i
FROM THE LEADERSHIP 

We are pleased to submit this report to the Director of the National Cancer Institute 

(NCI), and to the Advisory Committee to the Director. The Sarcoma Progress Review 

Group (PRG) accepted the charge to develop a roadmap for the next 5 years of 

sarcoma research. This report represents the collaborative effort of scientists, 

clinicians, industry representatives, patient advocates, and other professionals who 

participated in the Sarcoma PRG Roundtable Meeting October 8-10, 2003. We look 

forward to discussing these priorities and the plan for their implementation with the 

leadership of the NCI. 

We the undersigned members of the Sarcoma Progress Review Group concur with the 

enclosed report. 

Karen S. Antman, M.D. 

PRG Co-Chair 

Columbia University College of Physicians & Surgeons 

Herbert Irving Comprehensive Cancer Center 

Todd Golub, M.D. 

PRG Co-Chair 

Harvard Medical School/Dana-Farber Cancer Institute 

Whitehead Institute/MIT Center for Genome Research 

Lee J. Helman, M.D. 

PRG Executive Director 

National Institutes of Health, National Cancer Institute 

From the Leadership ii 
We the undersigned members of the Sarcoma Progress Review Group concur 

with the enclosed report. 

Karen O. Anderson, Ph.D. 

William G. Kraybill, M.D. 

Laurence H. Baker, D.O. Marc Ladanyi, M.D. 

Robert S. Benjamin, M.D. Crystal L. Mackall, M.D. 

Vivien H.C. Bramwell, Ph.D., Robert B. Marcus, M.D. 

M.B.B.S., F.R.C.P.C. 

George D. Demetri, M.D. Paul S. Meltzer, M.D., Ph.D. 

Glenn Merlino, Ph.D. Christopher Denny, M.D., Ph.D. 

Janet F. Eary, M.D. Paul A. Meyers, M.D. 

Jonathan A. Fletcher, M.D. Cherie Nichols, M.B.A. 

Judith K. Jones, M.D., Ph.D. Perry D. Nisen, M.D., Ph.D. 

Progress Review Group Concurrences iii 
We the undersigned members of the Sarcoma Progress Review Group concur 

with the enclosed report. 

Herman D. Suit, M.D., D.Phil. Norman Scherzer 

Poul H.B. Sorensen, M.D., Ph.D. Mark O. Thornton, M.D., Ph.D. 

Louise C. Strong, M.D. 

Matt van de Rijn, M.D., Ph.D. 

Progress Review Group Concurrences iv 
Report of the Sarcoma Progress Review Group (PRG) 

ACKNOWLEDGMENTS 

This report is the product of months of intense work and drew on the combined 

expertise and efforts of many individuals. The Sarcoma PRG particularly 

acknowledges the contributions of the following groups: 

• The many scientists, clinicians, advocates, and other professionals who 

generously gave of their time and knowledge. Without their participation, this 

report would not have been possible. In particular, the 112 participants in our 

Sarcoma PRG Roundtable Meeting, including the individuals who served, along 

with PRG members, as Co-Chairs of our Roundtable Breakout Groups. 

• The staff of the NCI Office of Science Planning and Assessment, under the 

leadership of Cherie Nichols, who provided ongoing guidance and technical 

support throughout the process of preparing this report. In particular, we 

acknowledge the hard work and dedication of Margaret Ames, who coordinated 

the full PRG process, as well as James Corrigan, Kevin Callahan, Stephanie 

Glezos Bell, Marilyn Duncan, DJ Joya, Annabelle Uy, Deborah Duran, and Julie 

Schneider. 

• The staff of Science Applications International Corporation (SAIC) and the 

science writers who assisted in logistics, documentation, and report preparation. 

We thank Beth Mathews-Bradshaw for overall support; Nancy Volkers for 

serving as lead writer; Eric Levine and Glenn Bell for preparing of resource 

material; Catherine Kappel Hall for managing SAIC work; Rob Watson and Mary 

Ann Wood for conference support; and Debby Berlyne, Elaine Berry, Gregory 

Cole, Laura Janusik, Anita Sabourin, Maneesha Solanki, and Jeffrey Zalatoris for 

serving as science writers. 

Acknowledgments v 
Report of the Sarcoma Progress Review Group (PRG) 

Table of Contents 

The Challenges of Sarcoma........................................................................................... 1 

The Process ................................................................................................................... 2

The Priorities ................................................................................................................. 2 

 Priority 1 ................................................................................................................. 3 

Priority 2 ................................................................................................................. 6

Priority 3 ................................................................................................................. 7

Priority 4 ................................................................................................................. 8

 Priority 5 ................................................................................................................. 8

 Priority 6 ................................................................................................................. 9

Appendices 

Appendix A: Cross-Cutting Breakout Group Reports.............................................. A-1 

Platforms for Discovery...................................................................................... A-2

Translation of Therapeutic Targets and Experimental Models to 

Clinical Settings.................................................................................................. A-8

Innovative Clinical Trials ................................................................................. A-12

Optimizing Existing Care ................................................................................. A-19

Appendix B: Science-Centric Breakout Group Reports............................................B-1 

Better Biology and Discovery..............................................................................B-2

Better Immunology ..............................................................................................B-9

Better Access to Annotated Tissue ....................................................................B-15

Better Models and Preclinical Testing ...............................................................B-19

Better Prevention ...............................................................................................B-23

Better Diagnosis and Prognostication................................................................B-28

Better Imaging ...................................................................................................B-32

Better Clinical Studies .......................................................................................B-36

Better Communication and Outcomes ...............................................................B-41 

Appendix C: About the NCI’s Progress Review Groups ..........................................C-1 

Appendix D: Sarcoma PRG Membership Roster ..................................................... D-1 

Appendix E: Sarcoma PRG Roundtable Participants Roster ....................................E-1 

Table of Contents vi 
Report of the Sarcoma Progress Review Group (PRG) 

THE CHALLENGES OF SARCOMA 

Sarcomas comprise about 1 percent of adult and 15 percent of pediatric malignancies. 

It is estimated that in 2003, about 11,700 Americans were diagnosed with sarcoma 

and 5,200 died from the disease.1 However, these figures are probably 

underestimates, and the number of Americans with each sarcoma subtype is unknown. 

Current diagnostic coding systems categorize cancers by location and therefore make 

identification of sarcomas difficult. For example, physicians once viewed 

gastrointestinal stromal tumor (GIST) as one of the rarer subtypes of sarcoma. 

However, in a recent review of 1,500 intra-abdominal tumors for a genetic marker for 

GIST, researchers discovered 400 cases, of which only 100 had been diagnosed as 

GIST. (The other 300 had been diagnosed as other sarcoma subtypes.) 

Diagnosis is delayed in many patients by the lack of experience of primary physicians, 

who often attribute the initial mass to common benign lesions. Once diagnosed, 

patients cannot rely on a uniform standard of care, resulting in wide variations in care 

and outcomes. New therapies are desperately needed, but the fragmentation of 

biological, translational, and clinical research makes it difficult to initiate innovative 

and timely studies. 

Generally, a disease of younger adults and children, sarcoma’s mortality rate is 

disproportionately high compared with other cancers common in these age groups, 

such as testicular cancer and Hodgkin’s disease. 

Several germline mutations confer a risk of sarcoma. High-risk groups include 

families with hereditary retinoblastoma, Li-Fraumeni syndrome, Werner’s syndrome, 

neurofibromatosis, and other conditions. The downstream effects of these genes and 

the mechanism(s) of malignant transformation remain largely unknown. The tissue of 

origin for many sarcomas is defined (bone for osteosarcomas, smooth muscle for 

leiomyosarcomas, fat for liposarcomas, etc.), but for some subtypes, such as Ewing’s 

sarcoma, it remains unclear. 

In addition to radiation therapy for prior cancer (in both children and adults), other 

environmental risk associations include arsenic and polyvinyl chloride (plastics 

manufacturing) exposures and angiosarcoma, dioxin (Agent Orange) exposures in 

forestry workers and soft-tissue sarcomas, asbestos exposures and mesothelioma, and 

viral causes in immunosuppressed patients (HHV8 in Kaposi’s sarcoma and EBV in 

leiomyoblastoma arising in the setting of immunosuppression). 

However, in the vast majority of cases, specific risk factors are absent and there is also 

no evidence of germline predisposition. Genetic studies have found that sarcomas 

segregate into two major types: those with specific genetic translocations and simpler 

karyotypes, and those with complex karyotypes but without specific genetic 

alterations. The significance of these two major types and how these differences 

might translate into targeted treatments remains uncertain. 

Since the 1950s, limb-sparing surgery, radiation therapy, and chemotherapy have 

improved sarcoma survival rates or reduced recurrence rates. Today, surgery—often 

coupled with radiation therapy—is usually the primary treatment for sarcoma, 

although some rhabdomyosarcomas and Ewing sarcomas can be cured with only 

radiation and chemotherapy. Most patients who die from sarcoma have 

1 http://www.cancer.org/docroot/STT/stt_0.asp 

Priorities of the Sarcoma Progress Review Group 1 
Report of the Sarcoma Progress Review Group (PRG) 

chemotherapy-resistant metastatic disease. Only a few chemotherapy drugs are 

effective, and the rarity and heterogeneity of sarcoma make testing new agents 

challenging. 

Given the lack of a uniform standard of care, the difficulty in diagnosis, and the lack 

of new treatments (with the exception of imatinib for GIST, considered by many to be 

a model for tailored molecular therapy), most sarcoma patients have been underserved 

by the medical and research communities. 

THE PROCESS 

At a planning meeting in June 2003, the PRG organized a roundtable meeting to 

consider progress, identify gaps, and highlight research needs across the field of 

sarcoma research. 

The meeting planners identified four cross-cutting areas and nine science-centric areas 

as the foci of breakout sessions. The four cross-cutting areas were Platforms for 

Discovery, Translation of Therapeutic Targets and Experimental Models to Clinical 

Settings, Innovative Clinical Trials, and Optimizing Existing Care. The 

science-centric areas were Better Biology and Discovery, Better Immunology, Better 

Access to Annotated Tissue, Better Models and Preclinical Testing, Better Prevention, 

Better Diagnosis and Prognostication, Better Imaging, Better Clinical Studies, and 

Better Communication and Outcomes. 

The Roundtable Meeting, which included 112 participants, was held October 8-10, 

2003, in Philadelphia. Each participant attended one cross-cutting group and one 

science-centric group. The cross-cutting groups met first; each group identified three 

priorities for sarcoma research over the next 5 years and presented them to the 

Roundtable. In the context of the cross-cutting groups’ presentations, each 

science-centric group then met, identified three priorities, and presented them to the 

Roundtable. 

Finally, the cross-cutting groups reconvened and revisited their original priorities in 

the context of the presentations from the science-centric groups. On the morning of 

the last day, the cross-cutting groups presented final priorities. The Roundtable 

participants reviewed these priorities and reached consensus on six high-priority 

recommendations. 

THE PRIORITIES 

Over the 3-day meeting, PRG Roundtable participants reiterated the need for some 

type of center or “governing body” to support sarcoma research. This struggle to 

organize the parts into a larger whole is not happening in a vacuum; both the NCI, in 

its Strategic Priorities for 2015,2

 and the National Institutes of Health (NIH), in its 

Roadmap,3

 have recognized the need for integrated and cooperative research plans. 

Furthermore, addressing these priorities for sarcoma may result in a framework that 

can serve as a model for research and treatment for other rare cancers and diseases. 

The six high-priority recommendations are listed subsequently. Three of the four 

cross-cutting groups included a priority about centralization; thus, Priority 1 carries 

extra weight. Although Priorities 2-6 are numbered, they are not ranked in order of 

importance. 

2 http://cancer.gov/directorscorner/directorsupdate-08-27-2003 

3 http://nihroadmap.nih.gov/ 

Priorities of the Sarcoma Progress Review Group 2 
Report of the Sarcoma Progress Review Group (PRG) 

PRIORITY 1. 

Create a dedicated, sarcoma-specific organizational structure—the Sarcoma 

Research Consortium (SRC)—to serve as a focal point for sarcoma clinical 

trials and related clinical- and laboratory-based research and to enhance 

networks of investigators and centers committed to sarcoma research. 

Sarcomas are a heterogeneous and uncommon group of malignancies. Optimal 

treatment requires close collaboration among multiple disciplines with special 

expertise in the diagnosis and treatment of sarcomas. The current decentralized 

system does not support the effective interaction between experts or collaboration 

among interested researchers. Resources for studying the many subtypes of sarcoma 

are fragmented, resulting in a few small, inadequately powered studies. Centrally 

coordinated initiatives and strong networks will facilitate multidisciplinary research 

and data sharing, streamline the research process, and produce more reliable results 

per funding dollar spent. The resulting system also will be a model for studying other 

rare cancers and rare diseases. 

A unifying theme of the PRG was the need to create a new organizational structure 

that would maximize the delivery of state-of-the-art clinical care to sarcoma patients 

and facilitate the conduct of clinical- and laboratory-based sarcoma research. 

Therefore, the Roundtable proposed the creation of an SRC. 

Implicit in the creation of the SRC is the notion that specialized expertise in sarcoma 

patient care and/or sarcoma research is required to move the field forward. The intent 

is not, however, to create a structure that is exclusive. Rather, the SRC represents an 

organizational umbrella that can accommodate, and indeed welcomes, participation by 

any investigator or center committed to sarcoma research. 

The concept of the SRC (Figure 1) resonates with both the NCI Strategic Priorities 

for 2015 and the National Institutes of Health (NIH) Roadmap themes. NCI’s 

Strategic Priorities stress the need for an integrated clinical trials system and seamless 

integration of the elements of drug discovery from beginning to end. Similarly, the 

Roadmap’s themes of “Research Teams of the Future” and “Re-engineering the 

Clinical Research Enterprise” recognize the need for new organizational models and 

partnerships to move research forward. 

SRC funding may be drawn from cooperative groups, grants, the pharmaceutical 

industry, and philanthropy. Centralizing the sarcoma research enterprise will 

streamline the research process and make the SRC attractive to funding sources. 

