as the axilla, popliteal fossa, femoral triangle, and the entire subcutaneous compartment present problems of target volume delineation that must be evaluated on an individual basis.2 Evaluation of the region in terms of potential tissues involved or tissues that have already been surgically violated is paramount in deciding the most appropriate volume to treat. Again the principles are determined by the proximity of the most reliable barrier to tumor invasion (hopefully an intact durable anatomical boundary). Alternatively, an effective distance (e.g. 2-5 cm, where anatomically feasible) is maintained from the highest risk area, most typically manifested by the existing GTV or the pre-operative GTV; this should bear in mind the surgical-pathologic findings at the time of the resection.

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2.6

Margins for geometric uncertainty

An additional feature in radiotherapy target delineation concerns allowance for uncertainties in set up and treatment delivery. A region of additional margin must be defined to account for geometric uncertainty and is especially important where there is respiratory movement (e.g. abdominal and thoracic areas). The expansion of volume should be defined around the Clinical target volume (CTV) as the Planning Target Volume (PTV) to insure the inclusion of the areas at risk in the treated area.5, 6 A similar margin should be used when protecting normal tissues vulnerable to radiotherapy (e.g. the spinal cord in paraspinal, retroperitoneal or head and neck sarcomas) because

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uncertainties in set up and treatment delivery may equally result in inadvertent treatment of these structures. The additional zonal expansion surrounding these structures is termed a planning risk volume (PRV).6

2.7

Influence of scheduling of modalities

Pre-operative and post-operative RT represent the two usual approaches to external beam delivery for STS but effectively comprise two disease ‘scenarios’ from the standpoint of delineating targets. Pre-operative RT approaches can focus on the extent of definable disease (generally using imaging characteristics) and the choice of target is based on the anatomic location, containment by barriers to spread, estimated distance from the GTV that may contain microscopic disease, and allowance for geometric uncertainty. In contrast, post-operative radiotherapy volumes must encompass all surgically manipulated tissues and are often less specific because anatomic planes have been disrupted and no longer provide barriers to contain tumor growth and are consequently significantly larger.3, 7 Another consideration that is relevant to cases undergoing induction chemotherapy is the determination of the pre-chemotherapy volume in chemoresponsive tumors. In these situations, vigorous tumor response will likely have manifested by the time radiotherapy is ordinarily scheduled to commence and little if any radiologically apparent disease may be present at the time of radiotherapy planning. The initial pre-chemotherapy volume must be the reference for treatment planning and imaging studies must be carefully performed and recorded to facilitate subsequent RT planning.2

3 DELIVERY

3.1

VOLUMETRIC TREATMENT PLANNING AND Evolution of volumetric-based planning

The initial introduction of adjuvant radiotherapy more than two decades ago took place in an era when limb conservation had only recently become established as an alternative to amputation.8-10 The paradigm involved the use of radiotherapy to sterilize a broad field of tissue that generally targeted an entire muscle compartment from which the tumour had been resected and almost exclusively involved post-operative radiotherapy. Subsequently a desire to minimize morbidity resulted in progressive reduction in radiation treatment volumes and evidence accumulated that smaller radiation field margins could be used without compromising the very high rates of local control which were being achieved. 10-12 Refinement of external beam radiotherapy (EBRT) fields was limited by imprecise cross-sectional imaging

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and treatment planning and delivery systems could not tailor radiation dose to irregularly shaped volumes. Consequently, for many years conventional radiotherapy technique for limb STS essentially comprised two parallel opposed rectangular fields.10 Over the last decade unprecedented improvements in treatment planning and delivery have become available. Two new approaches, three-dimensional conformal radiotherapy (3D CRT) and intensity-modulated radiation therapy (IMRT), have been successfully applied to the treatment of other cancers, but their application to the management of STS is very new. The introduction of 3D CRT and IMRT is an important opportunity to reevaluate many aspects of the current treatment paradigm, which had evolved under the technological constraints of the past.

3.2

Three-Dimensional Conformal Radiotherapy (3D CRT)

3.2.1

The elements of 3D CRT

Three-dimensional conformal irradiation has been described as “external-beam radiation therapy in which the prescribed dose volume (treatment volume) is made to conform closely to the target volume”. 13 The increased conformality in comparison to two-dimensional techniques is made possible by innovations in hardware associated with the treatment apparatus, as well as in software which allows improved calculations of the absorbed dose and improved presentation of the results.

3.2.2

The multi-leaf collimator (MLC)

Simple modulation of the treatment beam to improve conformality may be achieved by physical blocks, missing-tissue compensators, physical wedges or dynamic wedges generated by moving collimators, but the single most important hardware innovation in the development of 3D CRT has been the multi-leaf collimator (MLC). This device consists of multiple interlocking finger-like blocks mounted in the treatment head of a linear accelerator, which may be advanced from either side by individual motors under computer control. The sides of the leaves interlock and are ‘dove-tailed’ together to minimize radiation leakage in between the leaves. In the past, conformation required the manufacture and handling of individual physical blocks. The ability of an MLC to rapidly change configuration under computer control, and to produce individualised beam shaping represents a significant advance and has made the delivery of complex multi-beam treatment plans practical and achievable. Furthermore, the MLC facilitates modulation of beam intensity by superimposing a smaller radiation field within a larger field (beam segmentation). 3.2.3 3D CRT plan calculation, visualization and evaluation

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The hallmark of three-dimensional planning is the calculation of the absorbed radiation dose throughout the volume of interest, rather than in selected axial cross-sections only. This allows accurate assessment of the dose deposited by beams that are not aligned with the axial plane (non-coplanar beams) and provides many more beam configurations, which may be utilized to produce optimal conformality to the target volume. Software that permits clear presentation of treatment data is an integral part of such planning systems. The effects of a candidate treatment plan on multiple sub-volumes may be evaluated, representing tumour and other structures of interest including normal tissues. These include features such as beam’s eye views (BEV) (i.e. visualization of any beam along its central axis irrespective of its direction and that include the target volume and tissues to be avoided in the view) (figure 2) and room’s eye views (that allow rapid visual

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assessment of coverage of the target volume by a single beam and the potential for collision of couch and gantry). Presentation of dose distributions in different planes and in three dimensions allow assessment of RT dose perturbation within and adjacent to the target volume, including ‘hot spots’ and ‘cold spots’. 3D CRT procedures facilitate development of a plan which deposits dose to the target volume with minimal dose to surrounding tissues. The degree of conformality may be quantified by the conformity index (CI), which is the ratio of volume enclosed by the prescription isodose surface to the planning target volume (PTV). 14 This is somewhat helpful in comparing candidate plans but in practice it is more useful to compare dose-volume histograms (DVHs) for volumes of interest (figure 3), 15 as the CI does not fully reveal the effects on critical structures.

3.3

Intensity modulated radiotherapy (IMRT)

3.3.1

The elements of IMRT

The impact of computer technology enhancements has provided the opportunity for extraordinary improvement in the physical basis of radiation therapy. Leading these advances in the contemporary era is the development of intensity-modulated radiotherapy (IMRT). IMRT is an advanced form of three-

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dimensional conformal radiotherapy in which radiation beams are not only shaped at their perimeters, but also include variable intensity across the profiles of the beams. This permits the creation of exquisite conformation of dose to targets of irregular shape while generating high dose gradients between tumor and normal tissues. In addition to the use of intensity modulated beams, the other key enhancement of IMRT over conventional conformal treatments, is the use of computer assisted iterative treatment plan optimization. In its complete form, IMRT combines inverse treatment planning (where dose to normal tissues as well as target regions is specified in advance), with computer controlled dynamic beam shaping and filtration (usually with MLC). 3.3.2

The mechanism of IMRT

The IMRT concept relies on the fact that multiple beams crossing a target from different directions do so with great redundancy that can be harnessed to provide substantial flexibility in distributing dose. Instead of permitting the full intensity of a beam to traverse the target, the dose in part(s) of the field aperture is reduced in a variable way (by programming the configuration and timing of the MLC leaf positions), according to the requirements. This can permit sparing of a structure on the one hand or delivery of relatively enhanced dose to the target in another part of the field aperture thereby causing deliberate perturbation of the RT dose distribution of a beam. At the same time, the variable dose incurred in components of the aperture of a given beam by this process can be compensated by enhancing or reducing the dose in components of the apertures of other beams directed at the target from other directions. In this way a ‘beam’ directed from a given direction, can be fashioned to comprise numerous (e.g. dozens to hundreds) of mini-beams (termed beamlets) with variable shape and intensity of radiation exposure. The ultimate result from the combination of numerous beams of different direction, intensity patterns, and shape provides an unprecedented three dimensional configuration to the composite dose distribution from all beams. Ironically, it is now reasonably certain that the capability of placing dose and avoiding tissues is significantly more precise than our knowledge of what issues are indeed involved and the measures required to minimize geometric uncertainty related to normal physiologic movements in the patient (eg. breathing, adjustment related to hollow viscous filling and emptying, etc). 3.3.3

Dose ‘sculpting’ and ‘painting’

Using the IMRT approach, the delivered RT dose can be fitted to volumes tailored to complex shape specifications. These can be both shaped externally (i.e. convex shaping), as in traditional fields, but also the external ‘surface’ of the intended RT dose region can be excavated thereby providing concave or indented shaping (‘dose sculpting’)16 that permit previously

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inaccessible target areas to be treated while avoiding adjacent vulnerable anatomy that may be partially surrounded by the target (figure 4). Most radiotherapy treatment plans, including 3D CRT plans and IMRT plans that use ‘dose sculpting’ strategies, accept a certain amount of dose heterogeneity within the target volume as a by-product of efforts to conform a given isodose to the periphery. This apparently anomalous situation can be further enhanced with IMRT where the opportunity exists to create deliberate variation in absorbed dose within the target. This has been termed ‘dose painting’ 16 and provides further opportunity to relatively spare normal tissues while delivering even more intense dose accumulation into diseased tissues.

3.3.4

Inverse Planning

IMRT targeting comprises a powerful engineering accomplishment employing concepts of radiation physics, advanced computation, and a revolution in hardware design. To achieve this an intended dose distribution is displayed on anatomic details obtained from thin CT scan slices upon which the target and the anatomic areas of risk are outlined. The CT scan also provides the radiation attenuation properties of tissues, which are necessary for the computation of absorbed dose. This is accomplished using numerical models that approximate the radiation transport physics in tissues. The planning objective includes two important specifications: a description of the required dose to each part of the target and the normal tissues in the treated region; and the importance of achieving that dose in relative terms compared to the other structures (target or normal tissues) as a ‘weighting’ expressed in a mathematical equation. Altogether this process is characterized as ‘inverse planning’, in which the requirements for the dose configuration in the patient is specified precisely in advance in mathematical terms and computer technology is then used to calculate the intensity pattern specifications of each beam to achieve the intended result. Thus the clinical objectives are specified mathematically in the form of an objective function (also called the score function or cost function)17 (see table 1). In practice the number of beams and selection of their orientation are chosen by the treatment planner because the computerized optimization process outlined below that searches for the optimal plan would not be possible, in practical terms, with our current computation tools. This process can be facilitated by the use of libraries of plans (including number and direction of beams) that successfully met a need in the past and the development of ‘class solutions’ that generally fit the problem at hand. Following the specification of treatment goals, an iterative search algorithm is used to compute the intensity patterns that optimize the dose distribution throughout the normal tissues and the target. Many thousands of

27

28

iterative calculations are generally required to solve the mathematical task of calculating an objective function that takes account of the ‘desired dose’, the ‘calculated dose’ (at each iteration), and the weighting (or priority) to eventually achieve a distribution of radiation dose in the volume that comes as close as possible to what is intended.

A variety of computational methods are available for this process, all with their own advantages and disadvantages, which in itself compromises an active area of research. These include different degrees of accuracy in accounting for tissue heterogeneity corrections, geometric dose reproduction (e.g. adjustment and synchronization of leaf position to take account of leakage between the leaves of the MLC and passage of radiation through multileaves of partial depth, the method of objective function calculation, and, of great

29

practical importance, speed of performing the calculations).17, 18 Unfortunately, the optimization process must be repeated several times if the initial result is not satisfactory. This may arise if the planning objectives cannot be met and may include excessive dosing of areas including ‘hot spots’ in normal tissues that exceed tolerance and rendering the plan vulnerable from a safety perspective, or if parts of the target do not receive reliable dose coverage.

4

RATIONALE FOR VOLUMETRIC-BASED PLANNING

4.1

Reducing late tissue adverse events

One of the main potential advantages to conforming the treated volume to the target volume is to reduce toxicity to surrounding tissues. Nonrandomised studies of limb STS have demonstrated an association of radiation field size with limb oedema and tissue induration 19 and of radiation dose with increased oedema, decreased muscle strength, decreased range of motion, fibrosis and worse functional outcome in general 19, 20. More recently, these findings have also been borne out in a prospective fashion in the comparison of different outcomes following pre-operative compared to post-operative radiotherapy. The latter generally requires higher doses and larger fields and is associated with significantly higher rates of fibrosis and edema two years following completion of treatment compared to the pre-operative approach.21 Because of its ability to produce high dose volumes with concave surfaces, IMRT will usually be able to spare some subcutaneous tissue to reduce the risk of lymphoedema.22 In addition, late (i.e. many years following treatment) irradiation induced bone fracture is evident with doses of exceeding 60 Gy in weightbearing bone 23, and minimization of dose to, or even complete avoidance of, such structures would seem desirable in reducing the risk of this debilitating complication. Dose modeling studies have shown that the ability of IMRT to produce high dose volumes with concave surfaces can substantially lower mean dose to the femur and the volume of bone irradiated to 95% of the prescription dose.24 This may reduce the incidence of late fracture, particularly in the setting of postoperative radiotherapy where higher doses are prescribed.

