Targeting Treatment of Soft Tissue Sarcomas

184 Pages·2004·4.083 MB·English

by  Caroline Seynaeve MD, PhD, Jaap Verweij (auth.), Jaap Verweij, Herbert M. Pinedo (eds.)

TARGETING TREATMENT OF
SOFT TISSUE SARCOMAS
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Verweij, J., Pinedo, H.M. (eds): Targeting Treatment of Soft Tissue Sarcomas. 2004. ISBN 1-4020-7808-0.
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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
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eBookISBN: 1-4020-7856-0
Print ISBN: 1-4020-7808-0
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Table of Contents
1. Targeted therapy: Ready for prime time? 1
C. Seynaeve and J. Verweij, Erasmus University Medical Center,
Rotterdam, The Netherlands
2. Volume-based radiotherapy targeting in soft tissue sarcoma 17
Iain Ward, Tara Haycocks, Michael Sharpe, AnthonyGriffin,
Charles Catton, David Jaffray, Brian O’Sullivan, Princess Margaret
Hospital, University of Toronto, Toronto, Canada
3. Preoperative therapy for soft tissue sarcoma 43
Janice N. Cormier, Howard N. Langstein,Peter W. T. Pisters,
TheUniversity of Texas M.D. Anderson Cancer Center, Houston, TX, USA
4. TNF-based isolated limb perfusion: A decade of experience with 65
antivascular therapy in the management of locally advanced
extremity soft tissue sarcomas
Dirk J Grünhagen, Flavia Brunstein,TimoL.M. ten Hagen, Albertus N.
van Geel, Johannes H.W. de Wilt, and Alexander M.M. Eggermont,
Erasmus University Medical Center, Rotterdam, The Netherlands
5. Pitfalls in pathology of soft tissue sarcomas 81
Judith V.M.G. Bovée and Pancras C.W. Hogendoorn, Leiden Universtiy
Medical Center, Leiden, The Netherlands
6. Molecular biology and cytogenetics of soft tissue sarcomas: 99
Relevance for targeted therapies
Jonathan Fletcher, Brighams’ and Womens Hospital, Boston, MA, USA
7. KIT and PDGF as targets 117
Jaap Verweij, Erasmus UniversityMedical Center, Rotterdam,
The Netherlands
8. Targeting mutant kinases in gastrointestinal stromal tumors: 129
A paradigm for molecular therapy of other sarcomas
Mike C. Heinrich, Christopher L. Corless, Portland, OR, USA
9. Targeting other abnormal signalling pathways in sarcoma: 151
EGFR in synovial sarcomas, in liposarcoma
Jean-Yves Blay,Isabelle Ray-Coquard, Laurent Alberti,
Dominique Ranchere, Hospital Edouard Herriot, Lyon, France
10. Angiogenesis: A potential target for therapy of soft tissue sarcomas 169
K. Hoekman and H.M. Pinedo, Free UniversityMedical Center,
Amsterdam, The Netherlands
Index 181
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
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. ofMedical Oncology,
Erasmus University Medical Centre-Daniel den Hoed Cancer Centre,
Groene Hilledijk 301
3075 EA Rotterdam, the Netherlands
2
1 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 metastaticdisease is only amenable to
curativetherapy 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
softtissue sarcoma (STS) has been hampered by the wide range of histological
appearances, withoverlappingarchitectural 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 “one-
size-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, surgicaloperating
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
availablechemotherapeuticagents 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
3
groups facilitating cross-talk with respect to the communication of trial results
and the initiation of new ideas for further studiesgreatly 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 histopathologicaldifferences to each other
and resulting in clarification of the classification of different sarcoma subtypes,
and the molecular identification of oncogenes and protein productsthatwill
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 trialdesign will also undergochange 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 alsoremain of paramount importance.
On the way to a new approach and further advance in systemic therapy
in STS, variousissues 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 CHEMOTHERAPY AT THE BEGINNING OF THE
CENTURY
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 oflimited value
(Seynaeve/Verweij, 1999; O’Sullivan et al, 2002). The value of these drugs has
been studied in neo-adjuvant, adjuvant and metastaticsetting.
2.1 (Neo-)Adjuvant Chemotherapy
The value of neo-adjuvant or adjuvant chemotherapycontinues to be a
matter of debate. Although the onlyrandomisedstudyinvestigating the value of
neo-adjuvant therapy, by means of standard doses ofadriamycin/ifosfamide,
conducted by the EORTC failed to show any benefit in disease free and overall
4
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 distantdisease free, disease-free and overall survival
being 75% and 44%, 70 and 42%, and 87% and 58% respectively, all being
statisticallysignificant. 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 approachshould be investigated in randomised studies to
avoid for bias in the comparative groups before it can be incorporated as
standard ofcare.
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 chemotherapyregimen 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 timepoint (Frustaci
et al, 2001). Long term follow-up data from this study are therefore crucial,
especially, where two other small studies using intensive
anthracycline/ifosfamideregimensfailed 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
relevantinformation 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 onlymodest gains in survival with the use of known
chemotherapeutic agents, studies in the last decades ofthe century have
focused on schedule optimisation and/ordose intensification (Bramwell et al,