Priorities of the Sarcoma Progress Review Group 3 
Report of the Sarcoma Progress Review Group (PRG) 

Figure 1. The Sarcoma Research Consortium 

*SCE = Sarcoma Center of Excellence 

The SRC will consist of the following: 

1. A national, multidisciplinary group of investigators that provides 

leadership for sarcoma research 

A critical aspect of the SRC is the integration of clinical and laboratory 

investigators committed to sarcoma research. SRC leadership will include 

clinicians and researchers at SCEs, as well as additional leaders elected on a 

regular basis (e.g., every 4 years). SRC leadership positions will not be 

restricted to SCE members; investigators interested in sarcoma biology 

research who may not reside within an SCE will be encouraged to participate. 

Leaders will come from all relevant disciplines (e.g., surgery, medical 

oncology, pediatric oncology, radiation therapy, radiology, pathology, cancer 

biology, and patient advocacy). 

The establishment of this national sarcoma leadership structure will ensure 

that the sarcoma research agenda receives adequate attention (which can be 

difficult for rare diseases within larger cooperative groups) and incorporates 

broad, multidisciplinary involvement of the sarcoma research community. 

2. Sarcoma Centers of Excellence 

SCEs will have both multidisciplinary expertise in sarcoma patient care 

(surgery, medical oncology, pediatric oncology, radiation therapy, pathology, 

and radiology) and see a sufficient number of sarcoma patients on a regular 

basis (> 50 patients per year). The SRC will establish criteria for an SCE and 

Priorities of the Sarcoma Progress Review Group 4 
Report of the Sarcoma Progress Review Group (PRG) 

designate approximately 10 to 20 SCEs around the country. The seed money 

for the SCEs will come from money that is currently provided to cooperative 

groups for rare cancer research; funds will be augmented by money from 

other sources. 

SCEs will conduct sarcoma clinical trials and serve as clearinghouses for 

annotated clinical data (with associated tissue/blood/serum samples). They 

will work with other sarcoma researchers, advocates, and physicians to 

elevate the standard of care for all sarcoma patients. 

SCEs will provide care to as many sarcoma patients as is feasible, either in 

person or “virtually” through consultations and other interactions with 

community physicians. Using available evidence, the SRC will sanction 

treatment “best practices” and strongly encourage their use at SCEs. 

3. A common infrastructure to support and accelerate sarcoma research 

Such infrastructure would likely include the following goals: 

• Establishing a centralized sarcoma tumor and tissue repository (possibly 

in coordination with the National Biospecimen Network). This 

repositioning will help rapidly achieve a “critical mass” of tissue for this 

collection of rare diseases, guarantee uniformity of pathological 

annotation, and facilitate the acquisition of material. 

• Generating renewable biological resources (e.g., cell lines, animal 

models, antibodies, and DNA constructs). 

• Generating selected data (e.g., DNA microarray data or molecular 

measurements in the context of clinical trials). This task would likely be 

contracted to experienced laboratories, and the guiding principle would be 

to make such data freely available to the public as rapidly as possible. 

Within this framework, the SRC will take the following steps: 

1. Establish a national clinical trial agenda and oversee the conduct of such 

trials. 

The SRC will schedule sarcoma clinical trials and assist in clinical trial 

design. This centralization will expedite testing of novel therapeutic 

approaches in this rare patient population; in addition, a more consistent 

approach to trial design will increase the comparability of clinical trial results. 

Clinical trials will continue to include both investigator-initiated and 

industry-sponsored trials and will be performed primarily, but not exclusively, 

at the SCEs. NCI Cancer Trials Support Unit members and cooperative 

groups will have access to these studies. 

The SRC will coordinate certain aspects of the clinical trials, including 

(1) centralized statistical services, (2) standardized data collection methods 

and data storage, (3) centralized pathology review, and (4) centralized sample 

collection and banking. When possible, these activities will leverage existing 

organizations if this can be achieved in a cost-effective manner and if the 

results will be of sufficiently high quality. 

Most patient samples will be obtained from SCEs, but a mechanism will be 

established whereby interested clinicians or patients can contribute available 

Priorities of the Sarcoma Progress Review Group 5 
Report of the Sarcoma Progress Review Group (PRG) 

tissue material even if patients are not being treated on a clinical trial or being 

seen at an SCE. 

2. Serve as an information resource for sarcoma researchers, clinicians, and 

patients. 

Using existing electronic information resources of NCI, the SRC will partner 

with NCI to refine a subset of resources specific to sarcoma. For clinicians, 

this will include clinical trial information, referral information, clinical care 

best practice guidelines, and diagnostic information. For patients, it will 

include appropriately written information related to sarcoma, including 

background information, clinical trial information, contact information for 

nearby SCEs, and resource information such as patient support networks and 

advocacy groups. This information resource also will bring together valuable 

data relevant to sarcoma biology research (e.g., annotation of sarcoma cell 

lines, sources of useful reagents, biotechnology and pharmaceutical company 

contact information, and genomic data relevant to sarcoma, such as 

microarray data). 

The NCI’s cancer biomedical informatics grid (CaBIG) – a common 

informatics platform integrating diverse data types and supporting analytic 

tools – will be an integral part of this effort. 

The SRC will partner with NCI surveillance to establish and maintain 

databases of NIH-funded sarcoma research and of accurate statistics on 

incidence and mortality (including optimization of coding and reporting 

methods identifying sarcoma diagnoses). 

3. Partner with NCI and other institutes in the conduct of sarcoma 

research, including efforts to increase the accuracy of sarcoma incidence 

and mortality data. 

A range of federal research agencies should be invited to partner scientifically 

and financially with the SRC to minimize the need for new infrastructure. 

Other potential support agencies include the National Institute of 

Environmental and Health Sciences, the National Institute of Allergy and 

Infectious Diseases, the National Institute of Diabetes & Digestive & Kidney 

Diseases, the National Institute of Nursing Research, the National Institute on 

Aging, the Department of Veterans Affairs, the Department of Defense, the 

Centers for Disease Control and Prevention, the Centers for Medicare & 

Medicaid Services, the Agency for Healthcare Research and Quality, and the 

Environmental Protection Agency. 

It is expected that Priorities 2-6 would be realized within the context of the 

SRC. 

PRIORITY 2. 

Fund and foster research focused on key areas of sarcoma biology most likely 

to advance the field. 

The following areas are included: 

• the developmental biology of mesenchymal tissues, 

Priorities of the Sarcoma Progress Review Group 6 
Report of the Sarcoma Progress Review Group (PRG) 

• mutational targets in growth signaling pathways, 

• downstream targets of fusion proteins, 

• cellular checkpoints and apoptotic pathways in the sarcoma context, and 

• immunobiology of human sarcomas. 

These areas represent the major knowledge gaps in sarcoma biology; bridging these 

gaps will advance the field at both the basic and translational levels. 

A better understanding of mesenchymal developmental biology should allow for 

better transgenic models, help in interpretation of expression-profiling data, and 

identify shared mesenchymal differentiation pathways and antigens amenable to novel 

therapeutic approaches. 

A focus on the mutational targets in growth signaling pathways should clarify the role 

of cooperating mutations in translocation sarcomas and may identify signaling 

pathways shared by diverse sarcomas. 

A comprehensive analysis of fusion protein target genes will clarify the biology of 

translocation-associated sarcomas and may reveal common themes and pathways 

amenable to therapies with broad utility. 

A better understanding of cellular checkpoints and apoptotic pathways in sarcomas 

may reveal new therapeutic targets. 

Both the NCI and NIH emphasize the need to understand the complexity underlying 

biological systems and to provide new strategies for diagnosing, treating, and 

preventing disease. 

PRIORITY 3. 

Develop sarcoma-specific animal model systems (including new models and 

metastatic models). 

Model systems are important for both understanding the biology of cancer and 

identifying potential treatments, as well as diagnostic and prognostic markers. Most 

patients who die from sarcomas die from metastatic disease, but research in metastasis 

is hindered by the dearth of models specifically addressing sarcoma metastasis. Many 

sarcomas are hypothesized to result from fewer genetic abnormalities than many 

carcinomas because of the diagnosis of many sarcomas in children. Therefore, 

recapitulating metastatic disease in sarcoma models may be easier and more accurate 

than for more complex carcinoma-derived metastatic tumors. The results of 

investigating sarcoma metastases can be applied to other cancers. 

Both the NCI Strategic Priorities and the NIH Roadmap recognize the need for 

integrated approaches to biological research, including the use of models. The NIH 

Roadmap’s “New Pathways to Discovery” theme recognizes that basic biological 

knowledge is tied to the development of useful models in any disease, including 

cancer. NCI’s Integrative Cancer Biology priority has as its first objective to 

“generate models that recapitulate the interactive, dynamic, and spatial relationships 

between molecules in a cell, between cells, between cells and their microenvironment, 

and between the organism and the macroenvironment.” 

Priorities of the Sarcoma Progress Review Group 7 
Report of the Sarcoma Progress Review Group (PRG) 

PRIORITY 4. 

Fund and foster comprehensive approaches to sarcoma profiling and target 

discovery. 

Approaches include the following: 

• Comprehensive sarcoma profiling (genome, transcriptome, and proteome) to 

identify novel therapeutic targets, new markers for diagnosis, susceptibility, and 

prognosis, for prediction of treatment response and definition of intermediate 

endpoints. 

• High-throughput screens and functional genomic approaches to identify novel 

therapeutic targets and critical pathways regulating sarcoma growth and survival. 

Because targeted screening of specific pathways is limited by current knowledge of 

sarcoma biology, screening (compounds, RNAi, and functional genomics) may be 

essential to identify novel targets associated with pathways not currently implicated in 

sarcomagenesis. Sarcoma profiling is currently fragmented and focuses largely on 

expression profiling. Global understanding of specific sarcomas remains elusive. 

Molecular profiling and targeted therapeutic interventions have the potential to alter 

the terrain of cancer research. The NCI and NIH have recognized these approaches as 

integral to future research and highlight them in their respective strategic plans. 

PRIORITY 5. 

Develop a centrally available toolkit of core reagents and access to technology 

platforms for sarcoma research including cell lines, model systems, annotated 

tissue banks, biomarkers, and imaging. 

Current resources are inadequate for current or planned research endeavors. The 

toolkit will enable new technology to define novel and valid biomarkers, imaging, and 

surrogate markers to take advantage of the unique biology of sarcoma subsets and 

encourage rational, targeted, and timely clinical development. 

In its “New Pathways to Discovery” theme, the NIH Roadmap highlights the need for 

a “toolbox” that consists of technologies, databases, and other scientific resources. 

NCI’s Strategic Priorities include plans to establish a regional network of highthroughput laboratories for existing and emerging biomarkers of cancer risk, as well 

as to facilitate the collaborative development of a national, regulatory-compliant, 

privacy-protected, standardized network of annotated biological sample(s). 

Priorities of the Sarcoma Progress Review Group 8 
Report of the Sarcoma Progress Review Group (PRG) 

PRIORITY 6. 

Design prospective clinical trials whose principal objective is to compare early 

surrogate (intermediate) markers to conventional endpoints. Such trials 

should be tightly linked to appropriate tissue banking and incorporate novel 

statistical methodologies appropriate to sarcomas. These trials should be 

conducted concurrently with a series of innovative therapeutic trials. 

In areas where controversy exists as to optimal therapy, a trial focused on a surrogate 

(intermediate) endpoint may be viewed as innovative and therefore attractive to 

patients and their physicians. Furthermore, successful identification of a surrogate 

endpoint will allow more rapid conduct of clinical trials and will be very attractive to 

the pharmaceutical industry. 

In its Strategic Priorities for 2015, one NCI objective is to develop, validate, and 

approve surrogate markers as endpoints to shorten the time necessary for conducting 

clinical trials. The need for improved assessment of clinical outcomes is highlighted 

in the NIH’s “Re-engineering the Clinical Research Enterprise” Roadmap theme. 

Priorities of the Sarcoma Progress Review Group 9 
Report of the Sarcoma Progress Review Group (PRG) 

Appendix A 

Cross-Cutting Breakout Group Reports 

Platforms for Discovery ........................................................................................... A-2 

Translation of Therapeutic Targets and Experimental Models 

to Clinical Settings............................................................................................. A-8 

Innovative Clinical Trials....................................................................................... A-12

Optimizing Existing Care....................................................................................... A-19 

Appendix A: Cross-Cutting Breakout Group Reports A-1 
Report of the Sarcoma Progress Review Group (PRG) 

PLATFORMS FOR DISCOVERY 

Co-Chairs: 

Marc Ladanyi Paul S. Meltzer 

Participants: 

Iqbal Ahmed Mark A. Israel Poul H.B. Sorensen 

Charles D. Blanke Deborah R. Jaffe Matt van de Rijn 

Ernest U. Conrad Alfred Knudson Leonard Wexler 

Jody Cummings Lora Kutkat Richard B. Womer 

Jonathan A. Fletcher Elizabeth L. Layne Jerome W. Yates 

Matthew Freedman Norman Scherzer 

Gilles J. Frydman Julie A. Schneider 

INTRODUCTION 

Cytogenetic and molecular genetic studies indicate that sarcomas have two broad 

types of biology. The first group of sarcomas, those with fusion genes due to 

reciprocal translocations, contains specific genetic alterations and, usually, simple 

karyotypes. The second group of tumors is defined by nonspecific genetic alterations 

and, typically, complex unbalanced karyotypes, representing numerous genetic losses 

and gains. These two classes of sarcomas differ in many fundamental areas, such as 

telomere maintenance mechanisms and in their incidence in p53-mutant or knockout 

mouse models, in bilateral retinoblastoma and Li-Fraumeni syndrome, and as 

radiation-induced sarcomas. 

While this broad dichotomy crosses the boundaries between bone and soft-tissue or 

pediatric and adult sarcomas, awareness is increasing of the need to consider 

individual clinicopathologic entities separately in terms of prognostic markers and 

therapeutic targets. In the past, the relative uniformity or paucity of treatment options 

in sarcomas shaped a minimalist view of sarcoma classification, in which sarcomas 

were considered more by histologic grade, size, depth, and location than by specific 

histopathologic subtypes. This “lumping” approach may have hampered studies of 

biological prognostic markers because the power of certain markers may vary 

substantially among sarcoma subtypes. Likewise, low response rates to conventional 

or experimental therapies in studies combining multiple sequence tagged site types 

may have obscured higher response rates in individual unrecognized sarcoma types. 

Studies based on translocation analysis and, more recently, on global gene expression 

profiling have confirmed that the histopathologic classification of sarcomas 

corresponds with distinct biological entities, with some notable exceptions, such as the 

group of sarcomas historically termed “malignant fibrous histiocytomas.” 