4.2

Facilitate curative radiotherapy

Lesions in proximity to vital structures may need specific volume modifications in order to encompass disease while sparing normal tissue. This may be particularly attractive in disease sites where critical organ tolerance may be paramount yet undertreatment of the target poses additional risks. This may involve potentially achieving kidney protection, spinal cord or

30

lung avoidance in different situations. This differs from the discussion of late tissue toxicity (section 4.1), because the context here concerns whether radiotherapy can be delivered at all with curative intent, out of concern for life threatening complications to critical anatomy. This approach may be best exemplified by retroperitoneal sarcomas and paraspinal tumours. Retroperitoneal sarcoma frequently recurs locally, despite optimal surgery, and radiotherapy is often used pre-, intra- or postoperatively to improve control.25-28 Local recurrences are still the rule, however. The need to observe the tolerance of bowel, liver, kidneys and other organs generally requires that lower doses be prescribed than for sarcomas at other sites and target coverage is often compromised. 3D CRT and MRT provide the opportunity to treat large and complex retroperitoneal tumor volumes that were previously close to impossible to treat. These modalities are especially well suited to pre-operative radiotherapy because the target is in situ with less risk of intra-abdominal contamination so that the region to be treated can be readily defined. In addition, bowel is both mobile and displaced by the tumor and treatment is well tolerated 28 in contrast to the post-operative setting 29 where the bowel is frequently tethered in the surgical bed making safe delivery of substantive doses of radiotherapy problematic. In addition, a problem that is especially difficult is presented by the large right sided retroperitoneal sarcoma where tumor is in direct proximity to the liver and frequently ‘hooded’ by this stucture. Standard radiotherapy cannot achieve safe coverage of the target while permitting the liver to be spared. Even 3D CRT is problematic for these lesions and IMRT presents many advantages (figure 5). Paraspinal tumors also pose prodigious problems for the safe delivery of radiotherapy. The real possibility exists for the spine to be severely injured by the treatments themselves (radiotherapy and surgery are both severely constrained by normal tissue tolerance) or by tumor. Target volumes partially enveloping the spinal cord pose a challenge in dose delivery not previously achievable with standard planning but that can be overcome with IMRT (see figure 3 and 4, and table 2).

4.3

Retreatment

Reirradiation of limb soft tissue sarcoma after local recurrence has been shown to contribute to limb conservation, although there is a risk of inducing radionecrosis, chronic ulceration and fracture. 30, 31 Brachytherapy has been advocated as the optimal radiation modality for this situation 31-34 but IMRT has the potential advantages, through inverse planning, to tailor the dose to treat sites inaccessible to brachytherapy. This approach has been used successfully to retreat vertebral metastases, including sarcoma,35 and it is well suited to locally recurrent STS.

31

32

4.4

Reduction of acute radiation morbidity

Combined modality treatment of STS improves local control,36, 37 but some structures may suffer enhanced toxicity. It is plausible that in the future IMRT may ameliorate this problem. For instance, preoperative radiotherapy increases the incidence of major wound complications compared with postoperative radiotherapy 3, despite reducing late fibrosis and oedema.21 One potential strategy to enhance wound healing might be to investigate the use IMRT to avoid irradiating skin in the region of the planned wound.38 Highly conformal RT may also reduce adverse interactions with chemotherapy. Ifosfamide is a drug that is being actively investigated in combination with radiotherapy because of its high activity against sarcoma,39, 40 but the incidence of moist desquamation of skin may be increased.39, 41 One suggestion is that IMRT may allow the radiation dose to skin to be limited to avoid this problem.38 3D CRT has also been used to reduce radiation toxicity to bone marrow, so that the intensity of chemotherapy is not compromised. 42

33

4.5

Radiation dose escalation

An intriguing aspect in considering the radiotherapy of many STS sites is that the results of treatment are generally satisfactory in terms of local control. The therapeutic strategy must therefore focus on the opportunity to either reduce the intensity of treatment application or modify radiotherapy volumes compared to traditional approaches. The exception may be retroperitoneal sarcoma where the local control rates, even with adjuvant radiotherapy, have been disappointing although the reason for this are multifactorial and with strong potential that the tumor is being underdosed and the target area at risk is not covered due to organ tolerance (see section 4.2). It is plausible that retroperitoneal sarcoma results could improve if doses to tumour were escalated while conformally avoiding organs at risk. This is probably achievable with IMRT.43

5

APPLYING VOLUMETRIC-BASED PLANNING

5.1

Multidisciplinary interactions

For several reasons, several specialties should be involved when very selected treatment RT volumes are proposed. Predominantly this applies to interaction between the radiation medicine disciplines and surgical oncology, medical imaging, and pathology, but also extends to medical oncology collaboration. We have already noted that prior surgical interventions may influence the choice of target tissues at risk in a striking fashion. We also discussed the implications of absence of pretreatment appropriate imaging since initial chemotherapy may eliminate all evidence of overt disease before radiotherapy can be administered. Clearly both circumstances may equally result in a situation where the use of selected conformal volumes may prove impossible. In retroperitoneal sarcoma, following pre-operative radiotherapy that may have treated a generous portions of involved or adjacent liver, it is very important that the surgical team be aware of the area of liver that has been treated so that sufficient liver is left intact in the patient if partial liver resection is contemplated. This information can only be imparted by detailed review of the planning and dosimetry records by the surgeons with the radiation oncologists and treatment planners 44 As high intensity dose escalation chemo-radiotherapy techniques evolve, there may be opportunity to spare superficial tissues using IMRT and prevent acute and long term skin and subcutaneous morbidity that may be a hallmark of the concurrent use of chemotherapy and radiotherapy. In this way as treatment strategies evolve, it is likely that the evolution to more selective radiotherapy volumes will require more rather than less interaction among the disciplines. Hopefully, it may be possible to develop

34

protocols where anatomic areas treated by one discipline may be avoided deliberately by the other to reduce the overall morbidity.

5.2

Imaging and image fusion

Imaging is key to the application of 3D CRT and IMRT. Targets as well as structures to be avoided must be identified accurately with respect to anatomical site and local extension to surrounding structures. They must then be delineated on the images of the radiotherapy planning system. Usually the radiation oncologist will examine the other images beside the planning CT images, mentally ‘coregister’ them and then electronically contour the structures by drawing on the latter. This obviously has potential to introduce error. An alternative, which is often used when adjacent critical structures require narrow margins for uncertainty, is to fuse the two sets of images. This is routinely done in the planning of stereotactic IMRT for skull base sarcoma. It is then relatively simple for the oncologist to trace around the MRI image of the structure and the resulting contour is registered on the CT image. The use of other methods of simulation are being investigated, such as MR simulators and combination PET / CT simulators.

5.3 variability

Reduction in geometric uncertainty and treatment

‘Geographic miss’ is a serious error as it exposes the patient to toxicity without the prospect of tumour control. However, as radiation treatment becomes more conformal the risk of geographic miss increases because any error is more likely to move the CTV out of the high-dose volume. Uncertainty is an important component in radiotherapy. The quality assurance requirements for IMRT present new and unique problems and involve technical issues at the radiotherapy delivery level as well as the planning problems already discussed. 45, 46 Consistency in set up and the use of appropriate immobilisation (see section 6.1) of anatomic regions should be integral to the planning process to insure that correct anatomic treatment and avoidance takes place. While strict immobilisation is not necessarily an integral part of 3D CRT or IMRT, in practice unless attention is directed towards reducing movement, much of the benefit of highly conformal treatment will be lost and the risk of unsatisfactory treatment increased.47

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6

DOSE HETEROGENEITY AND DOSE DISPERSION

6.1

‘Dose dumping’

An increase in dose heterogeneity within the target volume is commonly encountered in IMRT plans, frequently beyond the 95% -107% range that is commonly considered acceptable.5 This phenomenon has been noted in the treatment of many sites, including the thigh. 24 It is enhanced by a tendency for users to ascribe high priorities to conformality and target coverage rather than dose homogeneity in the objective function. 48 Generally, provided the radiotherapy is prescribed such that no part of the PTV is underdosed and the ‘hot spots’ fall within the GTV away from sensitive normal structures, adverse consequences are unlikely. When computer-assisted dose optimisation takes place in the IMRT planning process, the algorithm will consider all plans that satisfy the specified geometric and dosimetric constraints. This may result in high doses being dispersed into unexpected sites, and represents the converse of delivering inadequate dose to the target because unintended dose may be delivered to normal structures. This phenomenon is called ‘dose dumping’. Examples are the allocation of high doses to skin and subcutaneous tissues in a plan to treat limb sarcoma or to brain in the treatment of skull base disease. Experience generally allows prediction of when this might occur, but all IMRT plans should be carefully examined for unanticipated ‘hot spots’. If identified, the optimisation may need to be repeated after adjustment of contours for the relevant tissue and allocating appropriate constraints, and the incidence of ‘dose-dumping’ is reduced with experience.

6.2

Increased integral dose

In order to achieve highly conformal irradiation of the target, IMRT plans tend to use more beams than traditional RT approaches. Therefore more normal tissue can fall within the irradiated volume. Furthermore, the complexity of IMRT treatments, with many beamlets being delivered at less than 100% intensity, results in wider dispersion of lower doses of radiation but effectively a higher patient whole-body (or integral) dose than is the case with conventional external beam radiotherapy. 17 Concerns have been expressed that this could substantially enhance the rate of radiation carcinogenesis in cancer survivors49, 50 . This may be acceptable for older adults but in younger patients, particularly children, very careful consideration should be applied to balancing as yet unproven improvements in local control and toxicity against possible second malignancies. In principle, the excess radiation leakage that may lead to excess secondary cancers can be reduced by careful consideration in the design of radiation treatment technologies of the future.

36

7

OTHER MODALITIES

External beam photon therapy is only one method of delivering volumetric-based radiotherapy. Postoperative brachytherapy has been shown in a prospective randomised trial to improve local control of high grade STS over resection alone.36 However, it requires skills and facilities that are not available in many centers but the advantages of a short overall treatment time and irradiation of less normal tissue than traditional EBRT are understandably attractive.34 Technological enhancements now also permit full 3D planning for brachytherapy with dose-volume histograms and other tools employed by 3D CRT.51 There is also no reason why brachytherapy treatment planning systems should not be extended to include inverse planning capability, which might allow further sparing of nearby critical structures. The low integral dose resulting from brachytherapy makes it a useful option for recurrent tumour in previously irradiated tissue.52 In proton beam irradiation, high-dose volume treatment volumes can be made to conform precisely to the target by varying the depth and breadth of the ‘Bragg peak’. 53 If the peak is positioned at the target, there is no dose deposited in deeper tissues but also less dose in superficial tissues than if photon beams were used. Therefore proton RT has the advantage of a lower integral dose to normal tissues. The major drawback to the application of this technology is the cost of constructing facilities for delivery and currently it is only available at a handful of sites. Nevertheless, work is underway to improve access by increasing the number of treatment units and to improve its capability by introduction of intensity modulated proton beam (IMPT) planning and delivery. 53

Modulated electron therapy (MERT) is an investigational modality, which shows promise in the treatment of superficial targets. Modulation of electron beam energy, as well as intensity, allows limitation of the depth of penetration with a reduction in the dose to tissues that lie beyond tumour.54 This may result in a lower integral dose than photon IMRT produces. Theoretical applications include breast tumours (with sparing of lung) and situations where large areas of scalp need to be treated, such as for angiosarcoma (with sparing of underlying brain).

8

FUTURE PERSPECTIVES

8.1

Biological targeting / ‘dose-painting’

In STS, it has long been appreciated that biological heterogeneity exists. If different subvolumes have different biology, they may require different radiation doses to eradicate malignant clones. Larger radiation doses may be needed if clonogen density is greater, if hypoxia is present or if there is intrinsic

37

radioresistance. A number of functional imaging modalities are showing potential to identify such regions and could permit a biological target volume (BTV) to be conceived within the GTV on the basis of such imaging characteristics.16 These could include the incorporation of single positron emission tomography (PET), single photon emission computed tomography (SPECT)55, or proton MR spectroscopy (MRS).56, 57 Other novel applications of MRI include the identification of regions of hypoxia using blood-oxygen level dependent (BOLD) imaging sequences.58 The ability of IMRT to design and deliver specific nonuniform dose distributions within a target (‘dose painting’) has provided the capability to target different parts of the CTV. The BTV might be targeted to receive a higher radiation dose than the surrounding gross tumour, resulting in “biological conformality” as well as physical conformality.16 In this way, a paradigm of “multidimensional conformal radiotherapy” potentially acknowledges biological tumour heterogeneity in addition to the goals of physical conformality.16

8.2

Image-guided radiotherapy using on-line imaging

A highly active area of research is the use of CT imaging at the time of radiotherapy delivery. This reduces uncertainty regarding the positions of the target and organs at risk, as they no longer need to be inferred from images acquired days or weeks earlier. If the CT scanner and the linear accelerator gantry are mounted about the same axis, then the coordinates of structures of interest can be related directly to the radiotherapy delivery system, rather than to surface markings on the patient that are in turn related to the delivery system. One approach, under development at our centre is flat-panel cone-beam computed tomography where a kilovoltage photon source is mounted at 90° to the treatment head.59 A cone-shaped beam passes through the patient and is collected by a flat detector mounted on the opposite side during a single rotation to construct high-resolution images that allow adjustments to the treatment plan to be made to improve target coverage (adaptive radiotherapy). An alternative strategy is to mount a linear accelerator onto the ring gantry of a helical CT scanner to produce a treatment and imaging system known as helical tomotherapy. As well as delivering rotational IMRT, the transmitted portion of the beam is collected by a detector array on the opposite side of the gantry to produce megavoltage CT images that can be compared to the planning images to verify the accuracy of the delivered treatment.60

8.3

Clinical assessments

A key recommendation from the recent U.S. National Cancer Institute State-of-the-Science meeting on adult sarcomas in June 2002 included the view that IMRT) is a promising technique that should be actively studied in wellcontrolled trials of patients with soft tissue sarcomas.61 To achieve this,

38

prospective assessment of outcome should include established and validated methods of measurement for normal tissue toxicity, functional assessment, quality of life and careful evaluation of acute and late complications and local control of disease. There is an urgent need to correlate toxicity with modern measures of delivered dose, such as DVHs that allow assessment of the effects of partial organ tolerance and of inhomogeneous irradiation of whole organs. Certain structures, not previously considered avoidance targets, may be spared toxicity provided appropriate dose limits can be defined. For example, individual lymphatic trunks can be identified by indirect lymphography.62 Avoidance of these might allow more reliable prevention of lymphoedema following limb irradiation. In the long term, is conceivable that every part of the irradiated volume, including bone, joints and muscle beyond the PTV, might be contoured and assigned dose limits to reduce late toxicity.