Sarcomas with Specific Translocations and Simple Karyotypes 

This molecular pathologic class of sarcomas is more often seen in children, 

adolescents, and young adults. In all, at least 12 types of sarcoma, accounting for 

about a third of all sarcomas, are characterized by specific translocations. In addition 

to providing very specific diagnostic markers, the fusion genes resulting from these 

translocations encode chimeric proteins central to the biology of these tumors, acting 

Appendix A: Cross-Cutting Breakout Group Reports A-2 
Report of the Sarcoma Progress Review Group (PRG) 

as abnormal transcription factors that deregulate the transcription of multiple 

downstream genes and/or pathways. 

The key role of these chimeric proteins in the pathogenesis of these cancers is 

supported by their demonstrated necessity for in vitro growth of the corresponding 

sarcoma cell lines and the impact of relatively minor variability in the structure of 

these chimeric proteins (due to cytogenetic or molecular variant breakpoints) on tumor 

phenotype and clinical behavior in some specific sarcomas. Potentially specific 

therapeutic targets include the resultant fusion proteins themselves as well as genes 

that are key downstream targets of these aberrant transcription factors. The latter may 

be more biologically accessible, but the current list of validated downstream target 

genes remains small. 

Because the earliest known genetic lesion (the specific translocation) can be separated 

from late or secondary lesions, this group of sarcomas is amenable to a fairly simple 

model in which the earliest known genetic event is a specific chromosomal 

translocation in a specific precursor cell or stem cell. In most cases, this is an 

apparently random event, but in rare cases, it may be related to radiotherapy- or 

chemotherapy-induced DNA damage. 

Whether secondary genetic alterations are necessary in the biology of this class of 

sarcomas (for instance, in kinase signaling pathways) remains unclear. The best 

studied secondary genetic alterations, p53 mutations and p16CDKN2A/p14ARF 

deletions, define small but clinically aggressive subsets in several of these sarcomas. 

However, no evidence is available to indicate that these two intersecting pathways are 

functionally altered in the remaining majority of cases. Highly prevalent (and 

therefore presumably necessary) secondary genetic alterations have so far not been 

identified in any of these sarcomas. 

Certain translocation-associated sarcomas appear to be dependent on specific growth 

signaling pathways (insulin-like growth factor, platelet-derived growth factor 

receptor, and MET), but it generally remains unclear how much this relationship 

reflects their induction by the specific aberrant transcription factors versus preexisting activation of these pathways in the precursor cells of these sarcomas. So far, 

the genes encoding these signaling molecules have not shown mutations or other 

structural alterations in translocation-associated sarcomas. 

Sarcomas with Complex Karyotypes Lacking Specific Genetic Alterations 

This second molecular pathologic group of sarcomas is characterized by complex, 

unbalanced karyotypes lacking specific translocations, with many genomic gains and 

losses. This group makes up approximately two-thirds of sarcomas. Prototypical 

tumors in this group include osteosarcoma, malignant fibrous histiocytoma, 

liposarcoma (other than myxoid type), angiosarcoma, leiomyosarcoma, adult 

fibrosarcoma, and skeletal chondrosarcoma. Their often complex and unbalanced 

karyotypes reflect a biology in which chromosomal instability associated with 

checkpoint defects (DNA damage and cell cycle checkpoints) plays a critical role, 

producing pathogenic gene copy number changes in tumor suppressor genes and 

oncogenes. The mechanisms of chromosomal instability may include chromosomal 

fusion-bridge-breakage cycles (secondary to dysfunctional eroded telomeres), 

impaired nonhomologous end joining, or increased centrosome numbers. 

The degree of chromosomal or genomic instability in these sarcomas appears to 

correlate with p53 inactivation. Thus, in sarcomas with nonspecific genetic 

Appendix A: Cross-Cutting Breakout Group Reports A-3 
Report of the Sarcoma Progress Review Group (PRG) 

alterations, p53 pathway inactivation may be a common early event, needed to 

overcome checkpoints triggered by senescence, telomere erosion, or double-strand 

breaks. The more widespread role of p53 inactivation in this class of sarcomas may 

also account for its limited ability to define distinct clinical subsets in these tumors. 

Unlike sarcomas with simple karyotypes, certain etiologic factors or predisposing 

conditions are well described in this class of sarcomas, notably, ionizing radiation and 

constitutional p53 or Rb mutations. 

Gastrointestinal Stromal Tumors (GISTs): A Biologically Unique Sarcoma 

Most GISTs show simple karyotypes and are unique in that they constitute the only 

sarcoma type with a specific recurrent activating mutation (in KIT) as the primary 

genetic abnormality. The success of therapeutic targeting of KIT in GISTs has 

demonstrated the importance of structural genetic alterations in credentialing targets, a 

notion also supported by the generally disappointing results of similar approaches on 

nonmutated kinase targets in other sarcomas. 

PRIORITY 1. 

Fund and foster focused research on key areas of sarcoma biology most likely to 

advance the field. 

• Developmental biology of mesenchymal tissues. 

• Mutational target identification in growth signaling pathways. 

• Downstream targets of fusion proteins. 

• Cellular checkpoints and apoptotic pathways in the sarcoma context. 

• Immunobiology of human sarcomas. 

Rationale 

• These areas represent the major knowledge gaps in sarcoma biology. Bridging 

these gaps will advance the field at both the basic and translational levels. 

• The stem cells or precursor cells that give rise to sarcomas are largely unknown 

and mouse models for sarcomagenesis remain limited. A better understanding of 

mesenchymal developmental biology should allow for more successful and more 

representative transgenic models; should help in interpretation of expression 

profiling data; and may identify shared mesenchymal differentiation pathways 

and antigens amenable to novel therapeutic approaches. 

• A systematic focus on the tyrosine kinome of sarcomas should clarify the role of 

cooperating mutations in translocation sarcomas and may identify signaling 

pathways shared by diverse sarcomas. 

• A comprehensive analysis of fusion protein target genes will be necessary to 

clarify the genesis of translocation-associated sarcomas and may reveal 

candidates for highly targeted therapies or common themes and pathways

amenable to therapies with broader utility. 

• A better functional understanding of cellular checkpoints (cell cycle, p53, and 

telomeres) and apoptotic pathways in sarcomas as they relate to the cellular 

response to fusion proteins or karyotypic complexity may aid in the 

understanding of and refine responses to conventional chemotherapies and may 

reveal further therapeutic targets. 

Appendix A: Cross-Cutting Breakout Group Reports A-4 
Report of the Sarcoma Progress Review Group (PRG) 

• Sarcomas provide an important opportunity for the development of specific 

immunotherapies because many or most express differentiation antigens and/or 

tumor-specific fusion proteins. This opportunity is strengthened by recent 

progress in basic tumor immunology. 

Proposed Mechanisms 

• Requests for applications (RFAs) addressing these key areas. 

• Other funding mechanisms attracting both junior investigators and current 

leaders in developmental, stem cell, and sarcoma biology to focus on these key 

areas of normal and neoplastic mesenchymal biology. 

• Interdisciplinary symposia on mesenchymal development and differentiation and 

sarcoma biology. 

• A centralized infrastructure at NCI to link investigators to specific inhibitory 

compounds currently available in the public or private sector with potential 

activity toward newly identified targets. 

Issues of Importance 

• Progress in understanding mesenchymal development and differentiation lags far 

behind that in the hematopoietic system. There remains a gulf between the data 

emerging from the studies of developmental biologists and the field of sarcoma 

cell and molecular biology. 

• The current, piecemeal, gene-by-gene approach to gene discovery driven by 

multiple independent investigators has proven to be slow and inefficient in 

identifying new therapeutic targets among fusion protein transcriptional targets 

and growth signaling pathways. 

• It remains difficult for investigators to identify sources of promising compounds 

under development that may be relevant to sarcoma biological systems under 

investigation in their laboratories. 

PRIORITY 2. 

• 

• 

discovery. 

growth and survival. 

Fund and foster comprehensive approaches to sarcoma profiling and target 

Comprehensive profiling (genome, transcriptome, and proteome) of 

specimens from patients with sarcomas (including both neoplastic and nonneoplastic tissues) to identify novel therapeutic targets; identify new 

markers for diagnosis, susceptibility, and prognosis; predict treatment 

response; and define intermediate endpoints. 

High-throughput compound screens and functional genomic approaches to 

identify novel therapeutic targets and critical pathways regulating sarcoma 

Rationale 

Because targeted screening of specific pathways is limited by current knowledge of 

sarcoma biology, broad-based screens (e.g., compounds, RNA interference, and 

functional genomics) may be essential to identify novel targets associated with 

pathways not currently implicated in sarcoma biology. Comprehensive sarcoma 

Appendix A: Cross-Cutting Breakout Group Reports A-5 
Report of the Sarcoma Progress Review Group (PRG) 

profiling is presently fragmented and focuses largely on expression profiling. A 

global understanding of specific sarcomas remains elusive. 

Proposed Mechanisms 

• Provide support for integrating molecular profiling efforts to clinical trials so that 

the best available technologies are applied to the best annotated clinical 

specimens. This could be through RFAs or supplements to cooperative group 

awards, or through a newly established sarcoma clinical trials group. 

• Fund center(s) to establish additional validated sarcoma cell lines to be deposited 

at the American Type Culture Collection (ATCC): 

– Select 10 sarcoma cell lines to add to the NCI 60-cell-line panel. 

– Review and validate sarcoma cell lines currently available at ATCC. 

• Provide support and centralized infrastructure to link individual sarcoma

investigators with promising disease-specific models to centers carrying out 

high-throughput compound and genomic screens. 

Issues of Importance 

• Suitable laboratory models and assays representing a full spectrum of sarcoma 

types must be developed. Focused research efforts are limited by current 

knowledge. Therefore, comprehensive, unbiased screens are needed to provide a 

more global understanding of the biology of sarcomas and to identify currently 

unanticipated targets and pathways. 

• It is difficult for sarcoma investigators to interface with centers that have 

optimized screening technology platforms (e.g., RNA interference or small 

molecule) to bring these technologies to bear on sarcoma-specific systems. 

• Current molecular profiling datasets do not include the full spectrum of sarcoma 

types or adequate numbers of clinically annotated specimens. In addition, the 

available datasets do not combine multiple modalities of profiling and molecular 

characterization, such as mutations in the p53 pathway and cell cycle 

checkpoints. Available molecular profiling data currently reside on disparate 

platforms in dispersed databases and are therefore difficult to mine and crossreference. 

PRIORITY 3. 

centers committed to sarcoma research. 

Create a dedicated organizational structure to serve as a focal point for sarcoma 

clinical trials and related research, and enhance networks of investigators and 

Rationale 

Resources for studying the many forms of sarcoma are fragmented, resulting in many 

small, inadequately powered studies. Centrally coordinated initiatives and strong 

networks will facilitate multidisciplinary cooperative research and data sharing. 

Proposed Mechanisms 

• Foster central coordination of sarcoma clinical trials and related research in order 

to complete the following goals: 

– Develop shared bioinformatics resources to optimize data exchange and 

mining from existing and developing molecular profiling studies and 

Appendix A: Cross-Cutting Breakout Group Reports A-6 
Report of the Sarcoma Progress Review Group (PRG) 

etiology/susceptibility studies, and increase representation of less common 

sarcomas. 

– Oversee the establishment of banks of tissues, cell lines, xenografts, and 

molecular resources for distribution to the sarcoma research community. 

– Link biological specimens to clinical trials and encourage collection of 

adequate frozen specimens from the majority of patients. 

• Foster or enhance sarcoma research networks through new funding mechanisms 

including Specialized Programs of Research Excellence grants, RFAs for P01 

awards, and philanthropic consortia. 

Issues of Importance 

The greatest challenge is to develop a coordinating organization with a structure and 

mission that would be acceptable to the sarcoma clinical and research community and 

would also meet the concerns of patient advocacy groups, while addressing regulatory 

compliance issues. 

CONCLUSION 

The preceding priorities are designed to build on recent progress in sarcoma research 

and new technologies in biomedical research. They are also designed to overcome 

organizational and scientific limitations that have impeded progress in this group of 

relatively uncommon cancers. 

Based on a recognition that both highly specific targeting and wide spectrum 

approaches may be needed to advance the treatment of these cancers, these 

approaches should facilitate the identification of new sarcoma type-specific 

therapeutic targets, while also providing platforms for the discovery of broader 

therapeutic approaches related to shared underlying mechanisms of sarcomagenesis. 

Appendix A: Cross-Cutting Breakout Group Reports A-7 
Report of the Sarcoma Progress Review Group (PRG) 

TRANSLATION OF THERAPEUTIC TARGETS AND 

EXPERIMENTAL MODELS TO CLINICAL SETTINGS

Co-Chairs: 

George D. Demetri Perry D. Nisen 

Participants: 

Barry Anderson Robert L. Ilaria Glenn Merlino 

Frederic G. Barr Carl H. June Charles E. Nearburg 

Robert S. Benjamin Chand Khanna Rachel Nosowsky 

Jerry W. Call Ching C. Lau Richard J. O’Reilly 

Christopher Denny Stephen L. Lessnick Brian Rubin 

Mikhail L. Gishizky Crystal L. Mackall Stephen X. Skapek 

Gerard C. Grosveld Anna T. Meadows Annick D. Van den Abbeele 

INTRODUCTION 

For the patient, the process of scientific discovery is only effective if it is able to 

translate research results into effective new treatments. Advancing the field of 

sarcoma research requires redirecting the momentum of biological, biochemical, and 

molecular genetic understanding of mesenchymal tissues and mesenchymal neoplasia 

in a targeted and effective manner toward the needs of patients with sarcomas. 

Sarcomas offer unique strengths as models of clinical translational research, and these 

strengths are disproportionately great compared to the relatively low incidence of 

these diseases. This is due to the specific molecular markers and targetable 

mechanisms of neoplasia that characterize specific subtypes of sarcomas. The 

translation of the molecular understanding of gastrointestinal stromal tumors (GISTs) 

into clinical practice, for example, has provided a crucial proof-of-concept that 

genetically simpler sarcomas should serve as models for hypothesis-driven 

translational investigations in patients. 

Advances in the molecular understanding of sarcoma pathobiology have not always 

been optimally translated into new patient-oriented initiatives by the research and 

clinical communities. The field is currently hampered by small-scale, uncoordinated 

research conducted by investigators dispersed throughout the country, who may or 

may not have a particular interest in applying the results of fundamental research to 

sarcoma as a practical extension of their work. This dispersed and uncoordinated 

structure has resulted from (and is maintained by) certain logistical factors, such as the 

relatively uncommon incidence and prevalence of sarcomas across the country. The 

large-scale cooperative group mechanisms have traditionally failed to foster sarcoma 

research as well, resulting in a series of small-scale, unidisciplinary investigations 

throughout the country. This has led to an inefficient and ineffective dilution of 

expertise and a lack of focus on the key strengths of sarcoma as a powerful system for 

translational therapeutics research. Additionally, the current uncoordinated system 

often leaves care for sarcoma patients outside of optimal multidisciplinary approaches. 

The system also leaves researchers without a robust and reliable supply of sarcoma 

tissue samples with annotated connections to patient outcomes, which are necessary to 

understand this set of diseases more completely. 

Appendix A: Cross-Cutting Breakout Group Reports A-8 
Report of the Sarcoma Progress Review Group (PRG) 

Establishing a novel NCI-funded scientific and clinical mechanism to focus on and 

enable sarcoma-directed research will actively facilitate the translation of basic 

research discoveries into new targeted therapeutic research studies to advance the field 

of research and patient care targeted to improving the lives of patients and families 

touched by sarcomas. The implications of this work will be far greater than for 

sarcomas alone, however, since this mechanism will serve as a model for research and 

clinical translational therapies in other orphan diseases of low incidence. 

PRIORITY 1. 

Create the Sarcoma Research Consorti

comprised of sarcoma-focused scienti The SRC will 

Start-up funding from 

um (SRC) led by a steering committee 

fic and clinical leaders. 

develop strategy, implement plans, and influence the direction of translational 

research through resource allocation and coordination. 

NCI will ensure rapid initiation of this effort. Other sources of funding to 

maintain the SRC and its activities will be developed into a robust funding model 

that will include support from the philanthropic sector, the biopharmaceutical 

industry, and other private sector sources. 

Rationale 

The currently decentralized system does not support effective interactions between 

sarcoma-focused experts or collaboration among interested researchers. Moreover, 

the centralized mechanisms currently in place, built around traditional oncology 

cooperative group mechanisms designed to study diseases of higher prevalence, are 

inadequate to foster optimal collaboration in this area. Setting up a multidisciplinary 

steering committee would allow sarcoma experts to develop strategies before 

implementing actions. 

Issues of Importance 

• Jump-start sarcoma research with a rapid infusion of funding that might be 

offered as supplements to sarcoma-focused cancer centers and as special requests 

for applications. These mechanisms can focus resources on sarcoma research 

and create an “affirmative action plan for sarcomas” to stipulate that a portion of 

the research and trials infrastructures will specifically support sarcoma research. 

This will maximize the impact from funding and focus on high-priority scientific 

initiatives in this important field. 

• Develop aggressive and measurable metrics of success. For example, the 

number of adult sarcoma patients enrolled in protocols should be doubled within 

1 year, the number of clinical trials should be tripled in 3 years, and an annotated 

tissue bank of 100 samples should be created in 1 year. A majority of patients 

with sarcoma should be enrolled into protocols, with an early emphasis on 

annotated tissue collection protocols. 

• Construct the SRC to make sarcoma the paradigm for orphan disease 

translational research, as well as a model for collaboration across the age 

spectrum of pediatrics to adult care. 

• Provide impetus and sustain momentum in sarcoma translational research 

through a responsible new funding model (to be started by rapid infusion of 

targeted government funding with the aim of acquiring and directing industrial 

Appendix A: Cross-Cutting Breakout Group Reports A-9 
Report of the Sarcoma Progress Review Group (PRG) 

and philanthropic support toward this field) to enable more robust translational 

science. 

PRIORITY 2. 

tissue banks, biomarkers, and imaging. 

Develop a centrally available tool kit of core reagents and access to technology 

platforms for sarcoma research, including cell lines, model systems, annotated 

Rationale 

• Current resources are not adequate for current or planned research endeavors, 

and many important scientific and translational opportunities may go untapped. 

The tool kit will (1) interest the biopharmaceutical industry and basic science 

investigators and facilitate their translational research activities by focusing on 

the unique scientific strengths of sarcoma-selective targets, (2) enable new 

technology to define novel and valid biomarkers and imaging and surrogate 

markers to take advantage of the unique biology of sarcoma subsets, and 

(3) encourage rational clinical development with rapid speed and rational 

targeting. 

• Existing cell lines are inadequately annotated. Many subtypes of sarcomas 

(especially those afflicting adults) are underrepresented by currently available 

cell lines. 

• Sarcoma pathobiology may yield exceptionally clear answers to general 

questions of neoplastic disease mechanisms, and it is important to engage as 

broad a community as possible in research for which sarcoma would be an ideal 

translational model. 

Issues of Importance 

• Expand the NCI 60-cell-line panel to include at least five sarcoma cell lines, to 

be chosen by SRC. 

• Collect and classify tissue in annotated repositories to be made available to 

researchers. 

• Supplement existing NCI-funded cell culture core facilities to generate and 

characterize new cell lines. Make them available through a sustainable 

mechanism, such as American Type Culture Collection (ATCC), or explore 

collaborative interaction and expansion with the Cooperative Human Tissue 

Network. 

• Optimize nonmurine models (e.g., sporadic canine sarcoma) through intramural 

comparative oncology programs and/or extramural veterinary collaborators. 

• Expand the “Houghton model” for pediatric sarcomas to adult sarcomas as a 

preclinical screening and predictive framework. 

• Evaluate preclinical molecules against robust standardized methods. 

Appendix A: Cross-Cutting Breakout Group Reports A-10 
Report of the Sarcoma Progress Review Group (PRG) 

CONCLUSION 

The discussions of this group led to consensus that the promise of sarcoma 

translational research can and should be optimized by developing a new mechanism to 

foster sarcoma-specific translational research as a model for orphan disease research. 

With sarcoma researchers dispersed around the country, this mechanism will require 

the formation of viable research collaborations between geographically distant 

sarcoma-focused researchers. Novel funding mechanisms need to support such 

collaborations across institutional boundaries to maintain and expand a critical mass 

of sarcoma translational science. Additionally, the heterogeneity of sarcoma and the 

rarity of distinct sarcomas require that a centrally available tool kit of sarcomaspecific core reagents and access to technology platforms for sarcoma research be 

developed to support basic and translational research. Together, these actions should 

not only bring about major advancements in sarcoma research but also provide 

insights that will extrapolate to many other more common forms of cancer as well. 

Appendix A: Cross-Cutting Breakout Group Reports A-11 
Report of the Sarcoma Progress Review Group (PRG) 

INNOVATIVE CLINICAL TRIALS 

Co-Chairs: 

Laurence H. Baker Vivien H. C. Bramwell Paul A. Meyers 

Participants: 

Tamara Barnes Anne E. Kazak Peter F. Thall 

Janet F. Eary Philip A. Leider Timothy J. Triche 

Mark C. Gebhardt Robert B. Marcus, Jr. David H. Viskochil 

James Hadley Brian O’Sullivan Margaret von Mehren 

Peter J. Houghton Mary Ellen Rybak Sharon W. Weiss 

Judith K. Jones Scott Saxman Jay Wunder 

Howard L. Kaufman Dempsey S. Springfield 

INTRODUCTION 

While sarcomas as a group represent a significant proportion of all cancers, individual 

histologic entities are rare. This represents the principal obstacle to clinical trials for 

the treatment of sarcomas. Additionally, optimal clinical care and high-quality 

clinical research in these diseases require extensive collaboration from a broad array 

of medical specialties, but not all institutions that treat sarcomas have all the necessary 

specialties. Moreover, virtually all clinical trials of treatments for sarcomas rely on 

the endpoints of survival and event-free survival (EFS), so results have taken years to 

accrue and even longer to report. 

Important priorities for clinical research in sarcoma are to lower the barriers to 

participation in clinical research trials and to develop surrogate endpoints that allow 

more rapid identification of promising therapies. In addition, because only a fraction 

of patients with sarcomas receive optimal treatment in their first encounter with a 

physician, the proportion of patients who are treated according to existing guidelines 

for the management of sarcomas must be increased, even if these patients do not 

participate in a clinical trial. 

Barriers to Clinical Trial Participation 

• Children and adults with sarcomas have different rates of participation in 

clinical trials. The Children’s Oncology Group (COG) currently mounts 

clinical trials for the most common sarcomas in children—osteosarcoma, 

Ewing’s sarcoma, and rhabdomyosarcoma. Participation by U.S. children 

younger than 21 in COG open trials averages 85 percent. Although 

participation in these trials is open to older patients, it drops sharply with age. 

Similarly, many trials designed to evaluate therapy in adults with soft-tissue 

sarcomas require that patients be 18 years or older, although little or no a priori 

biological reason exists to exclude children from participation in phase III trials. 

• In most U.S. centers, children are treated in a freestanding children’s hospital 

that does not accept older patients, who are typically seen by internal medicine 

oncologists at a university hospital. Some university hospitals collaborate 

closely with pediatric oncology groups and have open trials. However, at other 

Appendix A: Cross-Cutting Breakout Group Reports A-12 
Report of the Sarcoma Progress Review Group (PRG) 

centers, the internal medicine oncology group may be unfamiliar with the trials 

or lack Institutional Review Board (IRB) approval for trial participation. 

• Time gaps between open trials in the COG have sometimes been long. In the 

intervals between trials, trial participation obviously drops to zero. 

• It is difficult for children’s hospitals to open and maintain large numbers of 

trials with low accrual rates. It is also difficult for each group of oncologists to 

remain familiar with the many clinical trials so that they offer trial participation 

to every eligible patient. Moreover, data management resources and clinical 

trial regulatory groups are strained by the increase in the volume of trials, the 

heterogeneity of sarcoma trials, and the different data submission requirements 

for each cooperative group and trial. 

• The principal loyalty of each group tends to be allied to a cooperative group. If 

the trial originates from a different group, data submission requirements may be 

different from those familiar to the institution and data managers may struggle 

to accommodate the requirements of an unfamiliar group. 

• Several adult cooperative groups have sarcoma committees (Southwest 

Oncology Group [SWOG], Eastern Cooperative Oncology Group [ECOG], 

Cancer and Leukemia Group B, Radiation Therapy Oncology Group [RTOG], 

American College of Surgeons Oncology Group [ACOSOG], and National 

Cancer Institute of Canada Clinical Trials Group), and some of these have run 

competing studies. Where studies do not compete, multiple logistic and 

regulatory issues prevent the cross-group collaboration that could promote rapid 

accrual to studies. These logistical problems may also apply to collaborative 

development of new studies and have prevented the fostering of appropriate 

correlative biology studies. 

Enhancing Collaboration for Sarcoma Clinical Research 

Some steps have been taken to enhance collaboration for sarcoma clinical research: 

• The very successful initiation and completion of the North American Intergroup 

study (S0033) of STI-571 (imatinib mesylate—Gleevec) in metastatic 

gastrointestinal stromal tumors (GISTs), with rapid accrual of more than 700 

patients in 9 months, demonstrates a reservoir and prevalence of rare histologyspecific sarcomas that could be accessed through cooperative groups. This 

study has also established patients’ level of interest in participation in clinical 

trials of new modalities. Therefore, this study could be used as a model for 

intergroup collaboration on targeted therapies. 

• Dr. Ernie Borden was appointed Chair of the SWOG Sarcoma Committee early 

in 2001 and, in collaboration with Dr. Murray Brennan from ACOSOG and 

representatives from all the cooperative groups, organized a multidisciplinary 

meeting on soft-tissue sarcomas of adults, with sponsorship from the Cancer 

Therapy Evaluation Program. The state of the science meeting took place in 

June 2002. (The meeting content can be viewed at 

www.webtie.org/sots/meetings/sarcoma.) The U.S./Canada Sarcoma Intergroup 

will focus on three of the many recommendations that came out of the meeting: 

(1) molecular and pathological redefinition; (2) evaluation of targeted biological 

therapies, both alone and in combination with chemotherapy and radiation; and 

(3) strengthening sarcoma clinical research collaborations with ACOSOG, 

RTOG, and COG. The U.S./Canada Intergroup has two specific aims: 

Appendix A: Cross-Cutting Breakout Group Reports A-13 
Report of the Sarcoma Progress Review Group (PRG) 

– To assess, in histology-specific trials, molecular targeted therapies—a 

number of protocols are in various stages of development. 

– To prospectively correlate pathologic diagnoses and clinical outcomes of 

soft-tissue sarcomas of adults with identification of novel gene clusters by 

DNA microarray. 

• In the past 2 years, an organization has been formed of American institutions 

active in the Connective Tissue Oncology Society (CTOS). This organization 

has now launched three clinical trials enrolling several hundred patients, 

established a statistical center dedicated to sarcoma trials, and increased the 

interest of medical and pediatric oncologists in working together on those trials. 

Improving Participation in Clinical Trials 

Improving participation in clinical trials requires the following: 

• High-quality trials asking important questions. This requires the convening of 

representatives of all relevant specialties to discuss new therapeutic options and 

set priorities for clinical trial development. Currently, the only venue that 

brings together representatives of pathology, surgery, radiation oncology, 

pediatric and medical oncology, and biology is CTOS. 

• Widespread publicity about the availability of the trials to both practitioners and 

patients. This would require website development and maintenance, and emails and conventional mailings to physicians about trials. This type of 

education and publicity should improve both clinical care to all patients and 

participation in appropriate prospective trials for the treatment of sarcomas. 

• Benefit to the patient and physician from participation in trials. Unique 

translocations have been identified for most sarcomas, and modern diagnosis of 

sarcomas will require molecular pathology. National or regional laboratories to 

perform molecular pathology of sarcomas would serve several purposes: 

– They would standardize and improve diagnosis of sarcomas, ensuring that 

clinical trials were applied to truly homogeneous groups of patients. 

– The centers would archive the material from patients, which could then be 

made available for basic research in sarcomas. 

– With appropriate informed consent, the biological resources would be 

linked to a clinical trial with all appropriate clinical information, including 

outcome data. This would dramatically improve the quality and quantity of 

information available to sarcoma researchers for correlation with biologic 

investigations. 