9

CONCLUSION

RT targeting of STS presents considerable challenges in realizing optimum outcome in tissue and function preservation while maintaining high local control for most anatomic sites. While a highly effective adjuvant, RT delivered improperly may cause substantial disability by excessive volume or dose delivery. The advent of very precise treatment planning and delivery systems, including 3D CRT and IMRT, means it is now possible to choose to treat ideal volumes rather than ones that are merely feasible. At the same time precise knowledge of appropriate targets continues to evolve for the different clinical scenarios and will likely be greatly influenced in the future by enhanced imaging capability. Clinical trials are needed that include relevant end-points to measure improvements in the therapeutic ratio resulting from more precise RT targeting and without loss of local control. In addition, advancement of 3D CRT and IMRT over the next decade will rely on the consistent reporting and sharing of results concerning outcome of normal tissue from volumetric treatment planning.47

10

REFERENCES

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5. ICRU Report 50. Prescribing, Recording, and Reporting Photon Beam Therapy. Bethesda: International Commission on Radiation Units and Measurement; 1993. 6. ICRU Repor t62. Prescribing, Recording, and Reporting Photon Beam Therapy (Supplement to ICRU Report 50). Bethesda: International Commission on Radiation Units and Measurement; 1999. 7. Nielsen OS, Cummings B, O’Sullivan B, Catton C, Bell RS, Fornasier VL. Preoperative and postoperative irradiation of soft tissue sarcomas: effect of radiation field size. Int J Radiat Oncol Biol Phys 1991;21(6):1595-9. 8. Enneking WF, Spanier SS, Goodman MA. Current concepts review. The surgical staging of musculoskeletal sarcoma. J Bone Joint Surg Am 1980;62(6):1027-30. 9. Simon MA, Enneking WF. The management of soft-tissue sarcomas of the extremities. J Bone Joint Surg Am 1976;58(3):317-27. 10. Tepper J, Rosenberg SA, Glatstein E. Radiation therapy technique in soft tissue sarcomas of the extremity--policies of treatment at the National Cancer Institute. Int J Radiat Oncol Biol Phys 1982;8(2):263-73. 11. Lindberg RD, Martin RG, Romsdahl MM, Barkley HT, Jr. Conservative surgery and postoperative radiotherapy in 300 adults with soft-tissue sarcomas. Cancer 1981;47(10):23917. 12. Suit HD, Spiro I. Role of radiation in the management of adult patients with sarcoma of soft tissue. Semin Surg Oncol 1994;10(5):347-56. 13. Emami B, Graham MV, Michalski JM, Perez CA. Three-Dimensional Conformal Radiation Therapy: Clinical Aspects. In: Perez CA, Brady LW, editors. Principles and Practice of Radiation Oncology. 3rd ed. Philadelphia: Lippincott-Raven; 1998. p. 371-386. 14. Knoos T, Kristensen I, Nilsson P. Volumetric and dosimetric evaluation of radiation treatment plans: radiation conformity index. Int J Radiat Oncol Biol Phys 1998;42(5):116976. 15. Mohan R, Brewster LJ, Barest GD. A technique for computing dose volume histograms for structure combinations. Med Phys 1987;14(6):1048-52. 16. Ling CC, Humm J, Larson S, Amols H, Fuks Z, Leibel S, Koutcher JA. Towards multidimensional radiotherapy (MD-CRT): biological imaging and biological conformality. Int J Radiat Oncol Biol Phys 2000;47(3):551-60. 17. IMRT. Intensity-modulated radiotherapy: current status and issues of interest. IMRT Collaborative Working Group. Int J Radiat Oncol Biol Phys 2001;51(4):880-914. 18. Webb S. Advances in three-dimensional conformal radiation therapy physics with intensity modulation. Lancet Oncol 2000;1(1):30-6. 19. Robinson MH, Spruce L, Eeles R, Fryatt I, Harmer CL, Thomas JM, Westbury G. Limb function following conservation treatment of adult soft tissue sarcoma. Eur J Cancer 1991;27(12):1567-74. 20. Stinson SF, DeLaney TF, Greenberg J, Yang JC, Lampert MH, Hicks JE, Venzon D, White DE, Rosenberg SA, Glatstein EJ. Acute and long-term effects on limb function of combined modality limb sparing therapy for extremity soft tissue sarcoma. Int J Radiat Oncol Biol Phys 1991;21(6):1493-9. 21. O’Sullivan B, Davis A. A Randomized phase III trial of pre-operative compared to postoperative radiotherapy in extremity soft tissue sarcoma.[Abstract].Proc 43rd Annual Meeting, American Society of Therapeutic Radiology and Oncology. Int J Radiation Oncology Biol Phys 2001;51(3, supplement 1):151. 22. Millar BM, Bragg CM, Conway J, Robinson MH. Investigation of the use of intensity modulated radiotherapy (IMRT) in comparison with conformal radiotherapy in the management of soft tissue sarcoma.[Abstract]. Proc 43rd Annual Meeting, American Society of Therapeutic Radiology and Oncology. International Journal of Radiation Oncology Biology Physics 2001;51(3 (Supplement 1)):412. 23. Holt GE, Wunder JS, Griffin AM, Bell RS. Fractures following radiation therapy and limb salvage surgery for soft tissue sarcomas: high versus low dose radiotherapy.[Abstract] Proc Muskuloskeletal Tumor Society 2002:41.

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24. Hong L, Alektiar K, Hunt M, Leibel S. Intensity Modulated Radiotherapy for Soft Tissue Sarcoma of Thigh [Abstract]. Proc 44th Annual Meeting, American Society of Therapeutic Radiology and Oncology. Int J Radiat Oncol Biol Phys 2002;54 (2S):140-1. 25. Gieschen HL, Spiro IJ, Suit HD, Ott MJ, Rattner DW, Ancukiewicz M, Willett CG. Long-term results of intraoperative electron beam radiotherapy for primary and recurrent retroperitoneal soft tissue sarcoma. Int J Radiat Oncol Biol Phys 2001;50(1):127-31. 26. Petersen IA, Haddock MG, Donohue JH, Nagorney DM, Grill JP, Sargent DJ, Gunderson LL. Use of intraoperative electron beam radiotherapy in the management of retroperitoneal soft tissue sarcomas. Int J Radiat Oncol Biol Phys 2002;52(2):469-75. 27. Stoeckle E, Coindre JM, Bonvalot S, Kantor G, Terrier P, Bonichon F, Nguyen Bui B. Prognostic factors in retroperitoneal sarcoma: a multivariate analysis of a series of 165 patients of the French Cancer Center Federation Sarcoma Group. Cancer 2001;92(2):359-68. 28. Jones JJ, Catton CN, O’Sullivan B, Couture J, Heisler RL, Kandel RA, Swallow CJ. Initial results of a trial of preoperative external-beam radiation therapy and postoperative brachytherapy for retroperitoneal sarcoma. Ann Surg Oncol 2002;9(4):346-54. 29. Gilbeau L, Kantor G, Stoeckle E, Lagarde P, Thomas L, Kind M, Richaud P, Coindre JM, Bonichon F, Bui BN. Surgical resection and radiotherapy for primary retroperitoneal soft tissue sarcoma. Radiother Oncol 2002;65(3):137-43. 30. Graham JD, Robinson MH, Harmer CL. Re-irradiation of soft-tissue sarcoma. Br J Radiol 1992;65(770):157-61. 31. Nori D, Schupak K, Shiu MH, Brennan MF, Shupak K. Role of brachytherapy in recurrent extremity sarcoma in patients treated with prior surgery and irradiation. Int J Radiat Oncol Biol Phys 1991;20(6):1229-33. 32. Catton C, Davis A, Bell R, O’Sullivan B, Fornasier V, Wunder J, McLean M. Soft tissue sarcoma of the extremity. Limb salvage after failure of combined conservative therapy. Radiother Oncol 1996;41(3):209-14. 33. Pearlstone D, Janjan NA, Feig B, Yasko A, Hunt K, Pollock R, Lawyer A, Horton J, Pisters P. Re-resection with brachytherapy for locally recurrent soft tissue sarcoma arising in a previously irradiated field. Cancer J Sc Am 1999;5(1):26-33. 34. Crownover RL, Marks KE. Adjuvant brachytherapy in the treatment of soft-tissue sarcomas. Hematol Oncol Clin North Am 1999;13(3):595-607. 35. Milker-Zabel S, Zabel A, Thilmann C, Schlegel W, Wannenmacher M, Debus J. Clinical results of retreatment of vertebral bone metastases by stereotactic conformal radiotherapy and intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 2003;55(1):162-7. 36. Pisters PW, Harrison LB, Leung DH, Woodruff JM, Casper ES, Brennan MF. Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma. J Clin Oncol 1996;14(3):859-68. 37. Yang JC, Chang AE, Baker AR, Sindelar WF, Danforth DN, Topalian SL, DeLaney T, Glatstein E, Steinberg SM, Merino MJ, Rosenberg SA. Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol 1998;16(1):197-203. 38. O’Sullivan B, Bell R. Has “MAID” made it in the management of high-risk soft-tissue sarcoma. International Journal of Radiation Oncology Biology Physics 2003;56(4):915-916. 39. Cormier JN, Patel SR, Herzog CE, Ballo MT, Burgess MA, Feig BW, Hunt KK, Raney RB, Zagars GK, Benjamin RS, Pisters PW. Concurrent ifosfamide-based chemotherapy and irradiation. Analysis of treatment-related toxicity in 43 patients with sarcoma. Cancer 2001;92(6):1550-5. 40. Sauer R, Schuchardt U, Hohenberger W, Wittekind C, Papadopoulos T, Grabenbauer GG, Fietkau R. [Neoadjuvant radiochemotherapy in soft tissue sarcomas. Optimization of local functional tumor control]. Strahlenther Onkol 1999;175(6):259-66. 41. DeLaney TF, Spiro IJ, Suit HD, Gebhardt MC, Hornicek FJ, Mankin HJ, Rosenberg AL, Rosenthal DI, Miryousefi F, Ancukiewicz M, Harmon DC. Neoadjuvant Chemotherapy and Radiotherapy for Large Extremity Soft Tissue Sarcomas. International Journal of Radiation Oncology Biology Physics 2003;56(4): 1117-1127.

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42. Coles CE, Twyman N, Earl HM, Burnet NG. Conformal radiotherapy facilitates the delivery of concurrent chemotherapy and radiotherapy: a case of primitive neuroectodermal tumour of the chest wall. Sarcoma 2000;4(3):129-133. 43. Haycocks T, Kelly V, Islam M, O’Sullivan B, Swallow CJ, Catton CN. High resolution, intensity modulated radiation therapy (IMRT) for retroperitoneal soft tissue sarcoma (RPS) [Abstract]. Proceedings of the 7th Annual Meeting of the Connective Tissue Oncology Society. Sarcoma 2001;5(Supplement 1,):S24-S25. 44. O’Sullivan B, Wylie J, Catton C, Gutierrez E, Swallow CJ, Wunder J, Gullane P, Neligan P, Bell R. The local management of soft tissue sarcoma. Semin Radiat Oncol 1999;9(4):32848. 45. Low DA. Quality assurance of intensity-modulated radiotherapy. Semin Radiat Oncol 2002;12(3):219-28. 46. Dixon P, O’Sullivan B. Radiotherapy quality assurance: time for everyone to take it seriously. Eur J Cancer 2003;39(4):423-9. 47. Purdy JA. Dose-volume specification: New challenges with intensity-modulated radiation therapy. Semin Radiat Oncol 2002;12(3):199-209. 48. Pirzkall A, Carol M, Lohr F, Hoss A, Wannenmacher M, Debus J. Comparison of intensity-modulated radiotherapy with conventional conformal radiotherapy for complexshaped tumors. Int J Radiat Oncol Biol Phys 2000;48(5):1371-80. 49. Verellen D, Vanhavere F. Risk assessment of radiation-induced malignancies based on whole-body equivalent dose estimates for IMRT treatment in the head and neck region. Radiother Oncol 1999;53(3):199-203. 50. Hall EJ, Wuu CS. Radiation-induced second cancers: the impact of 3D-CRT and IMRT. Int J Radiat Oncol Biol Phys 2003;56(1):83-8. 51. Kovacs G, Hebbinghaus D, Dennert P, Kohr P, Wilhelm R, Kimmig B. Conformal treatment planning for interstitial brachytherapy. Strahlenther Onkol 1996;172(9):469-74. 52. Catton CN, Swallow CJ, O’Sullivan B. Approaches to local salvage of soft tissue sarcoma after primary site failure. Semin Radiat Oncol 1999;9(4):378-88. 53. Suit H. The Gray Lecture 2001: coming technical advances in radiation oncology. Int J Radiat Oncol Biol Phys 2002;53(4):798-809. 54. Ma CM, Pawlicki T, Lee MC, Jiang SB, Li JS, Deng J, Yi B, Mok E, Boyer AL. Energyand intensity-modulated electron beams for radiotherapy. Phys Med Biol 2000;45(8):2293311. 55. Nishizawa K, Okunieff P, Elmaleh D, McKusick KA, Strauss HW, Suit HD. Blood flow of human soft tissue sarcomas measured by thallium-201 scanning: prediction of tumor response to radiation. Int J Radiat Oncol Biol Phys 1991;20(3):593-7. 56. Nelson SJ. Multivoxel magnetic resonance spectroscopy of brain tumors. Mol Cancer Ther 2003;2(5):497-507. 57. Sijens PE. Phosphorus MR spectroscopy in the treatment of human extremity sarcomas. NMR Biomed 1998;11(7):341-53. 58. Baudelet C, Gallez B. How does blood oxygen level-dependent (BOLD) contrast correlate with oxygen partial pressure (pO2) inside tumors? Magn Reson Med 2002;48(6):980-6. 59. Jaffray DA, Siewerdsen JH, Wong JW, Martinez AA. Flat-panel cone-beam computed tomography for image-guided radiation therapy. Int J Radiat Oncol Biol Phys 2002;53(5):1337-49. 60. Mackie TR, Kapatoes J, Ruchala K, Lu W, Wu C, Olivera G, Forrest L, Tome W, Welsh J, Jeraj R, Harari P, Reckwerdt P, Paliwal B, Ritter M, Keller H, Fowler J, Mehta M. Image guidance for precise conformal radiotherapy. Int J Radiat Oncol Biol Phys 2003;56(1):89-105.

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61. Borden EC, Baker LH, Bell RS, Bramwell V, Demetri GD, Eisenberg BL, Fletcher CD, Fletcher JA, Ladanyi M, Meltzer P, O’Sullivan B, Parkinson DR, Pisters PW, Saxman S, Singer S, Sundaram M, Van Oosterom AT, Verweij J, Waalen J, Weiss SW, Brennan MF. Soft tissue sarcomas of adults: state of the translational science. Clin Cancer Res 2003;9(6):1941-56. 62. Partsch H, Stoberl C, Wruhs M, Wenzel-Hora BI. Indirect lymphography with iotrolan. Fortschr Geb Rontgenstrahlen Nuklearmed Erganzungsbd 1989;128:178-81.

Chapter 3 Preoperative therapy for soft tissue sarcoma

Janice N. Cormier, MD, MPH, Howard N. Langstein, MD, Peter W. T. Pisters, MD

The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030-4009

Correspondence to: Peter Pisters MD The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard Box 444 Houston, TX 77030-4009 USA

44

1

INTRODUCTION

A number of theoretical advantages are associated with the use of preoperative therapy for solid tumors. For patients with soft tissue sarcomas, a survival advantage has been difficult to establish, but there is evidence that induction therapy (e.g., chemotherapy, radiation therapy, or multimodality regimens) may result in cytoreduction that facilitates less radical surgical resections with improved postoperative function. This is particularly important for patients presenting with large tumors that are initially resectable only by means of amputation. The focus of this review is to summarize the rationale, treatment options and ultimate impact of induction therapy for patients with soft tissue sarcoma.

2

RATIONALE FOR INDUCTION THERAPY

2.1

Solid Tumors

The primary goal of induction therapy for solid tumors is to decrease the tumor burden. The concept of induction therapy, consisting of either preoperative local therapies (e.g., radiation, chemoradiation, or limb perfusion) or systemic therapy (e.g., chemotherapy), arose because surgical resection alone was inadequate for a number of tumors (1). There are several theoretical reasons for using induction or preoperative therapies for localized tumors. First, reducing the size of the tumor may enable margin-negative (R0) resections, resection of tumors that were initially unresectable, or less radical resections that allow preservation of function. Second, there may be systemic benefits from the early delivery of cytotoxic agents, such as elimination of micrometastatic disease and improved vascular delivery of therapies to undisturbed tumors (1). Finally, induction therapy allows rapid assessment of tumor response in situ. This is not possible with postoperative therapy, which requires long-term follow-up for assessment of its effectiveness (2). There are also potential disadvantages to induction therapy, including the associated toxicity (morbidity), possible ineffectiveness of induction therapy and delayed local treatment of the primary tumor, cost of therapy, and obscuring of pathologic staging information (3). When induction therapy includes radiation, the risk of wound-healing complications after surgery is increased. The effectiveness of induction therapy must be demonstrated prior to its generalization because many patients may be cured by locoregional treatment alone (1,3). The sequence of treatments -- chemotherapy, radiation therapy, and surgery-- may be important in determining outcomes for patients with some tumor types. Three categories of tumors have been defined with regard to

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induction chemotherapy: (1) tumors for which chemotherapy has been demonstrated to be the primary therapeutic modality (e.g., embryonal rhabdomyosarcoma, small cell lung cancer, and lymphoma), (2) tumors for which there is evidence of downstaging with chemotherapy (e.g., osteogenic and Ewing’s sarcoma, locally advanced breast cancer, anal carcinoma, and laryngeal cancer), and (3) tumors for which the benefits of induction chemotherapy have not been scientifically validated (e.g., esophageal cancer, gastric and pancreas cancers, non-small cell lung cancer, prostate cancer, cervical carcinoma, nasopharyngeal cancer, and soft tissue sarcomas) (1).

2.2

Sarcomas

Sarcomas are among the group of solid tumors for which the benefits of induction therapy have been difficult to establish. Survival benefits have not been definitively demonstrated because of the paucity of adequately powered randomized clinical trials. However, single-institution reports suggest that preoperative therapy enables tumor downstaging and organ sparing in some patients. Several distinct groups of sarcomas are recognized: soft tissue sarcomas, bone sarcomas (osteosarcomas and chondrosarcomas), Ewing’s sarcomas, and peripheral primitive neuroectodermal tumors. Since the late 1980s, preoperative chemotherapy has been the standard treatment for patients with osteosarcoma based on data from randomized controlled trials demonstrating a significant survival advantage with systemic therapy (4,5). The histologic subtypes rhabdomyosarcoma and Ewing’s sarcoma have been demonstrated to have a higher propensity for systemic metastases, and for these histologies, the addition of chemotherapy may have survival advantages and is considered standard care (6,7). The use of chemotherapy (preoperative or postoperative) for other sarcomas remains controversial. Patients with large (> 5 cm), high-grade, deep, extremity soft tissue sarcomas (American Joint Committee on Cancer stage III) commonly develop distant recurrence and subsequently die of sarcoma. Consequently, pre- or postoperative anthracycline-based chemotherapy is often considered in these patients.

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3

INDUCTION THERAPY OPTIONS

3.1.

Preoperative Radiation Therapy

3.1.1. Extremity and Trunk Sarcomas The primary goal of pre- or postoperative radiation therapy is to maximize local tumor control. Surgical resection and radiation therapy (external beam or brachytherapy) are generally considered standard treatment modalities for most patients with large, high-grade extremity soft tissue sarcomas. This therapeutic approach is based on data from two phase III trials demonstrating improved local control with the addition of radiation therapy for patients with localized extremity and trunk sarcomas (8,9). In the randomized trial from the National Cancer Institute (NCI), 91 patients with high-grade extremity tumors were treated with limb-sparing surgery followed by chemotherapy alone or by radiation therapy plus adjuvant chemotherapy. A second group of 50 patients with low-grade tumors were treated with resection alone or resection plus radiation therapy. The 10-year rate of local control for all patients receiving radiation therapy was 98%, compared with 70% for those not receiving radiation therapy (p = 0.0001) (8). Similarly, in the randomized trial from Memorial Sloan-Kettering Cancer Center, 164 patients with extremity or trunk sarcomas underwent observation or brachytherapy after conservative surgery. The 5-year local control rate for patients with high-grade tumors was 66% in the observation group and 89% in the brachytherapy group (p = 0.003) (9). No consensus exists on the optimal sequence of radiation therapy and surgery. Proponents of preoperative radiation therapy cite several advantages. First, multidisciplinary planning with radiation oncologists, medical oncologists, and surgeons is facilitated early in the course of therapy while the tumor is in place. Second, lower doses of preoperative radiation can more easily be delivered to an undisturbed tumor bed, which may have improved tissue oxygenation (10-12). Third, the size of preoperative radiation fields is smaller and the number of joints included in those fields is fewer than in postoperative radiation fields, and this may result in improved functional outcome (13). And finally, preoperative radiation may induce tumor shrinkage and thus facilitate surgical resection (11). On the other hand, critics of preoperative radiation therapy cite as disadvantages the difficulty of pathologic assessment of margins in irradiated specimens and the increased rate of wound complications. The only randomized comparison of preoperative and postoperative radiation therapy for soft tissue sarcoma conducted to date was performed by the National Cancer Institute of Canada Clinical Trials Group (14). This trial was designed to compare complications and functional outcomes of sarcoma patients treated with preoperative or postoperative external-beam radiation

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therapy. From October 1994 to December 1997, 190 patients were randomized to receive preoperative radiation therapy (50 Gy) or postoperative radiation therapy (66 Gy). At a median follow-up of 3.3 years, wound complications had occurred in 35% of patients given preoperative radiation therapy but only 17% of patients given postoperative radiation therapy (p = 0.01). The majority of wound complications occurred in patients with lower extremity sarcomas. Both groups achieved similarly high rates of local control and progression-free survival at 3 years (14). Interestingly, overall survival appeared to be improved in patients treated with preoperative radiation. These findings suggest that preoperative external-beam radiation therapy is effective but that patients should be informed of the increased risk for major wound complications — particularly for patients with lower extremity soft tissue sarcoma.

3.1.2. Retroperitoneal Sarcomas Based on the high rates of local control obtained with surgery plus radiation therapy in patients with extremity and trunk sarcomas, there has been interest in attempting such strategies for patients with retroperitoneal sarcomas. Administering preoperative radiation therapy to retroperitoneal soft tissue sarcomas is complex. Large tumors in proximity to vital radiosensitive anatomic structures frequently hinder safe delivery of treatment. However, there are several advantages to administering radiation therapy preoperatively for retroperitoneal sarcomas: the gross tumor volume is definable, which allows accurate treatment planning; tumors often displace radiosensitive viscera outside of the radiation field; and biologically effective radiation doses may be lower in the preoperative setting (15). Several groups have prospectively examined the effects of preoperative and intraoperative radiation therapy administered to patients with retroperitoneal sarcomas (16-19). These studies demonstrate that preoperative radiation doses of 45 to 50.4 Gy can be delivered to the retroperitoneum with acceptable treatment-related toxicity.

3.2

Preoperative Chemotherapy

Chemotherapy given either preoperatively or postoperatively for soft tissue sarcomas remains controversial. Soft tissue sarcomas encompass a diverse group of cancers that vary greatly in natural history and response to treatment, and the results of conventional chemotherapy regimens have generally been poor. While some histologic subtypes of sarcoma are very

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responsive to cytotoxic chemotherapy, most subtypes are resistant to current agents. The most active chemotherapeutic agents for bone sarcomas are doxorubicin, methotrexate, cisplatin, and ifosfamide. For Ewing’s sarcoma, doxorubicin, vincristine, cyclophosphamide, and ifosfamide have demonstrated response rates of up to 90% (20,21). Dactinomycin, vincristine, and etoposide are active only against small-cell sarcomas, including Ewing’s sarcoma, rhabdomyosarcoma, primitive neuroectodermal tumor, and neuroblastoma. For other subtypes of sarcoma doxorubicin and ifosfamide are the two most active agents, with consistently reported response rates of 20% to 40% (20,22,23). Both agents have demonstrated positive doseresponse curves (24,25). Response rates to ifosfamide at higher doses or in combination with doxorubicin have been reported to range from 20% to 60% in single-institution series (24,26-29). There are several theoretical benefits associated with early systemic treatment. In addition to early treatment of micrometastatic disease, preoperative systemic chemotherapy may induce primary tumor shrinkage, resulting in increased rates of limb salvage. In addition, a major deterrent to the use of postoperative chemotherapy has been the risk of adverse toxic effects in patients who do not respond to therapy. The ability to assess the effects of treatment by assessing tumor response in situ argues in favor of preoperative chemotherapy. Such an approach spares those patients who fail to respond to therapy from the prolonged toxicities of an ineffective treatment. Patients who are deemed to be responsive to preoperative chemotherapy can be treated postoperatively as well with hope of improving their outcome.

3.3

Multimodality Therapy / Chemoradiation

3.3.1

Extremity and Trunk Sarcomas

The objectives of sequential multimodality therapy or concurrent chemoradiation therapy are similar to those of other induction regimens, to achieve tumor reduction and provide local control while allowing the timely administration of systemic therapy to eradicate potential micrometastatic disease. Treatment approaches that combine systemic chemotherapy with radiosensitizers and concurrent external-beam radiation may improve diseasefree survival by treating microscopic disease while enhancing the treatment of macroscopic disease. Concurrent chemoradiation with doxorubicin-based regimens reportedly produces favorable local control rates for patients with soft tissue sarcoma (30,31). The initial experience involved intra-arterial doxorubicin combined with high-dose-per-fraction radiation therapy in patients with extremity soft tissue sarcomas. Since those findings were

49

published, several groups have attempted to evaluate the optimal route of administration (30,32-35), alternative chemotherapeutic agents (36-38), and the toxicity of combined therapies (39). The route of administration of doxorubicin, intra-arterial versus intravenous, was evaluated in a small phase III trial, which demonstrated no difference between the two routes in limb salvage, local recurrence, complications, or pathologic response (40). Given these results and the complexity of intra-arterial administration, intravenous administration of chemotherapeutic agents during concurrent chemoradiation is the current standard (31). Doxorubicin is the most commonly studied radiosensitizer for soft tissue sarcoma (31). A number of other agents have been evaluated, including idoxuridine (38), razoxane (36), and ifosfamide (41). In addition, various chemotherapy approaches have been studied including short-duration chemotherapy with concurrent rapid-fractionation radiation therapy (31), lowdose continuous-infusion chemotherapy with concurrent radiation therapy (42), and sequential chemotherapy and radiation therapy (43). The toxicity and responses for each approach appear acceptable, but additional survival data are required to determine if one is superior. It is difficult to make comparisons between chemotherapeutic agents and regimens because of the diversity of the patient populations, but in general preoperative chemoradiation combined with surgery has been demonstrated to be feasible, to have acceptable toxicity, and to result in favorable local control rates for patient with localized and locally advanced soft tissue sarcomas. Theoretical advantages of concurrent treatment notwithstanding, the concurrent use of local and systemic therapies decreases the total treatment time for patients with high-risk sarcoma. This decrease represents a specific advantage over current sequential multimodality treatment approaches, for which the total time for radiation, chemotherapy, surgery, and rehabilitation frequently exceeds 6 to 9 months. The toxicity associated with chemoradiation depends on the particular chemotherapeutic agent and route of administration as well as the radiation dose/fractionation regimen. Tumor factors such as size and anatomic site may also be critical in treatment-related toxicity. As with preoperative radiation alone, the rate of postoperative wound complications for patients treated with preoperative chemoradiation is high, reported as 26% in some series (30).

3.3.2

Retroperitoneal Sarcomas

Anatomic considerations favor preoperative over postoperative radiation for patients with retroperitoneal sarcomas (31), and pilot and phase I studies using idoxuridine-based and doxorubicin-based (44,45)

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chemoradiation have demonstrated that these approaches are safe and feasible for patients with retroperitoneal sarcomas. The Radiation Therapy Oncology Group is conducting a multicenter phase II trial of combined multimodality treatment for patients with intermediate- or high-grade retroperitoneal sarcomas (RTOG S-0124, www.rtog.org). Patients are given preoperative systemic therapy with doxorubicin and ifosfamide (up to 4 cycles) followed by preoperative external-beam radiation therapy (45 to 50 Gy) and then surgical resection with an intraoperative or postoperative radiation boost. The objective of the trial is to assess the feasibility, toxicity, and complications of this multimodality treatment regimen.

4

IMPACT OF PREOPERATIVE THERAPY

4.1

Scope of Surgery

The goal of surgical therapy for soft tissue sarcoma is to achieve grossly and microscopically negative (R0) margins of resection with the best possible functional result. Experience has demonstrated that surgical resection alone is generally inadequate treatment except for patients with small, superficial, well-differentiated lesions (46-48). The translation of a response to induction therapy (e.g., radiation therapy or chemotherapy) into a clinically meaningful outcome — reduction in the scope of surgical resection — is not well defined. A recent retrospective analysis examined the impact of preoperative chemotherapy on the scope of surgery. The study included a blinded assessment of imaging studies obtained before and after induction chemotherapy in 65 patients with stage II or III soft tissue sarcomas (49). The impact of induction chemotherapy was classified into one of three categories based on the perceived impact of induction chemotherapy on the planned surgical procedure: no change in planned surgical resection, decreased scope of resection, or increased scope of resection. The radiographic responses to preoperative chemotherapy included partial responses in 34%, minimal responses in 9%, stable disease in 31%, and progressive disease in 26%. Only 8 patients (12%) were believed to have downstaging sufficient to decrease the scope of their operation, and 6 patients (9%) had disease progression sufficient to increase the scope of their operation (49). Of interest, none of the 9 patients who were determined to require amputation prior to chemotherapy were able to undergo limb salvage after chemotherapy. Thus, there was no clear evidence to support the perception that patients with locally advanced extremity soft tissue sarcoma (resectable only by amputation) could be “downstaged” to permit function-preserving, limb-sparing surgery.