• Availability of trials at centers that are geographically convenient to patients. 

This will require the development of an infrastructure to support clinical trials at 

many institutions. The COG model works for pediatric centers, and CTOS has 

had success at mounting and executing clinical trials, including imatinib 

mesylate for selected sarcomas. 

• Increasing layers of review at every participating center makes the process of 

approval lengthy and cumbersome, and, in some cases, prevents participation. 

Data acquisition and management often receive no support. 

• Participation in clinical trials must be made easier and more convenient for data 

management staff. Ideally, all data submission should be completed through 

electronic remote data entry, which could be filtered to improve quality and 

much closer to real time. Central data repositories could monitor delinquent 

Appendix A: Cross-Cutting Breakout Group Reports A-14 
Report of the Sarcoma Progress Review Group (PRG) 

data reporting and seek redress much more quickly. The risk of error in data 

transmission and re-entry at the data center would be reduced, and availability 

of data to the statistician in usable form would be assured. 

• Rapid dissemination of results in the medical literature. The most recently 

completed large national prospective trial for Ewing’s sarcoma was reported in 

the literature 14 years after the trial opened. 

Surrogate Endpoints 

The only outcome variables currently considered to be reliable indicators of treatment 

efficacy are survival and EFS. Since median time to failure for some sarcomas is 

many years, trials run for years and results take years to accrue. For some of the 

diseases treated, novel techniques are available to assess response rapidly. For 

example, when patients with GIST are treated with imatinib mesylate, changes can be 

assessed in the tumor by positron emission tomography imaging within weeks of 

treatment initiation, and these changes correlate well with subsequent clinical 

response. Moreover, patients with osteosarcoma are typically treated initially with 

chemotherapy and then undergo definitive surgical resection of the primary tumor. 

Pathologic assessment of necrosis in the primary tumor strongly predicts subsequent 

EFS. In fact, the degree of necrosis observed after initial chemotherapy is the single 

strongest predictor of subsequent outcome. Similar results have been reported for 

Ewing’s sarcoma. For most other sarcomas, information about earlier response 

indicators that predict outcome is not available. For all early response markers, we 

need adequate prospective data acquisition to ensure that they predict outcome 

robustly so that they can be used to assess response at an earlier stage of treatment. 

Each clinical trial that is designed for the treatment of sarcomas should include early 

measurements of response so that significant experience with these modalities can be 

accumulated in a prospective manner. 

Novel Phase II Trial Design 

New agents for sarcomas are traditionally evaluated with a phase II trial design, in 

which eligibility is restricted to patients with measurable disease. Response outcome 

is assessed by radiologic imaging, and only agents that result in complete or partial 

objective responses are considered valuable for additional investigation. This 

approach may not be ideally suited to investigation of novel biological agents. Some 

of these agents might not be capable of inducing regression of bulky tumors even 

though they have activity against microscopic residual disease. Thus, conventional 

phase II designs run the risk of discarding potentially valuable new therapies. 

Novel trial designs are needed to evaluate novel therapies for sarcomas. These could 

include “adjuvant” phase II trials, where patients rendered clinically free of disease by 

surgery and/or radiotherapy would be eligible for entry. The relevant endpoint would 

be time to recurrence, measured through either randomization to treatment or 

observation, or comparison to an adequately robust historical control. Alternatively, 

the endpoint of interest could be survival from trial entry because stable disease with 

prolonged life is valuable to patients. The usual standard in phase II trials is to discard 

agents that do not result in measurable decrease in the size of tumors. However, 

investigators should be permitted to identify prolongation of life as a valuable 

endpoint, even if the therapy being tested does not result in objective shrinkage of the 

tumor. 

The statistical design of phase II trials also needs attention. The current CTOS trial of 

imatinib mesylate for sarcomas incorporates a novel hierarchical Bayesian approach 

Appendix A: Cross-Cutting Breakout Group Reports A-15 
Report of the Sarcoma Progress Review Group (PRG) 

to phase II trials to account for multiple subtypes of sarcomas. This approach, which 

was designed by Thall and colleagues (2003), allows improved use of limited numbers 

of patients to evaluate novel agents while minimizing the risk that the agents would be 

rejected as active. 

PRIORITY 1. 

Hypothesis: 

treatment in a community setting. 

: 

rates, and survival. 

Treatment of sarcoma patients in a comprehensive sarcoma center 

results in better diagnosis and improved survival in comparison to diagnosis and 

Recommendation Develop criteria to identify comprehensive sarcoma centers. 

Subsequently, complete a cohort study comparing patients treated in these 

centers with those who are not in terms of appropriateness of biopsy technique, 

diagnostic accuracy, appropriate use of diagnostic imaging, participation in 

clinical trials, collection and storage of appropriate tissues, local recurrence 

Rationale 

Sarcomas are a heterogeneous and uncommon group of malignancies. Optimal 

treatment requires close collaboration among clinicians from multiple disciplines with 

special expertise in the diagnosis and treatment of sarcomas. These include 

pathologists, musculoskeletal radiologists, surgical and orthopedic oncologists, 

pediatric and medical oncologists, radiation oncologists, and other surgical 

subspecialists when appropriate. 

In Ewing’s sarcoma, German data (Paulussen et al., 2003) demonstrated a survival 

advantage to those patients treated at centers seeing 10 or more patients per year. 

While we presume that this experience factor is associated with other sarcoma types, 

data need to be gathered and evaluated to confirm the preceding hypothesis. 

Issues of Importance 

• For some sarcomas, such as localized Ewing’s sarcoma and osteosarcoma, 

evidence clearly shows better outcomes for patients treated in experienced 

centers. Optimally, all patients with these sarcomas should be treated in sarcoma 

centers. For other sarcomas, the evidence is less clear; this question should be 

answered. In the interim, recognizing that not all patients will be able to receive 

care at a sarcoma center due to such issues as insurance, logistics, or cost, 

registration of such patients through the sarcoma centers, providing consultation 

and feedback to treating physicians regarding optimal care is encouraged. 

Appendix A: Cross-Cutting Breakout Group Reports A-16 
Report of the Sarcoma Progress Review Group (PRG) 

PRIORITY 2. 

• 

• 

• 

• 

• 

• 

: Develop a sarcoma-specific group to organize and conduct 

Monitor long-term ef

Hypothesis: A more efficient clinical trials system will improve recruitment and 

generate the knowledge needed to modify standards of care in sarcomas. 

Recommendation

clinical trials to: 

Foster constant, close communication with sarcoma biologists to design 

clinical trials based on promising preclinical results. 

Encourage the use of modern, translational scientific methods (tissue 

banking, gene expression, and modification). 

Further develop and refine a statistical design methodology to deal 

specifically with a disease category with multiple subtypes. 

Maximize the involvement of advocacy groups to promote and assist in 

recruitment to clinical trials. 

fects of therapeutic interventions. 

Support development of a national IRB to decrease barriers to clinical trials 

participation. 

Rationale 

Sarcomas are a unique group of diseases in which it has been difficult to make 

significant, consistent progress using the current clinical trials infrastructure. 

Issues of Importance 

• Current fragmentation of responsibility for sarcoma clinical research has failed to 

foster protocol development and conduct, and to support specimen acquisition 

and translational research. 

• We should set metric goals for progress with a timetable to meet them. 

• IRBs and scientific review committees need to be educated regarding novel 

statistical methodologies. 

PRIORITY 3. 

Hypothesis: 

: 

These trials should be 

Imaging or molecular biology studies can identify active therapies 

that will improve clinical outcomes earlier than conventional clinical endpoints. 

Recommendation Design prospective clinical trials whose principal objective is 

to compare early surrogate (intermediate) markers to conventional endpoints. 

Such trials should be tightly linked to appropriate tissue banking and incorporate 

novel statistical methodologies appropriate to sarcomas. 

conducted concurrently with a series of innovative therapeutic trials. 

Rationale 

In areas where significant controversy exists surrounding optimal therapy (often based 

on limited data), a trial focused on a surrogate (intermediate) endpoint will be viewed 

as innovative and therefore attractive to patients and their physicians. Furthermore, 

Appendix A: Cross-Cutting Breakout Group Reports A-17 
Report of the Sarcoma Progress Review Group (PRG) 

successful identification of a surrogate endpoint will allow more rapid conduct of 

clinical trials and will be very attractive to the pharmaceutical industry. 

Issues of Importance 

• A barrier of modern imaging is the lack of availability of dedicated imaging 

instruments, as well as related reimbursement issues. 

• A second barrier is the method by which the diagnostic biopsy is performed. For 

example, fine needle aspirate biopsy often does not provide sufficient tissue. 

CONCLUSION 

Improving the clinical trials process not only will lead to better outcomes for patients 

but, equally important, will also provide materials, insight, and laboratory discoveries 

to permit the succeeding generation of clinical trials to have an even greater impact on 

outcomes. 

A unifying theme of all of the breakout group’s discussions was the need for a 

sarcoma-specific consortium. Such a consortium will overcome barriers to clinical 

research in sarcomas and enhance translational research. 

REFERENCES 

1. Thall PF, Wathen JK, Bekele BN, Champlin RE, Baker LH, Benjamin RS. 

Hierarchical Bayesian approaches to phase II trials in diseases with multiple 

subtypes. Stat Med. 2003 Mar 15;22(5):763-80. 

2. Paulussen M, Ahrens S, Juergens HF. Cure rates in Ewing tumor patients 

aged over 15 years are better in pediatric oncology units. Results of GPOH 

CESS/EICESS studies. Proc Am Soc Clin Oncol. 2003. 22:816 (abstr 3279). 

Appendix A: Cross-Cutting Breakout Group Reports A-18 
Report of the Sarcoma Progress Review Group (PRG) 

OPTIMIZING EXISTING CARE 

Co-Chairs: 

William G. Kraybill Mark O. Thornton 

Participants: 

Karen H. Albritton Alberto Pappo Lynne S. Steinbach 

Karen O. Anderson Sharon E. Plon Herman D. Suit 

John S. J. Brooks Angela C. Riepel Abraham (Al) Sunshine 

Howard D. Dorfman Andrew E. Rosenberg Marny S. Tobin 

Holcombe E. Grier Vernon K. Sondak Asad Umar 

Robert (Bob) Maki Katherine Loy Stadler Jerome W. Yates 

INTRODUCTION 

The American Cancer Society has estimated that 8,300 soft-tissue sarcomas will be 

diagnosed in 2003. [1] Of these patients, 3,900 (45%) will die of their disease. The 

standard of care for these tumors varies by histologic type of sarcoma and location. 

For example, in this small group of tumors, appropriate management varies greatly for 

gastrointestinal stromal tumors, pediatric sarcomas, high-grade extremity sarcomas, 

and sarcomas of the retroperitoneum and uterus. Optimal care of these patients 

requires the multidisciplinary expertise of specialists with experience in the 

management of these tumors. Surgical, orthopedic, and medical oncologists; radiation 

therapists; and pathologists all have important roles in the management of these 

uncommon but complicated tumors. 

Quality of care is a primary issue in the current management of sarcomas, but the 

rarity of these tumors prevents most practitioners from developing experience in their 

management. For example, the standard management of extremity and torso sarcomas 

requires a needle biopsy or incisional biopsy, and excisional biopsy by inexperienced 

surgeons may contaminate tissue planes and make further treatment more problematic 

as a result of inappropriate incisions. [2] Of 202 patients referred to Roswell Park 

Cancer Institute with biopsy-proven sarcomas of the extremity, 109 (more than 50 

percent) underwent excisional biopsy. [3] Standards of care have been outlined by 

such groups as the National Comprehensive Cancer Network (NCCN). More 

objective assessments of what quality cancer care is for low-volume tumors, such as 

sarcomas, are difficult to obtain. [4] Most major assessments of quality of care, such 

as NCI’s Cancer Care Quality Measures Project (CanQUAL) project, emphasize highincidence tumors such as cancers of the breast, colon, lung, and prostate. Little is 

known about the quality of care in low-incidence tumors, such as sarcoma, primarily 

because most patients are treated by their primary providers and not by sarcoma 

specialists at multidisciplinary centers. 

Multiple reasons exist for patients not being referred to or not choosing to be managed 

in multidisciplinary centers. Travel to centers of excellence is frequently 

inconvenient, bothersome, and expensive. Additionally, physicians and surgeons in 

small- and moderate-sized hospitals often want to maintain control of patients in their 

respective communities for economic and other reasons. However, many physicians 

do not appreciate how complex the care of sarcoma patients has become and are not 

aware of the many alternative care strategies available. 

Appendix A: Cross-Cutting Breakout Group Reports A-19 
Report of the Sarcoma Progress Review Group (PRG) 

Many groups are beginning to address quality in meaningful ways. Specifically, the 

NCI’s CanQUAL, in collaboration with the National Quality Forum and the Rand 

Corporation, is addressing quality issues in four high-incidence, nonsarcoma tumors. 

However, low-incidence and highly variable tumors, such as sarcomas, are not 

receiving the same attention. 

PRIORITY 1A. 

multidisciplinary centers (SMCs). 

The standard of care for patients with sarcoma should be treatment at sarcoma 

Rationale 

SMCs will improve patient outcomes, increase participation in translational research 

and clinical trials, and increase the availability of tissue for research. 

Issues of Importance 

• SMCs will set the standard for providing expert care to patients afflicted with 

sarcoma. Institutions that meet pre-defined requirements would qualify to 

become SMCs. (See Priority 2 for SMC qualification requirements.) 

• Although optimal patient care would be provided at SMCs, patient barriers must 

be considered, such as insurance coverage, travel, and finances. For patients 

who are unable to overcome these barriers, alternatives must be established to 

optimize their care. Insurance companies should be advised of patient cost 

barriers and attempt to minimize/eliminate existing financial penalties. 

Increased provider awareness and education and improved communication 

between the treatment establishment and providers at SMCs would improve 

outcomes for patients unable to attend SMCs and enhance sarcoma trials and 

research activities. (This issue is further addressed in Priority 3.) 

• Improved patient care would result from increased research on sarcomas. SMCs 

have the potential to assist and enhance clinical, translational, and basic research. 

Currently, only 1–2.5 percent of sarcoma patients are enrolled in clinical studies. 

PRIORITY 1B. 

Define sarcoma multidisciplinary centers. 

Rationale 

SMCs must be defined to identify the health care institutions that could provide 

optimal care to sarcoma patients. 

Issues of Importance 

Eligibility criteria would eliminate the possibility of misleading patients who seek 

optimal care. 

The SMC requirements include the following: 

• A sarcoma group consisting of physicians with special interest in all specialties, 

including surgical, orthopedic, and medical oncologists; radiologists; 

pathologists; and oncology nursing as well as rehabilitation services. 

• One group member who is a member of a sarcoma-oriented medical 

organization, such as the Connective Tissue Oncology Society.

Appendix A: Cross-Cutting Breakout Group Reports A-20 
Report of the Sarcoma Progress Review Group (PRG) 

• Publications concerning sarcoma in peer-reviewed journals. 

• Sarcoma conferences, where sarcoma group members meet at least once per 

month to discuss patient care issues. 

• Approximately 50 newly diagnosed cases treated per year. 

• Imaging (magnetic resonance imaging > 1.0 Tesla; positron emission 

tomography scan desired). 

• Patient enrollment in clinical trials. 

• Strong support personnel. 

PRIORITY 2. 

Design, implement, and study best practices in sarcoma management. 

Rationale 

The low incidence of sarcoma results in a lack of outcomes data and precludes 

objective assessment of end results of sarcomas. 

Issues of Importance 

• Investigate the potential role of payers and other groups (e.g., Leapfrog Group) 

in financially supporting the assessment of outcomes in sarcoma management. 

Sarcoma treatment costs may be significantly reduced if sarcoma is managed by 

SMCs. By decreasing the number of patient surgeries, costs could be reduced. 

• Developing a registry would facilitate the availability of outcomes data. 

• An international conference is needed to define the appropriate management of 

resected sarcoma specimens with respect to pathologic classification, grading, 

margin status, and treatment effect. Similar conferences have been held for 

lymphomas. 

• Population-based studies are needed to evaluate the process of care and outcome 

results using retrospective data. This would provide a benchmark assessment of 

the quality of care and outcomes in patients from different populations and 

access to differing care providers. This could potentially be funded by 

supplements to NCCN Core Grants (P30). 

Appendix A: Cross-Cutting Breakout Group Reports A-21 
Report of the Sarcoma Progress Review Group (PRG) 

PRIORITY 3. 

treatment, and outcomes. 

Promote education among patients, providers, and payers concerning SMCs, 

Rationale 

Awareness of the advantages of referring sarcoma patients to SMCs should be 

increased. 

Issues of Importance 

• Educate and encourage pathologists and radiologists to facilitate referrals to 

SMCs. 

• Expand patient information resources. For example, four or five on-line sources 

could be selected that provide information about sarcoma. These websites would 

be reviewed and evaluated by patient advocacy groups for content quality. 

• Investigate potential additional roles of advocacy organizations. 

CONCLUSION 

Many if not most patients with sarcoma do not receive care that approaches what 

would currently be an acceptable standard. There are multiple reasons for this. Most 

primary care physicians, general surgeons, and general orthopedic surgeons have little 

or no experience in the management of these rare and complex tumors. There is a 

lack of broadly based outcomes data demonstrating the benefits of SMC care. 

Carefully obtained outcomes data will increase the pressure for improved care of 

sarcoma patients. Treatment at SMCs will result in specialized care to patients with 

sarcoma, better patient outcomes, and enhanced research efforts. 

SMC designation requires that specific criteria be met. Supplements to core grants 

(P30 awards) could be used to fund population-based studies to evaluate processes of 

care and outcome results using retrospective data. Such studies would provide 

objective information concerning the current management and outcomes of soft-tissue 

sarcomas in different populations. Educating patients, providers, and payers 

concerning SMCs and sarcomas is important for optimizing patient outcomes and 

expanding research. 

REFERENCES 

1. Jemal A, Murray T, Sammuels A, et al. Cancer statistics. Cancer J Clin. 2003. 

CA 53(1):5-26, 2003. 

2. Noria S, David A, Kandel R, et al. Residual disease following unplanned 

excision of a soft-tissue sarcoma of an extremity, J Bone and Joint Surg. 

1996. 78-A: 650-655. 

3. McKee MD, Whooley BP, Driscoll D. Excisional biopsy prior to wide 

resection of extremity sarcoma is associated with improved outcome. 

Proceedings ASCO. 2001. 20:365s(abstract 1456). 

4. Smith TJ, Hillner BE. Ensuring quality cancer care by the use of clinical 

practice guidelines and critical pathways. J. Clin. Oncol. 2001. 19:2886-97. 

Appendix A: Cross-Cutting Breakout Group Reports A-22 
Report of the Sarcoma Progress Review Group (PRG) 

Appendix B 

Science-Centric Breakout Group Reports 

Better Biology and Discovery .................................................................................. B-2 

Better Immunology .................................................................................................. B-9 

Better Access to Annotated Tissue......................................................................... B-15 

Better Models and Preclinical Testing ................................................................... B-19 

Better Prevention.................................................................................................... B-23 

Better Diagnosis and Prognostication .................................................................... B-28 

Better Imaging........................................................................................................ B-32 

Better Clinical Studies............................................................................................ B-36 

Better Communication and Outcomes ................................................................... B-41 

Appendix B: Science-Centric Breakout Group Reports B-1 
Report of the Sarcoma Progress Review Group (PRG) 

BETTER BIOLOGY AND DISCOVERY 

Co-Chairs: 

Christopher Denny Jonathan A. Fletcher Michael C. Heinrich 

Participants: 

Barry Anderson Marc Ladanyi Angela L. Riepel 

Mikhail L. Gishizky Ching C. Lau Stephen X. Skapek 

James Hadley Stephen L. Lessnick Richard B. Womer 

Robert L. Ilaria, Jr. 

INTRODUCTION 

In summarizing the known biology of sarcomas, one must be mindful that “sarcoma” 

is a complex disease category. Sarcomas can arise from, or differentiate toward, any 

of the many mesenchymal cell types that comprise the normal connective tissue 

structure, including fibroblasts, smooth and skeletal muscle, fat, nerve sheath, 

cartilage, and bone. In many cases, sarcomas evolve from more benign versions of 

the same tumors, and the biologic and clinical interface between benign and malignant 

can be difficult to define. In other sarcomas, such as Ewing’s sarcoma and synovial 

sarcoma, no demonstrable benign precursors to the malignant tumor have been 

identified and, in fact, the precise tissues of origin remain to be defined. 

For the most part, the identity and biological functions of the transformed progenitor 

cells in sarcomas have not been determined. The possibility of derivation from a 

mesenchymal stem cell, or at the least a noncommitted mesenchymal progenitor, is 

suggested by the examples of pulmonary chondroid hamartoma, triton tumor, and 

others. In pulmonary chondroid hamartoma, a transformed primitive mesenchymal 

cell can differentiate towards chondroid, adipose, smooth muscle, and skeletal muscle, 

and such components are typically admixed within an individual tumor. [1] However, 

in the more common types of sarcoma, the progenitor cell has not been identified. For 

example, the diagnosis of leiomyosarcoma is based on morphologic and 

immunophenotypic resemblance of the tumor cells to smooth muscle, but it is not 

clear whether the leiomyosarcoma progenitor cell is already committed to a smooth 

muscle differentiation pathway, or—alternately—whether it is a pluripotential 

mesenchymal cell in which smooth muscle differentiation results from the 

transforming mutations. Identification of sarcoma progenitor cells would greatly 

expedite the development of relevant in vitro and in vivo disease models. 

Over the last decade, a considerable amount of the biologic headway toward 

understanding sarcoma pathogenesis has come from the study of tumor-associated 

genomic abnormalities (Table B.1). [2,3] Unlike some mutations that can found in a 

broad array of cancers, a one-to-one relationship frequently exists between a certain 

chromosomal rearrangement and a particular sarcoma. Many of the sarcoma 

chromosomal rearrangements are translocations that create fusion oncogenes, 

resulting in the production of chimeric transcripts and proteins. Because these 

sarcoma fusion oncogenes are specific for particular sarcoma subtypes, they serve 

essential roles as molecular markers in sarcoma diagnosis. They have also provided 

mechanistic insights into sarcoma oncogenesis. 

Many fusion oncoproteins appear to function as aberrant transcriptional regulators, of 

which the PAX-FKHR oncoprotein in alveolar rhabdomyosarcoma and the EWS-ETS 

Appendix B: Science-Centric Breakout Group Reports B-2 
Report of the Sarcoma Progress Review Group (PRG) 

oncoproteins in Ewing’s sarcoma are well-characterized examples. [4-7] The 

transforming activity and biological consequences of these oncogenic transcription 

factors probably involve perturbations of proliferation and differentiation 

programs. [8,9] Although these transcription factor oncogenes appear to be essential 

to the development and maintenance of the corresponding types of sarcoma, it is 

unclear whether they are initiating oncogenic mutations or they are preceded by other 

mutations. Ectopic expression of fusion genes can be toxic in many cell types. This 

suggests that both additional genomic mutations and a compatible cell context are 

necessary for the genesis of most sarcomas. 

Table B.1: Recurrent Molecular and Cytogenetic Aberrations in Soft-Tissue Sarcomas 

Tumor Cytogenetic Event Molecular Event Frequency Diagnostic 

Utility? 

Alveolar soft part 

sarcoma 

t(X;17)(p11;q21) ASPL-TFE3 fusion >90% Yes 

Angiomatoid fibrous 

histiocytoma 

t(12;16)(q13;p11) FUS-ATF1 fusion ? Yes 

Clear cell sarcoma t(12;22)(q13;q12) EWS-ATF1 fusion >75% Yes 

Desmoplastic small 

round cell tumor 

t(11;22)(p13;q12) EWS-WT1 fusion >75% Yes 

Dermatofibrosarcom Ring form of COL1A1-PDGFB >75% Yes 

a protuberans chromosomes 17 and 22 fusion 

Endometrial stromal 

tumor 

t(7;17)(p15;q21) JAZF1-JJAZ1 

fusion 

30% Yes 

Ewing’s sarcoma t(11;22)(q24;q12) EWS-FLI1 fusion >80% Yes 

t(21;22)(q12;q12) EWS-ERG fusion 5–10% Yes 

t(2;22)(q33;q12) EWS-FEV fusion <5% Yes 

t(7;22)(p22;q12) EWS-ETV1 fusion <5% Yes 

t(17;22)(q12;q12) EWS-E1AF fusion <5% Yes 

Fibrosarcoma, 

infantile 

t(12;15)(p13;q26) ETV6-NTRK3 

fusion 

>75% Yes 

Gastrointestinal KIT or PDGFRA >85% Yes 

stromal tumor point mutation 

Monosomies 14 and 22 >75% No 

Inflammatory 2p23 rearrangement ALK fusion genes 50% Yes 

myofibroblastic 

tumor 

Liposarcoma 

Well-diff/Dediff 

Ring form of 

chromosome 12 

>75% Yes 

Liposarcoma 

Myxoid/Round-cell 

t(12;16)(q13;p11) TLS-CHOP fusion >75% Yes 

Rhabdoid tumor Deletion of 22q INI1 inactivation >90% Yes 

Rhabdomyosarcoma 

Alveolar 

t(2;13)(q35;q14) PAX3-FKHR 

fusion 

>75% Yes 

t(1;13)(p36;q14), PAX7-FKHR 10-20% Yes 

double minutes fusion 

Rhabdomyosarcoma 

Embryonal 

Trisomies 2q, 8 and 20 >75% Yes 

Synovial sarcoma t(X;18)(p11;q11) SYT-SSX1 or SYTSSX2 fusion 

>90% Yes 

Another functional class of sarcoma fusion oncogenes encode aberrant tyrosine 

kinases, resulting from fusion of an ectopic oligomerization domain to the catalytic 

domain of the tyrosine kinase protein. [10] The resultant fusion proteins function as 

Appendix B: Science-Centric Breakout Group Reports B-3 
Report of the Sarcoma Progress Review Group (PRG) 

constitutively oligomerized and constitutively activated tyrosine kinases. Examples 

include the ALK fusion oncoproteins in inflammatory myofibroblastic tumor [11] and 

the ETV6-NTRK3 fusion oncoprotein in infantile fibrosarcoma. [12] In addition, 

aberrant activation of tyrosine kinase oncogenes can result from intragenic point 

mutations, as in the case of KIT and PDGFRA mutations in gastrointestinal stromal 

tumors (GISTs). [13,14] Tyrosine kinase oncogenes are strongly transforming in cell 

culture, and the tyrosine kinase transforming activity is dependent on signaling 

through the phosphatidylinositol 3 kinase/AKT survival pathway and through the 

RAS/mitogen activated protein kinase kinase/mitogen activated protein kinase 

proliferation pathway. Some evidence indicates that tyrosine kinase oncogenes can be 

initiating mutations, as demonstrated by the germline KIT mutations in GIST 

kindreds. [15,16] 

Tumor suppressor genes also play essential roles in most, and perhaps all, sarcomas. 

Examples include p53 inactivation mutations in osteosarcoma [17] and SNF5/INI1 

mutations in rhabdoid tumors. [18] Both of these mutations can be found as germline 

aberrations in patients with cancer syndromes [19,20], and in that context can be 

regarded as initiating mutations in the development of the associated sarcomas. 

Several sarcoma oncogenes have already been used to advantage as therapeutic 

targets. Examples include the KIT and PDGFRA oncoproteins in GISTs [13,16,21] 

and activated PDGFRB—which results from oncogenic overexpression of the ligand 

PDGFB—in dermatofibrosarcoma protuberans. [22] Although essential oncogenes 

have been identified in many sarcomas, other oncogenes and tumor suppressor genes 

certainly remain to be identified in these tumors. Such genes probably play key roles 

in neoplastic progression, and their identification could provide additional therapeutic 

targets in sarcoma. 

These observations prompt the following underlying questions: 

• What are the progenitor cells that are transformed to give rise to different 

sarcomas?

• What are the dominant genetic pathways driving sarcoma development and 

maintenance?

• Which sarcoma oncogenic pathways are therapeutically tractable in the near 

future? 

PRIORITY 1. 

and industry. 

research to be supported by request for application or program announcement 

mechanisms. 

Enhance interactions among disciplines, including sarcoma biology, 

mesenchymal biology, and embryology, NIH should sponsor an annual or 

biennial symposium that is broadly inclusive of a range of scientific disciplines 

One objective would be to identify high-priority, cross-disciplinary 

Rationale 

Progress in sarcoma biology and in identifying new therapeutic targets will be enabled 

by greater interplay between researchers in the fields of sarcoma oncogenesis/biology 

and those studying normal mesenchymal development and embryogenesis. 