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4.2

Functional Status and Quality of Life

Treatment for sarcomas may result in significant functional disability and reduced quality of life (50). An adequate margin-negative (R0) tumor resection for soft tissue sarcoma includes removal of the tumor with a margin of normal tissue confirmed to be tumor-free by microscopic evaluation. The proximity of some tumors to vital anatomic structures often requires resection of such structures, including major motor nerves, resulting in significant postoperative functional impairment. In a prospective study evaluating functional outcome in patients with soft tissue sarcomas, large tumor size, postoperative complications, and neural sacrifice were associated with poor functional outcome (51). Treatment sequencing may have an impact on long-term functional outcome. Preoperative external-beam radiation therapy allows the delivery of lower doses of radiation to smaller volumes of tissue with potentially less long-term morbidity from tissue damage. In a large retrospective study, the incidence of delayed radiation-associated complications including soft tissue necrosis, bone fractures, osteonecrosis, edema, and fibrosis was 9% for postoperative radiation therapy and 5% for preoperative radiation therapy (p = 0.03) (52). The impact of the timing of radiation therapy on functional outcome was also examined in a randomized clinical trial supported by the National Cancer Institute of Canada (50). Two years following surgery, there were no differences in function or quality of life, with all measures returning to pretreatment levels, between the preoperative and postoperative radiation therapy groups. However, long-term follow-up is needed to assess the late manifestations of preoperative and postoperative radiation therapy, particularly with respect to physical function, limb edema, and bone fractures (14).

4.3

Pathologic Response

An advantage of preoperative therapy is the ability to assess tumor response in situ using radiologic imaging as well as pathologically following surgical resection. This strategy allows patients with unresponsive tumors to be identified and spared the toxicity and cost of additional treatment with a regimen that is not effective. The pathologic responses identified following induction chemotherapy have ranged from no response to complete response with no residual viable cancer cells. In most cases, responses are partial or incomplete. Studies have demonstrated that cells located in the wellvascularized tumor periphery are most likely to be affected by induction

52

chemotherapy and that if left untreated, these peripheral tumor cells are likely to be responsible for tumor recurrence (53). Chemotherapy-induced pathologic necrosis is a predictor of survival in patient’s who receive preoperative chemotherapy for osteogenic and Ewing’s sarcoma (54-57). However, the incidence of treatment-induced pathologic necrosis and its correlation with clinical outcomes are not well defined in patients with soft tissue sarcomas (2). Small studies have reported rates of complete pathologic tumor necrosis following doxorubicin-based induction chemotherapy of only 5% to 9% (58-60). In a retrospective analysis of 496 patients with intermediate- and high-grade extremity soft tissue sarcomas who were treated with preoperative therapy (consisting primarily of doxorubicin-based chemotherapy and radiation), complete pathologic responses were noted in 69 patients (14%). With a mean follow-up of 10 years, the 10-year local recurrence rate for patients with complete pathologic necrosis was 11%, compared to 23% for patients with less than 95% pathologic necrosis. However, the 10-year survival rate for patients with complete pathologic responses was 71%, compared to 55% for other patients (p = 0.0001)(2). Based on these results, the authors concluded that pathologic assessment of necrosis can be considered a surrogate endpoint for survival outcomes in patients with soft tissue sarcomas and, as such, can be used as a valid and timely endpoint by which novel agents and treatment protocols are evaluated (2).

5

SURVIVAL

5.1

Radiation Therapy

The relationship between local control and distant metastasis/diseasespecific survival has long been debated in the treatment of solid tumors. It is biologically plausible that with high-risk disease, more complete eradication of aggressive residual sarcoma could reduce the risk of distant progression and sarcoma-specific death. Important issues in this debate include (1) whether a local treatment modality can impact distant metastasis and tumorrelated mortality and (2) whether patients who have increased rates of local failure have an increased risk of subsequent distant metastasis. However, the prevention of local recurrence by either amputation or radiation therapy has not translated into a survival benefit in sarcoma patients (61). Examination of the published phase III trials of postoperative radiation for sarcoma indicates that local tumor control does not have an impact on disease-specific survival (62,63). However, the existing phase III trials (8,9,62,63) of postoperative radiation included relatively small numbers of patients at risk for recurrence — 52 patients in the NCI trial (J. Yang, personal communication) and 77 patients in the Memorial Sloan-Kettering

53

trial (M.F. Brennan, personal communication). If one accepts that the association between local control and survival is best addressed through studies of high-risk patients, then it is conceivable that the existing phase III trials may not be adequate for the assessment of a potential association. At least two large retrospective studies have examined the outcomes associated with preoperative versus postoperative radiation therapy (52,64). Both studies found no difference in the rates of local control and diseasespecific survival between the two treatment sequence groups. The only randomized comparison of preoperative and postoperative radiation therapy is the multi-institutional study performed by the National Cancer Institute of Canada Clinical Trials Group (14). With a median followup of 3.3 years, there were no differences in local recurrence, distant recurrence, or progression-free survival but there was a slightly higher overall survival rate in patients who received preoperative radiation therapy than in those who were treated with postoperative radiation therapy (p = 0.0481). It has been noted that there was a relative imbalance in the number of patients who died of other causes between the pre- and postoperative radiation arms. It is not clear whether this imbalance or other confounding factors could account for the significant survival difference or whether this observation indicates a significant clinical advantage associated with preoperative radiation. Interestingly, an improvement in disease-specific survival associated with the use of radiation has been demonstrated in phase III trials in other malignancies, including node-positive breast cancer (65-68) and some squamous cell carcinomas of the head and neck (69). A common theme in those reports was an examination of the relationship between local control and survival in subgroups of patients at high risk for distant metastasis.

5.2

Chemotherapy

In a meta-analysis of patients with extremity soft tissue sarcomas, the estimated survival benefit attributable to postoperative chemotherapy was only 7% (70). More recently, one randomized prospective trial of 104 patients with heterogeneous tumors reported an overall survival rate of 75 months for patients treated with surgery and chemotherapy versus 46 months for those treated with surgery with or without radiation (p = 0.03) (71). Two additional smaller randomized trials of patients with primary or locally recurrent soft tissue sarcoma also showed higher 5-year overall survival rates associated with chemotherapy, although the differences were not statistically significant (72,73). The interpretation of this complex literature is difficult, and there is no consensus on the role of chemotherapy for patients with localized high-risk soft tissue sarcoma (74,75).

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Although radiographic response rates to chemotherapy have been 20 to 30%, there have been conflicting reports regarding whether tumor response is associated with improved rates of disease-specific and overall survival (76,49,58). A major goal of preoperative or induction systemic therapy is the early eradication of micrometastatic disease. A single randomized phase II/III study attempted to examine the survival benefits associated with preoperative chemotherapy for soft tissue sarcoma (77). However, the study was closed prior to initiation of the phase III arm because of slow accrual. In the 134 patients randomized for the phase II study, the 5-year disease-free survival rate was 52% for the no-chemotherapy arm and 56% for the chemotherapy arm (p = 0.35).

6

SURGICAL COMPLICATIONS

6.1

Radiation Therapy

There are several studies which have examined the rate of postoperative wound complication following preoperative radiation therapy in patients with extremity soft tissue sarcoma (Table 1). In two large retrospective studies of preoperative versus postoperative radiation therapy (64,52), rates of postoperative wound complications were reported as 31% for preoperative radiation compared to 8% for postoperative radiation. Similarly, there was an increased rate of 18% (95% confidence interval 5% to 30%, p 90%) in ensuring healed wounds in a single-stage operation (81). Unlike the results with extremity sarcomas, there have been no reports of increased rates of wound complications in patients with retroperitoneal sarcomas who received preoperative radiation therapy (16). Long-term toxic effects of preoperative radiation therapy have been reported in only a small fraction of patients. In a report from the Massachusetts General Hospital, 4 of 37 retroperitoneal sarcoma patients treated with preoperative radiation therapy suffered from neuropathy, hydronephrosis, fistula formation, vascular injury and/or bowel complications (18). Similary, 4 of 41 patients treated at the Mayo Clinic were reported to have significant late toxic effects associated with combined therapy; these effects included duodenitis/gastric outlet obstruction, chronic pain, bowel obstruction requiring surgery, and, in one patient, death (16).

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6.2

Chemotherapy

There are few clinical data examining the relationship between preoperative chemotherapy and surgical complications following resection of soft tissue sarcomas. A single-institution retrospective analysis compared the rate of postoperative complications in 105 patients who received preoperative chemotherapy to that in 204 patients who were treated with surgical resection alone (82). The characteristics of the two treatment groups are presented in Table 2. The median interval between the end of chemotherapy and surgical resection was 45 days. Postoperative complication rates were similar in the

57

two treatment groups in both those with extremity sarcomas (34% versus 41%) and those with retroperitoneal/visceral sarcomas (29% versus 34%). The most common complications in both groups were wound infections.

7

CONCLUSIONS

Soft tissue sarcomas continue to represent a therapeutic challenge because of their rarity and the heterogeneity of the many histologic subtypes. The efficacy of preoperative therapy has been difficult to establish. However, there is evidence that induction therapy may result in reduction of tumor size that facilitates less radical surgical resections with improved postoperative function. Clinical evidence supports continued investigation of preoperative treatment approaches for soft tissue sarcomas. The use of preoperative therapy reinforces the need for cooperation among oncologic disciplines. The timing and sequence of treatment modalities should be discussed at the time of tumor diagnosis. Individual treatment decisions must weigh the estimated likelihood and severity of potential short- and long-term complications associated with one treatment sequence versus another.

8

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23. Benjamin RS, Legha SS, Patel SR, Nicaise C. Single-agent ifosfamide studies in sarcomas of soft tissue and bone: the M. D. Anderson experience. Cancer Chemother Pharmacol 1993;31:S174-9. 24. Patel SR, Vadhan-Raj S, Papadopolous N, et al. High-dose ifosfamide in bone and soft tissue sarcomas: results of phase II and pilot studies--dose-response and schedule dependence. J Clin Oncol 1997;15(6):2378-84. 25. O’Bryan RM, Baker LH, Gottlieb JE, et al. Dose response evaluation of Adriamycin in human neoplasia. Cancer 1977;39(5):1940-8. 26. Nielsen OS, Judson I, van Hoesel Q, et al. Effect of high-dose ifosfamide in advanced soft tissue sarcomas. A multicentre phase II study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 2000;36(1):61-7. 27. Frustaci S, Buonadonna A, Romanini A, et al. Increasing dose of continuous infusion ifosfamide and fixed dose of bolus epirubicin in soft tissue sarcomas. A study of the Italian group on rare tumors. Tumori 1999;85(4):229-33. 28. Palumbo R, Palmeri S, Antimi M, et al. Phase II study of continuous-infusion high-dose ifosfamide in advanced and/or metastatic pretreated soft tissue sarcomas. Ann Oncol 1997;8(11):1159-62. 29. Buesa JM, Lopez-Pousa A, Martin J, et al. Phase II trial of first-line high-dose ifosfamide in advanced soft tissue sarcomas of the adult: a study of the Spanish Group for Research on Sarcomas (GEIS). Ann Oncol 1998;9(8):871-6. 30. Eilber FR, Giuliano AE, Huth JH, Mirra JJ, Rosen G, Morton DL. Neoadjuvant chemotherapy, radiation, and limited surgery for high grade soft tissue sarcoma of the extremity. In: Ryan JR, Baker LO, eds. Recent Concepts in Sarcoma Treatment. Dordrecht, The Netherlands: Kluwer Academic Publishers, 1988: 115-22. 31. Pisters PW, Ballo MT, Patel SR. Preoperative chemoradiation treatment strategies for localized sarcoma. Ann Surg Oncol 2002;9(6):535-42. 32. Goodnight JE, Jr., Bargar WL, Voegeli T, Blaisdell FW. Limb-sparing surgery for extremity sarcomas after preoperative intraarterial doxorubicin and radiation therapy. Am J Surg 1985;150(1):109-13. 33. Levine EA, Trippon M, Das Gupta TK. Preoperative multimodality treatment for soft tissue sarcomas. Cancer 1993;71(11):3685-9. 34. Wanebo HJ, Temple WJ, Popp MB, Constable W, Aron B, Cunningham SL. Preoperative regional therapy for extremity sarcoma. A tricenter update. Cancer 1995;75(9):2299-306. 35. Temple WJ, Temple CL, Arthur K, Schachar NS, Paterson AH, Crabtree TS. Prospective cohort study of neoadjuvant treatment in conservative surgery of soft tissue sarcomas. Ann Surg Oncol 1997;4(7):586-90. 36. Rhomberg W, Hassenstein EO, Gefeller D. Radiotherapy vs. radiotherapy and razoxane in the treatment of soft tissue sarcomas: final results of a randomized study. Int J Radiat Oncol Biol Phys 1996;36(5): 1077-84. 37. Goffman T, Tochner Z, Glatstein E. Primary treatment of large and massive adult sarcomas with iododeoxyuridine and aggressive hyperfractionated irradiation. Cancer 1991;67(3):572-6.

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38. Sondak VK, Robertson JM, Sussman JJ. Preopertive idoxuridine and radiation for large soft tissue sarcomas: clinical results with five-year follow-up. Ann Surg Oncol 1998;5:106-112. 39. Pisters PW. Chemoradiation treatment strategies for localized sarcoma: conventional and investigational approaches. Semin Surg Oncol 1999;17(1):66-71. 40. Eilber FR, Giuliano AE, Huth JF, Weisenburger TH, Eckardt J. Intravenous (IV) vs. intraarterial (IA) Adriamycin, 2800r radiation and surgical excision for extremity soft tissue sarcomas: a randomized prospective trial [Abstract 309]. Proc Am Soc Clin Oncol 1990. 41. Cormier JN, Patel SR, Herzog CE, et al. Concurrent ifosfamide-based chemotherapy and irradiation. Analysis of treatment-related toxicity in 43 patients with sarcoma. Cancer 2001;92(6):1550-5. 42. Toma S, Palumbo R, Vincente M. Concomitant doxorubicin (DOXO) by continuous infusion (CI) and radiotherapy (RT) at low doses in locally advanced and/or metastatic soft tissue sarcomas (STS): long-term results of a phase II study [Abstract 520]. Proc Am Soc Clin Oncol 1995. 43. Kraybill WG, Spiro IJ, Harris J. Radiation Therapy Oncology Group (RTOG) 9514: a phase II study of neoadjuvant chemotherapy (CT) and radiation therapy (RT) in high risk (HR), high grade, soft tissue sarcomas (STS) of the extremities and body wall: a preliminary report [Abstract 348a]. Proc Am Soc Clin Oncol 2001. 44. Eilber F, Eckardt J, Rosen G, Forscher C, Selch M, Fu YS. Preoperative therapy for soft tissue sarcoma. Hematol Oncol Clin North Am 1995;9(4):817-23. 45. Pisters PWT, Patel SR, Pollock RE. Phase I trial of preoperative doxorubicinbased concurrent chemoradiation and electron-beam intraoperative radiation therapy (IORT) for resectable retroperitoneal sarcomas [Abstract 103]. Cancer J Sci Am 1998. 46. Alektiar KM, Leung D, Zelefsky MJ, Brennan MF. Adjuvant radiation for stage II-B soft tissue sarcoma of the extremity. J Clin Oncol 2002;20(6):1643-1650. 47. Fleming JB, Berman RS, Cheng SC, et al. Long-term outcome of patients with American Joint Committee on Cancer stage IIB extremity soft tissue sarcomas. J Clin Oncol 1999;17(9):2772-80. 48. Baldini EH, Goldberg J, Jenner C, et al. Long-term outcomes after functionsparing surgery without radiotherapy for soft tissue sarcoma of the extremities and trunk. J Clin Oncol 1999;17(10):3252-9. 49. Meric F, Hess KR, Varma DG, et al. Radiographic response to neoadjuvant chemotherapy is a predictor of local control and survival in soft tissue sarcomas. Cancer 2002;95(5):1120-6. 50. Davis AM, O’Sullivan B, Bell RS, et al. Function and health status outcomes in a randomized trial comparing preoperative and postoperative radiotherapy in extremity soft tissue sarcoma. J Clin Oncol 2002;20(22):4472-7. 51. Bell RS, O’Sullivan B, Davis A, Langer F, Cummings B, Fornasier VL. Functional outcome in patients treated with surgery and irradiation for soft tissue tumours. J Surg Oncol 1991;48(4):224-31.