Furthermore, the public health benefits of sarcoma research will be maximized 

through interactions between scientists in this field and those working on other aspects 

Appendix B: Science-Centric Breakout Group Reports B-4 
Report of the Sarcoma Progress Review Group (PRG) 

of mesenchymal pathology, such as atherosclerosis and osteoarthritis. Therefore, an 

active, prospective mechanism is needed to ensure progress in identifying sarcoma 

progenitor cells and generation of useful models for sarcomagenesis, and to expand 

the relevance of sarcoma research to other aspects of mesenchymal biology. Such a 

mechanism should not be limited to stimulating interaction among academic 

investigators but should also include fostering information exchange between sarcoma 

researchers and potential partners in the pharmaceutical or biotechnology industries. 

Issues of Importance 

• Commitment from NIH to support cross-cutting research symposia in sarcoma 

and mesenchymal biology. 

• Commitment from NIH to support cross-cutting research in mesenchymal 

embryology, biology, and oncogenesis. This should ideally include solicitation 

of multiple investigator applications R01 or similar mechanisms, so as to 

promote multi-institutional collaborations. 

PRIORITY 2. 

Provide mechanisms of support to identify therapeutically relevant sarcoma 

mutations by genomic analysis of the sarcoma kinome and to identify sarcoma 

therapy response biomarkers by proteomic profiling of clinical specimens. 

Rationale 

While individual investigator-initiated studies will continue to reveal mechanisms of 

sarcoma oncogenesis, additional opportunities exist to hasten progress in identifying 

essential and therapeutically tractable sarcoma mechanisms. Such efforts may require 

expertise or infrastructure that is presently unavailable to most independent 

investigators. For example, substantial gains could potentially be made by applying 

current high-throughput genomic technologies to the search for tumor-associated 

mutations in sarcoma biopsy specimens or cell lines. Gain-of-function kinase 

mutations have been shown to play central roles in certain sarcomas. Pharmacological 

inhibitors of these protein kinases are under development by many drug companies 

and could prove to be a valuable source of new therapeutic agents for sarcomas 

harboring activating kinase mutations. 

Issues of Importance 

• Assemble and prioritize a representative panel of sarcoma cell lines and/or tumor 

samples for kinome analysis. 

• Establish a coordinated system of specimen submission and publicly available 

data distribution for sarcoma kinome and other large-scale sarcoma genomic 

analyses. 

• Identify and prioritize the sarcoma clinical models with the highest likelihood of 

being informative in proteomic marker screens. 

Appendix B: Science-Centric Breakout Group Reports B-5 
Report of the Sarcoma Progress Review Group (PRG) 

PRIORITY 3. 

This should

Establish a central source of key resources to facilitate identification of essential 

aspects of sarcoma biology and enable their clinical translation. 

include both physical resources (cell lines, purified tumor-derived nucleic acids, 

viable cells, frozen tissue, tissue arrays, and expression constructs) and 

conduits to intellectual properties (expression microarray datasets and small 

molecule inhibitor “tool” compounds). 

Rationale 

Due to the rarity of individual sarcomas relative to other human malignancies, the lack 

of reagents can be a major impediment to established sarcoma researchers and, 

especially, to those trying to enter the field. A common resource for acquiring 

physical reagents would greatly benefit both groups. In addition, a mechanism for 

obtaining access to more restricted data (e.g., microarray data) or reagents (e.g., small 

molecule “tool” compounds) would be a boon. Up until now, obtaining these latter 

resources has been idiosyncratic and heavily reliant on establishing expedient 

interpersonal contacts. This has been particularly true for accessing small molecule 

inhibitors and other novel therapeutics developed by industry. Creation of web-based 

applications that offer initial contacts among investigators or conduits to 

pharmaceutical/biotechnology representatives could greatly enhance these potentially 

fruitful interactions. 

Issues of Importance 

• Infrastructure or support to create and distribute sarcoma tissue arrays, viable 

cells, frozen tumor, and sarcoma nucleic acid panels (both DNA and RNA), 

including at least 10 examples of each of the common types of benign and 

malignant mesenchymal tumors. 

• Support for the creation and validation of a panel of sarcoma cell lines, including 

three-to-five representative examples of each of the common types of sarcoma, 

to be housed and distributed in an established facility, such as the American 

Type Culture Collection (ATCC). 

• Collection and distribution of sarcoma oncogene expression constructs by a 

centralized resource, such as the ATCC.

• Determination of appropriate levels of accessibility to sarcoma datasets among 

investigators. 

• Establishment of mechanisms, perhaps involving an NIH liaison, to facilitate 

interactions between the academic sarcoma research community and the 

pharmaceutical industry.

CONCLUSION 

An urgent need exists to hasten the understanding of sarcoma biology and, in so 

doing, to identify novel therapeutic targets for these frequently disabling and/or lethal 

diseases. Although sarcomas are relatively uncommon and the sarcoma research field 

is commensurately small, much advantage can be gained by integrating sarcoma 

research with other disciplines in mesenchymal biology and pathology. A 

mesenchymal disease symposium should be initiated to highlight and promote such 

cross-disciplinary interactions and to identify high-impact research areas that warrant 

Appendix B: Science-Centric Breakout Group Reports B-6 
Report of the Sarcoma Progress Review Group (PRG) 

targeted funding emphasis from NIH. In addition, progress in sarcoma biology and 

therapeutics must be hastened by supporting strategic larger scale genomic and 

proteomic surveys, which will provide the necessary infrastructure for subsequent 

biologic and preclinical studies within individual investigator research laboratories. 

The ability to conduct such studies efficiently and to generalize novel findings to 

different types of sarcomas will require substantial expansion of centralized sarcoma 

reagent and data resources. Although centralization of resources is desirable 

generally, given that many types of sarcoma are rare, it is particularly important that 

sarcoma tissue arrays, cell lines, tissue and nucleic acid samples, oncogene expression 

constructs, pathway inhibitors, and expression data be more widely available to those 

in the sarcoma research community. 

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Report of the Sarcoma Progress Review Group (PRG) 

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Appendix B: Science-Centric Breakout Group Reports B-8 
Report of the Sarcoma Progress Review Group (PRG) 

BETTER IMMUNOLOGY 

Co-Chairs: 

Carl H. June Crystal L. Mackall 

Participants: 

Howard L. Kaufman Robert Maki Richard J. O’Reilly 

Hyam I. Levitsky Charles E. Nearburg Mark O. Thornton 

INTRODUCTION 

Over the last decade, exponential advances in tumor immunology have provided a 

sound scientific basis for pursuing immunotherapy for cancer. What was once a 

marginal enterprise in cancer therapy is now becoming a reality. Within the next 5 

years, the U.S. Food and Drug Administration is likely to approve new immune-based 

therapies for lymphoma, renal cell carcinoma, and melanoma. 

The roots of many modern concepts in tumor immunobiology originated in murine 

models of sarcoma, including seminal findings on T-cell antigen recognition, the role 

of heat shock proteins in innate and adaptive immune interactions, and immune 

surveillance. The application of these principles to the study of the immunobiology of 

human sarcomas provides a compelling opportunity for the development of new, 

targeted immunotherapies. Classical studies of methacholanthrene-induced sarcomas 

in mice gave rise to the basic principle that the T-cell-mediated response to cancer is 

tumor specific. Further investigation identified heat shock proteins expressed by 

murine sarcomas as molecular chaperones capable of presenting immunogenic 

peptides to the adaptive immune system, thus providing a mechanism for the 

specificity of antigen recognition. More recent data have shown that the capacity for 

heat shock proteins expressed by sarcomas to activate innate immunity through 

dendritic cell interactions leads to cross-presentation of tumor antigens and the 

subsequent development of adaptive immune responses. Therefore, murine sarcoma 

studies have provided perhaps the most dramatic demonstration of the critical role of 

the interactions between innate and adaptive immunity in inducing antitumor immune 

responses. Further, extensive studies of methacholanthrene-induced sarcoma growth 

in genetically targeted T-cell-deficient mice have provided unequivocal evidence that 

immune surveillance plays a role in preventing tumors. Thus, murine models of 

sarcoma have not only clearly identified sarcomas as immune-responsive tumors, but 

they have also provided seminal insights into the host–tumor interface that have 

influenced current thinking regarding the larger field of tumor immunology. 

To translate the insights gleaned from murine sarcomas into new immunotherapies for 

human sarcomas, specific targets of antigen recognition need to be identified. Tumor 

antigens have been identified primarily by dissecting the cell-mediated and humoral 

responses present in tumor-bearing patients that are directed toward autologous 

tumors or cDNA libraries derived from autologous tumors. Tumor antigens can be 

classified as belonging to one of the following groups: 

• Tissue differentiation antigens that are highly expressed in embryonal tissues but 

have limited expression on normal adults tissues (e.g., carcinoembryonic antigen 

in colon carcinoma and melan-A/Mart-1 in melanoma). 

Appendix B: Science-Centric Breakout Group Reports B-9 
Report of the Sarcoma Progress Review Group (PRG) 

• Cancer-testis antigens that are expressed on many neoplastic tissues and germ 

cells, presumably as a result of widespread genomic demethylation in neoplastic 

tissues (e.g., MAGE family). 

• Mutated self-proteins that often occur as a result of the malignant process itself 

and contribute to the growth/survival pathways of the malignant cell (e.g., 

mutated Cdk4). 

• Overexpressed self-proteins (e.g., n-MYC in neuroblastoma and HER2/neu in 

breast and ovarian cancer). 

• Viral antigens expressed by virally associated tumors (e.g., human papilloma 

virus in cervical carcinoma and HHV-8 in Kaposi’s). 

Our current understanding of the biology of human sarcomas suggests that they are 

likely to express tumor antigens from each of these categories; however, very little is 

known regarding the extent of tumor antigen expression in the wide array of human 

sarcoma histologies. Further, it is not known whether endogenous immune responses 

exist in patients whose sarcomas express genes that are antigenic in other histologies. 

Therefore, while the results of murine studies and the identification of an array of 

tumor antigens likely to be expressed by sarcomas provide reasons to surmise that 

immune responses may be exploited in sarcoma patients, very few studies aimed at 

defining tumor antigens in human sarcomas have been performed. 

Barriers to Progress 

The primary barrier to research in the immunology of sarcomas is the lack of a critical 

mass of investigators. Most tumor immunologists are focused on melanoma and renal 

cell carcinoma, which are classically defined as “immune-responsive” tumors. 

However, evidence from murine models and the plethora of antigenic targets that are 

now identified as potential tumor antigens suggest that even in the absence of 

spontaneous tumor regressions in human sarcomas, opportunities exist for 

immunotherapy of sarcomas. The funding of studies designed specifically to address 

the immunobiology of human sarcomas is necessary to increase the number of 

investigators. 

A second barrier to research in the field of immunology of sarcomas is the lack of 

reagents required to undertake basic studies to define tumor antigen expression in 

sarcomas; the critical first step in determining endogenous immune responses in 

patients with sarcoma. As tumor immunotherapy has become more antigen directed 

and molecularly targeted, sufficient quantities and accurately classified tissues for 

study from homogenous histologic groups must be available so that valid conclusions 

regarding antigen expression may be generated. Also necessary are viably 

cryopreserved cells from each of the sarcoma histologies to accurately determine 

whether molecular and immunohistochemical evidence for tumor antigen expression 

is accompanied by major histocompatibility complex-mediated presentation of tumor 

antigens. In addition, researchers must have access to immune effector cells from the 

patients from whom the tumors are derived in order to study patient responses. 

Peripheral blood mononuclear cells (PBMCs) are necessary in order to determine 

whether antigen expression in sarcomas leads to immune priming and whether 

immune responses directed toward a particular antigen can result in the killing of the 

sarcoma cell itself. HLA typing of patient samples and sarcoma cell lines is also 

required so that HLA restriction of candidate tumor antigens can be determined. 

A third major barrier to research in the field of immunology of sarcomas is the 

relative paucity of studies in human immunology compared to murine immunology. A 

Appendix B: Science-Centric Breakout Group Reports B-10 
Report of the Sarcoma Progress Review Group (PRG) 

plethora of information exists regarding immune responses toward murine sarcomas; 

however, this has not been translated to the biology, immunology, or clinical 

management of human sarcoma. To address this problem, general studies in human 

immunology and human tumor immunology need to be encouraged through funding 

mechanisms. Incentives for studies of human immunology and the availability of 

appropriate reagents for study will naturally lead more investigators to study the 

immunobiology of human sarcomas. 

Opportunities for Progress 

Sarcomas provide a major opportunity for progress in immunotherapy because the 

natural history of the disease results in a clinical scenario that is amenable to immune 

based therapy: 

• The primary treatment for sarcomas is surgery, which provides an ample source 

of antigen. The ability to viably cryopreserve sarcoma tissues can potentially 

provide the research community with substantial amounts of tissue for study and 

a ready source for whole-cell approaches to tumor vaccination. Currently, 

several “patient-specific” immunotherapy approaches have progressed to phase 

III trials after good results in phase II trials that provided evidence that such 

approaches using patient-derived tissue as an immunogen are potentially 

clinically applicable. 

• Chemotherapy is not effective for most histologies; therefore, patients with 

recurrent or progressive disease have not been heavily pretreated with cytotoxic 

agents and are therefore likely to be relatively immune competent compared to 

patients with other high-risk cancers. 

• Incurable sarcomas are often readily reduced to a state of minimal residual 

disease by surgery alone. 

• The lack of progress over at least two decades provides good historical controls 

for pilot studies. Optimization of such pilot studies in surgically resected highrisk patients could be guided by surrogate endpoints, such as the development of 

tumor-specific immune responses. 

• The lack of good alternative treatments means that very little competition exists 

for innovative therapies for high-risk sarcomas. Because tumor vaccines in 

general are safe, high-risk patients with fully resected tumors may be reasonable 

candidates for immune-based therapy trials. For many of these patients, 

although their risk for recurrence approaches 100 percent, no reasonable 

alternative therapies are available. 