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52. Zagars GK, Ballo MT, Pisters PW, Pollock RE, Patel SR, Benjamin RS. Preoperative vs. postoperative radiation therapy for soft tissue sarcoma: a retrospective comparative evaluation of disease outcome. Int J Radiat Oncol Biol Phys 2003;56(2):482-8. 53. Stephens FO. Induction chemotherapy: to downgrade aggressive cancers to improve curability by surgery and/or radiotherapy. Eur J Surg Oncol 2001 ;27(7):67288. 54. Lindner NJ, Scarborough MT, Spanier SS, Enneking WF. Local host response in osteosarcoma after chemotherapy referred to radiographs, CT, tumour necrosis and patient survival. J Cancer Res Clin Oncol 1998;124(10):575-80. 55. Rosen G, Caparros B, Huvos AG, et al. Preoperative chemotherapy for osteogenic sarcoma: selection of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy. Cancer 1982;49(6):1221-30. 56. Wunder JS, Paulian G, Huvos AG, Heller G, Meyers PA, Healey JH. The histological response to chemotherapy as a predictor of the oncological outcome of operative treatment of Ewing sarcoma. J Bone Joint Surg Am 1998;80(7):1020-33. 57. Picci P, Bohling T, Bacci G, et al. Chemotherapy-induced tumor necrosis as a prognostic factor in localized Ewing’s sarcoma of the extremities. J Clin Oncol 1997;15(4):1553-9. 58. Ottaiano A, De Chiara A, Fazioli F, et al. Neoadjuvant chemotherapy for intermediate/high-grade soft tissue sarcomas: five-year results with epirubicin and ifosfamide. Anticancer Res 2002;22(6B):3555-9. 59. Henshaw RM, Priebat DA, Perry DJ, Shmookler BM, Malawer MM. Survival after induction chemotherapy and surgical resection for high-grade soft tissue sarcoma. Is radiation necessary? Ann Surg Oncol 2001;8(6):484-95. 60. Rahoty P, Konya A. Results of preoperative neoadjuvant chemotherapy and surgery in the management of patients with soft tissue sarcoma. Eur J Surg Oncol 1993;19(6):641-5. 61. Brennan MF. More is less: systemic treatment for local control in soft tissue sarcoma. Ann Surg Oncol 2001;8(6):480-1. 62. Brennan MF, Alektiar KM, Maki RG. Sarcomas of the soft tissue and bone. In: DeVita V, Hellman S, Rosenberg SA, eds. Cancer: Principles & Practice of Oncology. Philadelphia: Lippincott Williams & Wilkins, 2001:1841. 63. Espat NJ, Lewis JJ. The biological significance of failure at the primary site on ultimate survival in soft tissue sarcoma. Semin Radiat Oncol 1999;9(4):369-77. 64. Cheng EY, Dusenbery KE, Winters MR, Thompson RC. Soft tissue sarcomas: preoperative versus postoperative radiotherapy. J Surg Oncol 1996;61:90-99. 65. Overgaard M, Jensen MB, Overgaard J, et al. Postoperative radiotherapy in highrisk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial. Lancet 1999;353(9165):1641-8.

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66. Overgaard M, Hansen PS, Overgaard J, et al. Postoperative radiotherapy in highrisk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial. N Engl J Med 1997;337(14):94955. 67. Ragaz J, Jackson SM, Le N, et al. Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med 1997;337(14):956-62. 68. Whelan TJ, Julian J, Wright J, Jadad AR, Levine ML. Does locoregional radiation therapy improve survival in breast cancer? A meta-analysis. J Clin Oncol 2000;18(6):1220-1229. 69. Mishra RC, Singh DN, Mishra TK. Post-operative radiotherapy in carcinoma of buccal mucosa, a prospective randomized trial. Eur J Surg Oncol 1996;22(5):502-4. 70. Tierney JF. Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Sarcoma Meta-analysis Collaboration. Lancet 1997;350(9092):1647-54. 71. Frustaci S, Gherlinzoni F, De Paoli A, et al. Adjuvant chemotherapy for adult soft tissue sarcomas of the extremities and girdles: results of the Italian randomized cooperative trial. J Clin Oncol 2001;19(5):1238-47. 72. Brodowicz T, Schwameis E, Widder J. Intensified adjuvant IFADIC chemotherapy for adult soft tissue sarcoma: a prospective randomized feasibility trial. Sarcoma 2000;4:151-160. 73. Petrioli R, Coratti A, Correale P, et al. Adjuvant epirubicin with or without ifosfamide for adult soft-tissue sarcoma. Am J Clin Oncol 2002;25(5):468-73. 74. Bramwell VHC. Adjuvant chemotherapy for adult soft tissue sarcoma: is there a standard of care? J Clin Oncol 2001;19(5):1235-1237. 75. Figueredo A, Bramwell VHC, Bell R, Davis AM, Charette ML. Adjuvant chemotherapy following complete resection of soft tissue sarcoma in adults: a clinical practice guideline. Sarcoma 2002;6:5-18. 76. Pisters PW, Patel SR, Varma DG, et al. Preoperative chemotherapy for stage IIIB extremity soft tissue sarcoma: long-term results from a single institution. J Clin Oncol 1997;15(12):3481-7. 77. Gortzak E, Azzarelli A, Buesa J, et al. A randomised phase II study on neoadjuvant chemotherapy for ‘high-risk’ adult soft-tissue sarcoma. Eur J Cancer 2001;37(9):1096-103. 78. Bujko K, Suit HD, Springfield DS, Convery K. Wound healing after preoperative radiation for sarcoma of soft tissues. Surg Gynecol Obstet 1993;176(2):124-34. 79. Peat BG, Bell RS, Davis A, et al. Wound-healing complications after soft-tissue sarcoma surgery. Plast Reconstr Surg 1994;93(5):980-7.

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80. Prosnitz LR, Maguire P, Anderson JM, et al. The treatment of high-grade soft tissue sarcomas with preoperative thermoradiotherapy. Int J Radiat Oncol Biol Phys 1999;45(4):941-9. 81. Langstein HN, Robb GL. Reconstructive approaches in soft tissue sarcoma. Semin Surg Oncol 1999;17(1):52-65. 82. Meric F, Milas M, Hunt KK, et al. Impact of neoadjuvant chemotherapy on postoperative morbidity in soft tissue sarcomas. J Clin Oncol 2000;18(19):3378-383.

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Chapter 4 TNF-based isolated limb perfusion: A decade of experience with antivascular therapy in the management of locally advanced extremity soft tissue sarcomas Dirk J Grünhagen, Flavia Brunstein, Timo L.M. ten Hagen, Albertus N. van Geel, Johannes H.W. de Wilt, and Alexander M.M. Eggermont Dept. of Surgical Oncology, Erasmus University Medical Centre-Daniel den Hoed Cancer Centre, Rotterdam, the Netherlands

Correspondence to: Alexander M.M. Eggermont, MD, PhD Professor Surgical Oncology, Head of Department Department of Surgical Oncology Erasmus University Medical Center - Daniel den Hoed Cancer Center 301 Groene Hilledijk 3075 EA Rotterdam The Netherlands Tel: 31-10-439 19 11 Fax: 31-10–439 10 11 E-mail: [email protected]

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1

INTRODUCTION

In the management of locally advanced extremity soft tissue sarcomas limb salvage has become all the more important in the light of evidence that amputations do not improve survival rates in patients with large (>5 cm) deep seated high grade sarcomas. Several studies have shown that marginal excisions with a high risk for local recurrence do not influence survival significantly (1-4). Of the 7800 new cases of STS diagnosed in the USA each year about 4700 occur in the extremities and tumors are often large at the time of diagnosis. (5) Treatment options for locally advanced extremity STS may consist of an amputation or a limb sparing extensive surgical procedure followed by radiation therapy. This combination may mutilate and compromise limb function considerably. Preoperative therapies to improve limb salvage rates have been propagated. Preoperative radiotherapy alone or in combination with intraarterial or intravenous chemotherapy has been reported to improve resectability rates of extremity soft tissue sarcomas. (6-8) Amputation may also be avoided and local control improved by combining a marginal resection in combination with brachytherapy to the tumor bed (9). Isolated limb perfusion is another strategy to deal with locally advanced soft tissue sarcomas which can be applied also in case of multifocal primary or multiple sarcoma recurrences in limbs, thereby expanding the patient population that can be successfully treated.

2

ISOLATED LIMB PERFUSION

The technique of isolated limb perfusion was pioneered by Creech and Krementz at Tulane University in New Orleans (10). Regional drug concentrations 15-25 times higher than those reached after systemic administration can be achieved by ILP without systemic side effects (11). Isolation of the limb is achieved by clamping and canulation of the major artery and vein, connection to an oxygenated extracorporeal circuit, ligation of collateral vessels and application of a tourniquet. Once isolation is secured, drugs can be injected into the perfusion circuit. Because of its efficacy and low regional toxicity profile melphalan (L-phenyl-alaninemustard) is the standard drug, most commonly used at a dose of 10 mg/L (leg) - 13mg/L (arm) perfused tissue (12). Tissue temperatures are monitored and radiolabeled albumen or erythrocytes is injected into the perfusion circuit to detect leakage into the systemic circulation by precordial scintillation probe (13). Leakage monitoring is mandatory especially for high dose tumor necrosis factor-alpha (TNF) perfusions in the treatment of soft tissue sarcomas. After 1-1.5 hours of perfusion the limb is rinsed with an electrolyte solution, cannulas are removed, and the vessels are repaired. Classification of acute tissue reactions after perfusion is done according to Wieberdink et al (14): (I) No reaction; (II) Slight erythema and/or edema; (III) Considerable

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erythema and/or edema with some blistering, slightly disturbed motility permissible; (IV) Extensive epidermolysis and/or obvious damage to the deep tissues, causing definite functional disturbances; threatening or manifest compartmental syndrome; (V) Reaction which may necessitate amputation.

3

TNF- BASED ISOLATED LIMB PERFUSION FOR STS

3.1 Inadequate results in STS with ILP with chemotherapeutic drugs only In contrast to the efficacy of melphalan- based ILP in patients with multiple intransit melanoma metastases, results wih ILP with melphalan, doxorubicin and a variety of other drugs for large soft tissue sarcoms were diiappointing. After studies in the seventies and eighties with poor response rates ILP for advanced SIS was largely abandoned (15-19). The reported studies are summarized in Table 1.

3.2 Results with ILP with TNF + Melphalan trials leading to approval of TNF Thanks to the pioneering work of Lejeune and Lienard this situation changed dramatically with the application of high dose TNF in the ILP setting (20). TNF-based ILP has been established as a highly effective new method of induction biochemotherapy in extremity soft tissue sarcomas with a 20-30% complete remission (CR) rate and about a 50% Partial Remission (PR) rate (2127). On the basis of results in a multicenter program in Europe TNF was

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approved and registered in Europe for the sarcoma-indication in 1998 (27). The European TNF/ILP assessment group evaluated 246 patients with irresectable STS enrolled in 10 years in 4 studies. All cases were reviewed by an independent review committee and compared with conventionally treated patients (often by amputation) of a population based Scandinavian STS database. In short: there were 246 patients with locally very advanced disease: Primary sarcomas in 55%, local recurrent sarcomas in 45%, multifocal primary or multiple local recurrences in 22 %. Overt concurrent metastatic disease in 15%. Tumors >10 cm in 46%. Grade III tumors in 66%. Previous radiotherapy (13%), chemotherapy (15%). Patients underwent 1 ILP (222 pts) or 2 ILPs (24 pts) of 90 minutes at 39-40° C with 2-4 mg TNF + melphalan (1013 mg/L limb volume). The first 56 pts also received A delayed marginal resection of the tumor remnant was usually (76%) done 2-4 months after ILP. Major responses were seen in 56.5 to 82.6 % of the patients after which usually resection of the sarcoma became possible. Limb salvage was achieved in 74%-87% in these 4 studies and in 71 % of the 196 patients who had been classified by the independent review committees as cases that normally could only have been managed by amputation (87%) or by functionally debilitating resection + radiotherapy (13%). Comparison with the survival curves based on a matched control study with cases from the Scandinavian Soft Tissue Sarcoma Databank showed that TNF had no negative effect on survival (p=0.96). It was concluded that the application of TNF in combination with melphalan in the setting of isolated limb perfusion represents a new and successful option in the management of irresectable locally advanced extremity soft tissue sarcomas (27).

3.3

Confirmatory single center reports on TNF + melphalan

Smaller single center studies with TNF+Melphalan have been reported recently by Lejeune (29) reporting a 17% CR and 64% PR rate in 22 STS patients treated for limb threatening STS tumors, achieving limb salvage in 77% of the patients. A similar limb salvage rate of 84% and excellent functional results were reported from the Berlin team regarding their experience in a series of 55 patients (30). We reported on very good outcome of 16 perfusions in 10 patients with multiple lymphangiosarcomas (Stewart Treves Syndrome), achieving a CR rate of 56% and a limb salvage rate of 80% (32). The Amsterdam group reported somewhat less favorable results in their experience in 49 patients. The limb salvage rate of 58% was felt to reflect the selection patients with particularly unfavorable characteristics (32). The French group reported recently on their experience in 72 patients. In a randomized phase II trial, utilizing various doses of TNF ranging from 0.5 mg to 4 mg, they observed a 35% CR rate and an overall limb salvage rate of 84%. No significant differences between the various TNF dosage groups were observed. In a particularly unfavorable group of patients with recurrent sarcomas after surgery

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and radiotherapy, with the recurrent sarcoma in the irradiated field, we reported on the Rotterdam experience in 24 patients. A response rate of 74% and a limb salvage rate of 67% was reported in these patients otherwise destined for amputation.

3.4

Safety in Elderly Patients

A very important message is given by the report on the Rotterdam experience with 50 TNF-based ILPs in patients older than 75 years with limb threatening tumors. Results were very favorable in the 34 perfusions for limb threatening sarcomas, with a 38% CR and a 38% PR rate, achieving limb salvage in 76% of the patients as well as in 16 perfusions for bulky melanoma intransit metastases resulting in a 75%CR and 25%PR rate. The procedure was proven safe in the elderly with the high reward of limb salvage which is of overriding importance in this age group as amputations lead to loss of independency in lives in the elderly (35). Moreover we reported on the absence of toxicity in patients without leakage and the relatively easy management and relative lack of toxicity in patients with high leakage of TNF during ILP (36, 37)

3.5

Results with TNF + Doxorubicine

Very similar results have been obtained by Italian perfusion groups with the drug doxorubicin in combination with TNF. Interestingly similar response and limb salvage rates are achieved while using lower doses of only 1 mg TNF instead of the usual doses of 2-4 mg used in combination with melphalan (28). The perfusions were performed at much higher temperatures (40-41 degrees), which leads to higher locoregional toxicity. Grade IV locoregional toxicity was reported in 25% as opposed to only 5% in the large TNF+Melphalan series (21,23,27). We found that with melphalan ILPs grade IV toxicity was clearly related to tissue temperatures of above 39 degrees when melphalan was administered (38) Therefore we have only allowed for tissue temperatures to rise to 39 degrees after melphalan has been added to the perfusion circuit the last 8 years and have hardly seen any cases with grade IV toxicity since, without a drop in response rates (27,31,34,35). Most likely therefore the higher regional toxicity in the Italian experience with doxorubicin is primarily related to the hyperthermia although doxorubicine may be responsible in part.

4

TNF-BASED ILP ACTIVE IN MANY HISTOLOGIES

Since the tumor vasculature in the target of TNF and of the TNF+chemotherapy combination it can be expected that this treatment is effective against a wide variety of tumor types as long as there is a welldeveloped vascular stromal component to the tumor. This is indeed the case.

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Apart from activity in some 20 different histological types of soft tissue sarcoma and activity in melanoma (39-43), the efficacy of TNF + melphalan ILP has also been demonstrated in various skin tumors (44), bony sarcomas (45) and limb desmoid tumors (46).

5 VASCULOTOXIC MECHANISM OF TNF + CHEMOTHERAPY The target of TNF is the tumor-vasculature. This common denominator in all these tumors makes the use of TNF very attractive and explains its efficacy in combination with chemotherapy across all these different histologies. The selective destructive effects of TNF-ILP on tumor-associated vessels have been illustrated in previous publications by means of pre- and post perfusion angiographies (23). Moreover in sarcoma patients’ magnetic resonance spectrometry studies we have clearly shown that the metabolic shut down of the tumor is virtually complete within 16 hours after the perfusion, confirming the likelihood of mediating its most important effects on the vasculature of the tumor (48). At the histopathological level we have also studied these intravascular effects such as thrombocyte aggregation, erythrostasis, endothelial and vascular destruction already in the early and late stages after ILP (48-49).

6

NEW INSIGHTS THROUGH LABORATORY MODELS

To further insight in the mechanisms underlying the positive results obtained with ILP in humans we developed in rats extremity perfusion models using the BN175 non immunogenic fibrosarcoma in Brown Norways rats and the ROS-1 osteosarcoma in WAG rats. In both models we could demonstrate that the tumor cells were resistant to TNF in vitro and that ILP in vivo with TNF alone had no major impact on tumor growth. In both models a strong synergistic antitumor effect leading to CRs in some 60-70 % was observed after ILP with TNF+Melphalan (50-51). TNF alone only caused some central necrosis and no regression of the tumor was observed as has been reported for the clinical setting as well. Histopathologically haemorrhagic necrosis was most prominent after ILP with both drugs. Early endothelial damage and platelet aggregation in the tumor vessels are observed after ILP with TNF + Melphalan and this is believed to lead to ischemic (coagulative) necrosis, which is in line with observations in patients. Our observations confirm that has its major effect on larger tumors, with well-developed vasculature in contrast to small tumors (diameter < 3 mm) with lack of developed capillary bed. TNF may exert its effect mainly through the neovasculature of the tumor, which is more abundant in large tumors. Moreover there are distinct similarities between tumor stroma generation and wound healing and observations by us that sites other than the tumor (recent wounds or skin overlying tumors only when invaded by tumor), which undergo

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angiogenesis, also become necrotic after ILP with TNF+ melphalan, but not after ILP with melphalan alone. We have demonstrated a number of crucial elements in our rat tumor models identifying the mechanisms for the strong synergy between TNF and Cytostatic drugs in ILP and have identified the prerequisites for an effective ILP:

6.1

Tumor vessel destruction

The vasculo-toxic effects of the combination of TNF + melphalan leading to haemorrhagic and anoxic coagulative necrosis as described above.

6.2

Enhanced drug uptake by the tumor

We have recently demonstrated that the addition of high dose TNF to the perfusate results in a 4-6 fold increased uptake by the tumor of the cytostatic drug. For Melphalan and for Doxorubicin is was demonstrated that this uptake was tumor specific and that no increased uptake was noted in the normal tissues, thus emphasizing the relatively selective action of TNF on the tumor-associated vasculature (52) This increase in concentration was also observed with doxorubicin (53). Moreover we have demonstrated that the effect correlates with the vascularity of the tumor. The more vascular the tumor the better the synergistic effect between TNF and the chemotherapeutic agent (54). Whether a TNF-mediated drop in interstitial pressure (55) in the tumor plays a role in this mechanism remains speculative.

6.3

Role of Leukocytes

We have shown that leukocytes play also an important role in the TNF-mediated antitumor effects. In rats that underwent total body irradiation and underwent an ILP at the time of absolute leukopenia the antitumor effect of an ILP with TNF+melphalan was very similar to the effects of a perfusion with melphalan alone. In the leukopenic rat the TNF-effect was lost and the synergy between TNF and Melphalan was no longer observed (56)

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6.4

Dose range for TNF

We demonstrated that 10 micrograms of TNF (a fivefold reduction of the “standard dose of 50 microgram” was the threshold dose for activity of TNF in our rat tumor extremity perfusion model. At 2 microgram all TNF-effects were lost (57). This finding would suggest that also in the clinical setting dose reduction without loss of activity could be explored as been also suggested by the clinical results in the UK (22) and in Italy (29) as well as the recent report from France (33).

6.5

Duration of ILP

As the pharmacokinetics of melphalan demonstrates that almost all melphalan uptake occurs over 20-30 minutes the minimal duration for an effective ILP should be 30 minutes. Shorter perfusion times are associated with a drop in CR and PR rates whereas longer than 30 minutes ILPs do not seem to further improve the results (57)

6.6

Mild Hyperthermia

Temperatures of 38-39 degrees Centigrade were shown to be essential for obtaining a good antitumor response without damage to the normal tissues in the limb. True hyperthermia (42-43degrees) resulted in an increase of CRs but was associated with very sever damage to the normal tissues. All antitumor efficacy was lost when perfusions were performed at room temperature. (57)

6.7

Hypoxia

We demonstrated that hypoxia can enhance the antitumor effects of an ILP with either TNF alone or Melphalan alone. Hypoxia did not further enhance the antitumor efficacy of an ILP with TNF+Melphalan as the synergy between these two agents “overrided” any minor enhancement mediated by hypoxia (57).

6.8

Interferon-gamma

In spite of many reports of the synergy between IFN-gamma and TNF both in vitro as well as in vivo in murine tumor models the role of IFNgamma not very strong in our rat models. We demonstrated that about a 10% increase in CR rate and an increase of about 20% in overall response rate was observed in our animal models (58), which resembles the situation in the clinic (43).

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6.9

Idiosyncratic toxicity

Interestingly unexpected interactions may lead to idiosyncratic reactions between TNF and certain cytostatic agents. Actinomycin D is commonly used in combination with melphalan in the clinical setting. When investigating whether TNF would enhance the efficacy of Actinomycin D we discovered that it did in an idiosyncratic and nondiscriminative way. The combination was more effective against the tumor than TNF+Melphalan, but this advantage was annulled by the toxicity of TNF+Actinomycin D to the normal tissues, resulting in the amputation of all extremities in these animal models. We sent out a strong warning to the clinic not to use TNF in combination with Actinomycin D (59).

6.10

Vasoactive drugs

Various vasoactive drugs have been and are being studied in our laboratory models. Nitric Oxide (NO) is an important molecule in the maintenance of both vascular tone and the integrity of the vascular wall and is highly produced in experimental and human tumors. We postulated that its inhibition could lead to hypoxia and an enhancement of TNF early vascular effects in the tumor. In our ILP BN 175 rat model we performed a response study with TNF in combination with the Arginine analogues L-NAME and LNA, which inhibit NO synthase. In rats treated with TNF combined with LNAME/LNA important and immediate antitumor effects were observed in all rats and necrosis of the skin at the tumor site. These effects are normally only observed when hypoxia or melphalan are added to TNF as described above. Typical TNF tumor response was observed, when NO synthase was inhibited during ILP (60). Another vasoactive drug is histamine, which is currently being studied. Also in this case we see a clear synergy with melphalan in our tumor models (61) These findings show the importance of agents that can change the pathophysiology of tumor vasculature, rheologic conditions en thereby can improve drug uptake in tumors. These findings underline the importance of investigating how to modulate tumor physiology and the potential that this approach has to improve efficacy of various standard agents.

7

CONCLUSIONS

Isolated limb perfusion methodology provides us an excellent tool in the clinic to obtain local control and avoid amputations of limbs in patients with limb threatening tumors. This has been largely achieved by the success of the antivascular TNF-based biochemotherapy in this setting. TNF, for the first time, has brought us an effective treatment against large, bulky tumors.

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Moreover Isolated limb perfusion is a albeit somewhat exotic, but very interesting research model to develop and study agents that modify the pathophysiology of large tumors that blocks effective penetration of cytotoxic drugs into the tumor. We can now manipulate and study the tumor vascular bed in ways that will identify “new” drugs that can enhance the activity of “old” drugs. Moreover it has proven to be a model system that may also facilitate the development of vector-mediated gene therapy and other innovative approaches. Much of these developments have been initiated by the application of TNF in this setting. TNF-based isolated limb perfusion is a very successful treatment option to achieve limb salvage in the management of advanced, multiple or drug resistant extremity tumors. TNF-based ILPs are now performed in some 30 cancer centers in Europe with referral programs for limb salvage. TNF-based antivascular therapy of cancer is here to stay and its potential needs to be studied further (62). Other drugs will follow and we may well learn through this model how to use them systemically more effectively as well.

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REFERENCES

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13. Klaase JM, Kroon BBR, Van Geel AN, Eggermont AMM, Franklin HR. Systemic leakage during isolated limb perfusion for melanoma. Br J Surg 1993;80:1124-1126 14. Wieberdink K, Benckhuijsen C, Braat RP, Van Slooten EA, Olthuis GAA. Dosimetry in isolation perfusion of the limbs by assessment of perfused tissue volume and grading of toxic tissue reactions. Eur J Cancer Clin Oncol 1982; 18:905-910 15. Krementz ET, Carter RD, Sutherland CM, Hutton I. Chemotherapy of sarcomas of the limbs by regional perfusion. Ann Surg 1977;185(5):555-564 16. Muchmore JH, Carter RD, Krementz ET. Regional perfusion for malignant melanoma and soft tissue sarcoma: a review. Cancer Invest. 1985;3:129-143 17. Pommier RF, Moseley HS, Cohen J et al. Pharmacokinetics, Toxicity, and Short-term results of cisplatin hyperthermic isolated limb perfusion for soft tissue sarcoma and melanoma of the extremities. Am J Surg 155:667-671, 1988 18. Klaase JM, Kroon BBR, Benckhuysen C, Van Geel AN, Albus-Lutter ChE, Wieberdink J. Results of regional isolation perfusion with cytostatics in patients with soft tissue tumors of the extremities. Cancer 64:616-621, 1989 19. Rossi CR, Vecchiato A, Foletto M, et al. Phase II study on neoadjuvant hyperthermicantiblastic perfusion with doxorubicin in patients with intermediate or high grade limb sarcomas. Cancer 73:2140-2146, 1994 20. Lienard D, Ewalenko, Delmotte JJ, Renard N, Lejeune FJ. High-dose recombinant tumor necrosis factor alpha in combination with interferon gamma and melphalan in isolation perfusion of the limbs for melanoma and sarcoma. J Clin Oncol 1992; 10:50-62 21. Eggermont AMM, Liénard D, Schraffordt Koops H, Rosenkaimer F, Lejeune FJ. Treatment of irresectable soft tissue sarcomas of the limbs by isolation perfusion with high dose TNF-a in combination with gamma-Interferon and melphalan. Fiers W and Buurman WA (eds), In: Tumor Necrosis Factor: Molecular and Cellular Biology and Clinical Relevance, Basel, Karger Verlag, 1993, pp 239-243 22. Hill S, Fawcett WJ, Sheldon J, Soni N, Williams T, Thomas JM. Low dose tumor necrosis factor-alpha and melphalan in hyperthermic isolated limb perfusion. Br J Surg 1993; 80:995-997 23. Eggermont AMM, Schraffordt Koops H, Lienard D, et al: Isolated limb perfusion with highdose tumor necrosis factor-alpha in combination with interferon-gamma and melphalan for nonresectable extremity soft tissue sarcomas: a multicenter trial [see comments]. J Clin Oncol 14:2653-65, 1996a 24. Santinami M, Deraco M, Azzarelli A, Cascinelli F, Chiti A, Costagli V, Manzi R, Quagliolo V, Rebuffoni G, Santoro N, Vaglini M. Treatment of recurrent sarcoma of the extremities by isolated perfusion using tumor necrosis factor alpha and melphalan. Tumori 1996;82:579-84 25. Eggermont AMM, Schraffordt Koops H, Klausner JM, et al: Isolated limb perfusion with tumor necrosis factor and melphalan for limb salvage in 186 patients with locally advanced soft tissue extremity sarcomas. The cumulative multicenter European experience. Ann Surg 224:75664; discussion 764-5, 1996b 26. Gutman M, Inbar M, Lev-Shlush D, Mozes M, Chaitchik S, Meller I, Klausner JM. High dose tumor necrosis and melphalan administered via isolated limb perfusion for advanced limb soft tissue sarcoma results in a > 90% response rate and limb preservation. Cancer 1997;79:112937 27. Eggermont AMM, Schraffordt Koops H, Klausner JM, Schlag PM, Kroon BBR, Gustafson P, Steinmann G, Lejeune FJ. Limb Salvage by Isolation Limb Perfusion with Tumor Necrosis Factor Alpha and melphalan for locally advanced extremity soft tissue sarcomas: results of 270 perfusions in 246 patients. Proceed ASCO 1999;11:497(abstract) 28. Rossi CR, Foletto M, Di Filippo F, Vaglini M, Anza M, Azzarelli A, Pilati P, Mocellin S, Lise M. Soft tissue limb sarcomas: Italian clinical trials with hyperthermic antiblastic perfusion. Cancer, 1999;86:1742-9 29. Lejeune FJ, Pujol N, Lienard D, Mosimann F, Raffoul W, Genton A, Guillou L, Landry M, Chassot PG, Chiolero R, Bischof-Delaloye A, Leyvraz S, Mirimanoff RO, Bejkos D, Leyvraz PF. Limb salvage by neoadjuvant isolated perfusion with TNFalpha and melphalan for nonresectable soft tissue sarcoma of the extremities. Eur J Surg Oncol 2000, 26:669-78

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30. Hohenberger P, Kettelhack C, Hermann A, Schlag PM. Functional outcome after preoperative isolated limb perfusion with rhTNFalpha/Melphalan for high-grade extremity sarcoma. Eur J Cancer 2001;37(6):S34-35 31. Lans TE, deWilt JHW, van Geel AN, Eggermont AMM. Isolated limb perfusion with tumor necrosis factor and melphalan for nonresectable stewart-treves lymphangiosarcoma. Ann Surg Oncol. 2002;9:1004-9 32. Noorda EM, Vrouwenraets BC, Nieweg OE, Slooten GW, Kroon BBR. Isolated limb perfusion with and Melphalan for Irresectable Soft Tissue Sarcoma of the Extremities. Ann Surg Oncol 2003;10;1:S36 33. Bonvalot S, Lejeune F, Laplanche A, Stoeckle E, Le Pechoux C, Vanei D, Lumbroso J, Terrier P, Aubert B, LeCesne A. Limb slavage by isolated limb perfusion (iILP) in patients with locally advanced soft tissue sarcoma (ASTS): a randomized phase II study comparing 4 doses of Proc. Am Soc Clin Oncol, 2003;22:823 34. Grünhagen D, Lans TE, de Wilt JHW, van Geel AN, Eggermont AMM. Management of Local Recurrences of Soft Tissue Sarcomas in an Irradiated Field after Prior Surgery and Radiotherapy: the Role of TNF-based Isolated Limb Perfusions to achieve Limb Salvage. Eur J Cancer 2003;39:in press 35. Etten van B, van Geel AN, de Wilt JHW, Eggermont AMM. Fifty Tumor Necrosis Factorbased Isolated Limb Perfusions for limb salvage in patients older than 75 years with limbthreatening soft tissue sarcomas and other exremity tumors. Ann Surg Oncol, 2003;27:32-37 36. Vrouwenraets BC, Kroon BBR, Ogilvie AC, Van Geel AN, Nieweg OE, Swaak AJG, Eggermont AMM. Absence of severe systemic toxicity after laekage controlled isolated limb perfusion with Tumor Necrosis Factor alpha and melphalan. Ann Surg Oncol, 1999;6:405-412 37. Stam, T. C., Swaak, A. J., de Vries, M. R., ten Hagen, T. L., Eggermont, A. M. Systemic toxicity and cytokine/acute phase protein levels in patients after isolated limb perfusion with tumor necrosis factor-alpha complicated by high leakage [In Process Citation] Ann Surg Oncol, 2000;4:268-75 38. Vrouenraets BC, Eggermont AMM, Hart AA, Klaase JM, van Geel AN, Nieweg OE, Kroon BBR. Regional toxicity after isolated limb perfusion with melphalan and tumour necrosis factor- alpha versus toxicity after melphalan alone. Eur J Surg Oncol. 2001;27:390-5 39. Lejeune FJ, Lienard D, Leyvraz S, Mirimanoff RO. Regional therapy of melanoma. Eur J Cancer 1993; 29A:606-612 40. Eggermont AMM, Liénard D, Schraffordt Koops H, Kroon BBR, Rosenkaimer F, Klaase JM, Schmitz PIM, Lejeune FJ. High dose tumor necrosis factor-alpha in isolation perfusion of the limb: highly effective treatment for melanoma in transit metastases or unresectable sarcoma. Reg Cancer Treat, 7:32-36, 1995 41. Eggermont AMM. Treatment of melanoma intransit metastases confined to the limb. Cancer Surveys, 26:335-349, 1996 42. Fraker DL, Alexander HR, Andrich M, Rosenberg SA. Treatment of patients with melanoma of the extremity using hyperthermic isolated limb perfusion with melphalan, tumor necrosis factor, and interferon gamma: results of a tumor necrosis factor dose-escalation study. J Clin Oncol, 1996;14:479-89 43. Lienard D, Eggermont AMM, Schraffordt Koops H, Kroon BBR, Towse G, Hiemstra S, Schmitz P, Clarke J, Steinmann G, Rosenkaimer F, Lejeune FJ. Isolated limb perfusion with tumour necrosis factor-alpha and melphalan with or without interferon-gamma for the treatment of in-transit melanoma metastases: a multicentre randomized phase II study. Melanoma Res, 1999;9:491-502 44. Olieman, A.F., Lienard, D., Eggermont, A.M., Kroon, B.B., Lejeune, F.J., Hoekstra, H.J. & Koops, H.S. Hyperthermic isolated limb perfusion with tumor necrosis factor alpha, interferon gamma, and melphalan for locally advanced nonmelanoma skin tumors of the extremities: a multicenter study. Arch Surg, 1999;134, 303-7 45. Bickels, J., Manusama, E.R., Gutman, M., Eggermont, AMM, Kollender, Y., Abu-Abid, S., Van Geel, A.N., Lev-Shlush, D., Klausner, J.M. & Meller, I. Isolated limb perfusion with tumour

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necrosis factor-alpha and melphalan for unresectable bone sarcomas of the lower extremity [In Process Citation]. Eur J Surg Oncol, 1999;25:509-14 46. Lev-Chelouche D, Abu-Abeid S, Nakache R, Issakov J, Kollander Y, Merimsky O, Meller I, Klausner JM, Gutman M. Limb desmoid tumors: a possible role for isolated limb perfusion with tumor necrosis factor-alpha and melphalan. Surgery 1999;126:963-967 47. Sijens PE, Eggermont AMM, Van Dijk P, Oudkerk M. magnetic resonance spectroscopy as predictor for clinical response in human extremity sarcomas treated by single dose melphalan isolated limb perfusion. NMR in Biomedicine 1995;18:215-224 48. Renard N, Liénard D, Lespagnard L, Eggermont AMM, Heimann R, Lejeune FJ. Early endothelium activation and polymorphonuclear cell invasion precede specific necrosis of human melanoma and sarcoma treated by intravascular high-dose tumour necrosis factor alpha Int J Cancer 1994;57:656-663 49. Nooijen PTGA, Eggermont AMM, Schalkwijk L, Henzen-Logmans S, DeWaal RMW, Ruiter DJ. Complete response of melanoma in-transit metastasis after isolated limb perfusion with tumor necrosis factor-alpha and melphalan without massive tumor necrosis: clinical and histopathological study of the delayed-type reaction patterns. Cancer Res 1998;58:4880-4887 50. Manusama ER, Nooijen PTGA, Stavast J, Durante NMC, Marquet RL, Eggermont AMM. Synergistic antitumour effect of recombinant human tumour necrosis factor with melphalan in isolated limb perfusion in the rat. Br J Surg 1996;83:551-555 51. Manusama ER, Stavast J, Durante NMC, Marquet RL, Eggermont AMM. Isolated limb perfusion in a rat osteosarcoma model: a new anti-tumour approach. Eur J Surg Oncol 1996;22:152-157 52. De Wilt JHW, ten Hagen TLM, de Boeck G, van Tiel ST, de Bruijn EA, Eggermont AMM. Tumour Necrosis Factor alpha increases melphalan concentration in tumour tissue after isolated limb perfusion. Br J Cancer 2000;82:1000-1003 53. Veen vd AH, Wilt de JHW, Eggermont AMM, van Tiel ST, ten Hagen TLM. augments intratumoural concentration of doxorubicin in isolated limb perfusion in rat sarcoma models and enhances antitumour effects. Br J Cancer,2000;82:973-980 54. B van Etten, M de Vries, M van IJken, T Lans, G Guetens, G Ambagtsheer, S van Tiel, G de Boeck, E de Bruijn, AMM Eggermont AMM, TLM Ten Hagen. Degree of tumour vascularity correlates with drug accumulation and tumour response upon TNF-based isolated hepatic perfusion. Br J Cancer. 2003;87:314-9 55. Kristensen CA, Nozue M, Boucher Y and Jain RK. Reduction of interstitial fluid pressure after TNF-alpha treatment of three human melanoma xenografts. Br J Cancer 1996;74:533536. 56. Manusama ER, Nooijen PTGA, Stavast J, de Wilt JHW, Marquet RL and Eggermont AMM. Assessment of the role of neutrophils on the antitumor effect of in an in vivo isolated limb perfusion model in sarcoma - bearing Brown Norway rats. J Surg Res 1998;78:169-175 57. DeWilt JHW, Manusama ER, van Tiel ST, van IJken MGA, ten Hagen TLM, Eggermont AMM. Prerequisites for effective isolated limb perfusion using tumour necrosis factor-alpha and melphalan in rats. Br J Cancer 1999;80:161 -166 58. Manusama ER, de Wilt JHW, ten Hagen TLM, Marquet RL, Eggermont AMM. Toxicity and antitumor activity of interferon-gamma alone and in combinations with TNF and Melphalan in isolated limb perfusion in the BN175 sarcoma tumor model in rats. Oncol Rep 1999;6:173-177 59. Seynhaeve ALB, de Wilt JHW, vanTiel SA, Eggermont AMM, ten Hagen TLM. Combination of Actinomycin D with TNF-a in Isolated Limb Perfusion results in improved tumour response in soft tissue sarcoma-bearing rats but is accompanied by severe dose limiting local toxicity. . Br J Cancer 2002; 86:1174-1179. 60. DeWilt JHW, Manusama ER, van Etten B, van Tiel ST, Jorna AS, Seynhaeve ALB, ten Hagen TLM, Eggermont AMM: Inhibition of Nitric Oxide Synthesis by L-NAME results in synergistic antitumour activity with melpahlan and tumour necrosis factor-alpha- based isolated limb. Br J Cancer, 2000:83: 1176-11

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61. Brunstein F, Hoving S, van Tiel S, ten Hagen TLM, Eggermont AMM. Synergistic antitumor activity of histamine in combination with chemotherapy in the regional treatment of soft tissue sarcomas. Eur J Cancer 2003;39:in press 62. Ten Hagen TLM, FJ Lejeune, Eggermont AMM. TNF is here to stay – Revisited, Trends in Immunology (Formerly Immunology Today), 2001;22:127-129

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Chapter 5 Pitfalls in pathology of soft tissue sarcomas

Judith V.M.G. Bovée and Pancras C.W. Hogendoorn

Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands

Correspondence to: Pancras C.W.Hogendoorn Dept. of Pathology, Leiden University Medical Center, PO Box 9600 2300 RC Leiden, The Netherlands

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1

INTRODUCTION

Soft tissue sarcomas are rare, constituting fewer than 1% of all cancers. Soft tissue tumors are generally regarded difficult by surgical pathologists, since they constitute a very heterogeneous, relatively uncommon group of tumors comprising more than 40 entities, with considerable morphological overlap between the diagnostic entities (1). However, distinction is essential since these entities differ widely in treatment and outcome. Classification of soft tissue tumors is assisted by immunohistochemistry, confirming the line of differentiation, and in the last decade also by molecular diagnostics, detecting tumor-specific translations. Histological grading schemes have been developed for soft tissue sarcomas as a group and seem to be a valuable predictor of patient survival for many, but not all, types of soft tissue sarcomas. Accurate histological subtyping is essential for accurate histological grading. Clinicians and pathologists should be aware of the limitations, prognostic significance, and relationship of histological subtyping and grading in the therapeutic management of soft tissue sarcomas.

2

HISTOPATHOLOGICAL TYPING OF SOFT TISSUE TUMORS

2.1

Method: Needle Biopsy Versus Open Biopsy

There has been a continuous debate over the past years whether coreneedle biopsies, or open biopsies should be used in the diagnostic process of soft tissue tumors. Though a diagnostic accuracy has been documented as high as 90% in bone tumors (2), this number is debated widely for soft tissue tumors. Unfortunately due to increasing economic issues in health care and patient expectations the work up of patients with soft tissue tumors focuses on speed and patient friendliness instead of accuracy and a scientific basis for treatment. As a result core needle biopsies become more and more popular complicating accurate diagnosis and making grading virtually impossible. This is especially worthwhile realizing the more and more popular use of preoperative chemotherapy and isolated limb perfusion, which if successful leave virtual no tissue left for definite diagnosis, meaning that a substantial number of patients will be treated with toxic therapies, while one honestly does not know what kind and grade of tumor has been treated. Core needle biopsies are however very useful for the differential diagnosis with metastatic carcinoma, melanoma and to rule out lymphoma. In a specialized hospital setting it is useful for the diagnosis of a number of tumors with consistent genetic abnormalities which can be very accurately assessed by molecular techniques

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on needle biopsies as well (3).

2.2

Classification of Soft Tissue Tumors

Classification of soft tissue tumors is based primarily on the line of differentiation displayed by the tumor (the type of tissue formed by the tumor) rather than the type of tissue from which the tumor arises. The classification of soft tissue tumors has been changing over the past decades. An increasing knowledge of immunohistochemical and molecular genetic characteristics has resulted in a more accurate classification and a better understanding of the biology of these tumors. For instance, malignant fibrous histiocytoma (MFH) was for long considered the most common adult soft tissue sarcoma. However, its line of differentiation could not be established and the group of tumors seemed very heterogeneous in terms of clinical behavior and ultimate outcome, questioning its existence as a real entity. Fletcher et al (4) showed in a retrospective study that MFH could be subclassified, and that this subclassification was prognostically relevant. For instance, pleomorphic MFH could be subclassified as dedifferentiated liposarcoma (metastatic risk