Appendix B: Science-Centric Breakout Group Reports B-11 
Report of the Sarcoma Progress Review Group (PRG) 

PRIORITY 1. 

immunobiology of human sarcomas. 

cryopreserved tumor cells and PBMC and (where possible) aphaeresis 

Develop the centrally available core reagents necessary to begin addressing the 

In addition to standard tissue banks and 

cell lines representing the wide variety of sarcoma histologies, viably 

specimens from patients with sarcoma should be made available. 

Rationale 

Standard tissue banks can only allow a very superficial screen for potential tumor 

antigens. Viably cryopreserved cells with matched lymphocytes are required to 

undertake immunologic studies. 

Issues of Importance 

Many tumor antigens have now been identified in other tumors, but the expression 

and immunogenicity of these molecules in sarcomas are largely unknown. Both (1) 

differentiation antigens and (2) mutated or amplified self-antigens that contribute to 

the neoplastic process are antigenic in other tumor models. Current understanding 

indicates that sarcomas represent an opportunity for rapid scientific progress based on 

the following: 

• Differentiation antigens are likely to be highly expressed in sarcomas comprised 

of primitive mesenchymal tissues. 

• Fusion proteins of sarcoma and their downstream transcriptional targets appear 

to be attractive candidates because of their critical role in the induction and 

maintenance of the relatively nonmutable transformed state. Such mutated or 

overexpressed transcription factors have been shown to be immunogenic in other 

model systems. 

Investing in the development of procedures to generate viably cryopreserved 

specimens will advance sarcoma research beyond immunobiology alone. Procedures 

for preservation developed under Good Clinical Practice conditions can serve as the 

basis for subsequent Good Manufacturing Procedures for immune-based therapies 

using whole cell vaccines. In addition, the development of such standard operating 

procedures will also facilitate the pursuit of other preclinical studies in sarcoma that 

rely heavily on the availability of xenograft models. 

PRIORITY 2. 

Fund sarcoma-specific immunobiology studies so that established 

immunologists will have an incentive to apply their expertise to sarcomas. 

Rationale 

Immunotherapy is device independent. The investigators and technology are already 

available and the infrastructure exists within established immunology laboratories to 

rapidly identify whether antigens present in other human tumors are expressed and 

immunogenic in human sarcomas. 

Applying state-of-the-art immunology reagents and expertise to the field of sarcoma 

biology can readily identify new immune-based therapies for sarcoma. Advances in 

knowledge have the potential for rapid translation to the clinic. Such studies are most 

likely to be successful if carried out by established human tumor immunologists; 

Appendix B: Science-Centric Breakout Group Reports B-12 
Report of the Sarcoma Progress Review Group (PRG) 

unfortunately, these investigators are currently focused on other diseases. The success 

of this recommendation requires that sarcoma-specific mechanisms encourage 

investigators to study sarcoma immunobiology. 

Issues of Importance 

Dramatic progress has been made in identifying and measuring immune responses to 

target antigens in the last decade. Immunologists have a variety of reagents available 

to identify, quantify, and characterize immune responses to specific antigens. For 

instance, tetramers for the accurate identification and quantification of antigenspecific T cells are now available for essentially any molecularly identified antigen. 

After identification, the T cells can be characterized for function and phenotype and 

sorted for subsequent expansion for therapeutic studies. Similarly, peptide-based 

assays, such as enzyme-linked immunospot, intracellular cytokine staining, and bead 

arrays, are readily available to quantify extremely low-level immune responses that 

are characteristic of endogenous responses. Older technologies could not measure 

these marginal responses. 

A plethora of human tumor antigens have now been defined. Access to standard 

tissue banks for use in microarray and immunohistochemical analyses will quickly 

identify the extent of sarcoma-specific antigen expression from antigens defined in 

other human tumors. Immunogenicity analyses of the same antigens in other human 

tumors and computer-based algorithms will allow prediction of epitopes that bind to 

unique HLA alleles. 

Established investigators in human tumor immunology can readily apply state-of-theart approaches to measure immune responses using peptides identified through tissue 

bank screening. Using PBMC from patients with sarcomas is relatively 

straightforward to determine whether endogenous immune responses exist toward 

these sarcoma-associated antigens. With the availability of viable cryopreserved 

tumor cells will come the validation of tumor antigen expression by demonstrating 

activation or lysis by peptide-specific T cells in response to sarcoma cells. 

In summary, applying state-of-the-art immunology reagents and expertise to the field 

of sarcoma biology can readily identify new immune-based therapies for sarcoma. 

Advances in knowledge have the potential for rapid translation to the clinic. Such 

studies are most likely to be successful if carried out by established human tumor 

immunologists; unfortunately, these investigators are currently focused on other 

diseases. The success of this recommendation requires that sarcoma-specific 

mechanisms encourage investigators to study sarcoma immunobiology. 

PRIORITY 3. 

sarcomas for a long-term investment in this field. 

Provide incentives to young investigators to study the immunobiology of 

Rationale 

The time is ripe to exploit advances in developmental biology, molecular pathways, 

and immunobiology to translational progress in sarcomas. The rate-limiting step for 

capturing these opportunities is the lack of investigators; therefore, young 

investigators should be targeted. Addressing basic immunobiologic principles in 

sarcomas, such as the capacity for immune responses to occur in bone versus lung, 

could lead to important insights for immunotherapy in general. 

Appendix B: Science-Centric Breakout Group Reports B-13 
Report of the Sarcoma Progress Review Group (PRG) 

Issues of Importance 

• Modest NCI-based funding initiatives, such as K08 or K22 mechanisms, would 

foster the interest of young investigators. Supplements to existing funding 

mechanisms for sarcoma would also provide incentives. 

• Exploring public–private partnerships (as exemplified by the Modell Foundation 

and the Leukemia Society) for funding young investigators could lead to 

significant increases in sarcoma researchers as well as funding. Partnering with 

the NCI would ensure a stringent peer-review process that would be valuable. 

The NCI would need to commit to working with private/philanthropic sources 

specifically interested in sarcomas. 

CONCLUSION 

The last decade has witnessed dramatic progress in understanding the immunobiology 

of and developing effective immunotherapies for cancer. There is every reason to 

believe that these advances in immune-based therapy for cancer in general could 

translate into effective immune-based therapies for sarcoma, since murine models of 

sarcoma have provided clear evidence that these are immune-responsive tumors. The 

cells of origin in sarcomas are likely to express candidate tumor antigens, and core 

technologies are now available to apply powerful immunologic reagents, such as 

tetramers and immunogenic peptides, for the rapid identification and characterization 

of tumor antigens in human sarcomas. Thus, relatively low-cost investments in young 

investigators, sarcoma-specific research incentives to current immunologists, and an 

optimized arsenal of reagents are highly likely to produce substantial, rapid, and longterm gains that will lead directly to clinical trials of novel, specific, nontoxic therapies 

for these many and varied tumors. 

Appendix B: Science-Centric Breakout Group Reports B-14 
Report of the Sarcoma Progress Review Group (PRG) 

BETTER ACCESS TO ANNOTATED TISSUE 

Co-Chairs: 

Norman Scherzer Matt van de Rijn 

Participants: 

Iqbal Ahmed Lora Kutkat Brian Rubin 

Jerry W. Call Rachel Nosowsky Julie A. Schneider 

Gilles J. Frydman 

INTRODUCTION 

With the recent increase in high-throughput technology, such as genome-wide 

expression profiling, comparative genomic hybridization, and the more detailed 

assessment of various molecular pathways within malignant cells, the need for access 

to tumor samples has increased. While obtaining sufficient specimens for most 

human neoplasms is difficult, this is especially difficult in the field of soft-tissue 

tumors. 

Sarcomas are relatively rare neoplasms and individual surgical centers do not obtain 

sufficient materials for studies. Additionally, a wide variety (over 80) of different 

diagnoses exist in the field of soft-tissue tumors, and as a result, the already small 

number of soft-tissue tumors includes a multitude of subgroups with even smaller 

numbers of samples to examine per subgroup. 

Several web-based patient groups have expressed an interest or have been 

instrumental in collecting these rare tissues, but a coordinated, centralized collection 

of samples—or at least a consensus approach to this issue—is desperately needed. 

Unfortunately, the many barriers to a solution of the problem of tissue access include 

the following: 

• Scattered and unfocused funding for sarcoma research and related tissue banking. 

• Inadequate annotation and nonuniform diagnosis leading to inadequate treatment 

and research interpretation. 

• Distribution and prioritization of the collected annotated tissue (legal issues 

dictate who actually has access to the tissues and how they may or may not be 

distributed). 

• Tension between Health Insurance Portability and Accountability Act (HIPAA) 

and institutional review board (IRB) regulations, and patient groups and 

researchers. 

• Patients’ tension over their desire for access to research data. 

The members of this breakout group agreed unanimously that the following priorities 

should be implemented to ensure access to these very important annotated tissues. 

Appendix B: Science-Centric Breakout Group Reports B-15 
Report of the Sarcoma Progress Review Group (PRG) 

PRIORITY 1. 

Establish an NCI-dedicated group for sarcoma. 

Rationale 

A dedicated group for sarcoma study will help focus the efforts on research and 

treatment, and facilitate the creation of the greatly needed centralized annotated 

sarcoma tissue bank. 

Issues of Importance 

• Sarcoma research cannot compete with the large number of more common tumor 

groups. Funding resources are currently fragmented among a multitude of 

institutions whose efforts are largely uncoordinated, leading to inadequate 

treatment and research interpretation. Integrating with large-scale tissue banking 

efforts is not likely to be a solution, as these efforts are not designed to address 

rare diseases like sarcomas. 

• A focused effort would facilitate collaborations among patients, their physicians, 

the medical community, and industry. 

• Centers of sarcoma expertise should comply with established criteria to include 

basic qualifications and ground rules for participation. Each group wishing to 

become a center of sarcoma expertise would have to satisfy certain criteria (such 

as seeing a minimum number of sarcoma patients and having adequate clinical 

support) and agree to certain ground rules pertaining to tissue and data collection 

and storage. As one ground rule, specimens collected at these centers would 

need to be cataloged according to set standards and be sent to the central bank 

with the appropriate clinical information and associated histology, as needed by 

the researchers. 

PRIORITY 2. 

bank. 

Provide for the organization of a single, centralized, sarcoma-focused tissue 

Rationale 

A centralized sarcoma-focused tissue bank would facilitate quality control and 

distribution of (accurately identified) specimens and provide access to frozen, 

paraffin-embedded, and viable material and serum 

Issues of Importance 

• Start with centers of sarcoma expertise, then move into the community. In 

theory, a center of sarcoma expertise would have access to a wider range of 

tumors and therefore be more likely to correctly diagnose a particular tumor. As 

the program grew, community centers would become a resource for the tumors 

they remove. Ideally, all centers would collect and send as much tissue as 

possible (i.e., more than one sample from each specimen) possibly reserving 

some for their own purposes. 

• Develop NCI/NIH-sanctioned protocols for tissue collection and distribution that 

address scientific and regulatory issues (HIPAA, Clinical Laboratory 

Improvements Amendments, IRB, etc.). From a privacy standpoint, HIPAA 

protects the data associated with the collected tissue. A vast number of IRBs 

Appendix B: Science-Centric Breakout Group Reports B-16 
Report of the Sarcoma Progress Review Group (PRG) 

(and medical professionals) are not comfortable with the provisions of HIPAA, 

which are often misunderstood. A statement by NCI or other organizations, such 

as the American Society of Clinical Oncologists (ASCO), to elucidate and solve 

the regulatory hurdles would greatly aid in the collection of tissues. Such a 

protocol would attempt to standardize collection, making it as simple and 

affordable as possible. 

• Design a protocol to standardize the collection and storage processes, which 

would greatly improve the viability of the collected tumors, and help IRBs 

become more comfortable with the protection of patients. 

• Map out a distribution system through a multi-sector committee. The 

competition for available samples could be fierce. A fair and balanced 

distribution of samples, not restricted to centers of sarcoma expertise, would be 

aided by a committee that includes patients, researchers, and representatives of 

industry and government. 

• Use pre-existing large-scale tissue analysis and genomic and proteomic facilities. 

Existing national tissue banks may not have the focus necessary to accommodate 

the collection of these very rare tumors. A pilot study should be conducted to 

see how many samples are currently available for research through existing 

systems. The pediatric Cooperative Human Tissue Network (CHTN) could 

serve as a model for the development of a centralized sarcoma tissue bank. 

• Address ownership issues, including ownership of data and related 

developments. Again, the provisions of HIPAA are largely misunderstood and 

need to be explored. The concerns of some patients regarding industry 

involvement (for-profit motivations versus novel therapies) need to be addressed. 

PRIORITY 3. 

Maintain and update clinical databases with outcome (survival/relapse) results. 

Rationale 

The ability to correlate outcomes of life, death, and recurrence with biological 

markers and treatment is critical. 

Issues of Importance 

• HIPAA and other regulatory issues are barriers to access, but these barriers are 

not insurmountable. A tension exists between HIPAA and the IRB regulations 

intended to protect patient rights and privacy, as well as patient groups seeking 

to contribute their tissues and researchers interested in studying these tissues. A 

centralized IRB approach would help quell concerns about the misunderstood 

HIPAA regulations and other patient privacy issues. 

• A separate tension occurs between patients who want access to research results 

and physicians whose studies are not set up to handle patient inquiries. 

• Researchers may lack adequate systems for quality control, such as those in 

clinical laboratories. 

• Data collection, standardization, and quality still require a resolution. The 

current bone marrow registry is a good model. 

• Information technology infrastructure and other support are needed. 

• Follow-up can be extremely poor and should be ongoing. 

Appendix B: Science-Centric Breakout Group Reports B-17 
Report of the Sarcoma Progress Review Group (PRG) 

CONCLUSION 

The existence of an NCI-sanctioned group dedicated to sarcoma research and 

treatment, together with a centralized tissue bank collecting samples that are annotated 

with adequate clinical follow-up would promote progress in this field enormously. 

However, the current HIPAA regulations continue to present major barriers that must 

be overcome. 

Appendix B: Science-Centric Breakout Group Reports B-18 
Report of the Sarcoma Progress Review Group (PRG) 

BETTER MODELS AND PRECLINICAL TESTING 

Co-Chairs: 

Glenn Merlino Poul H. B. Sorensen 

Participants: 

Jody Cummings Peter J. Houghton Chand Khanna 

Gerald C. Grosveld Mark A. Israel Stephen J. Tapscott 

INTRODUCTION 

Human sarcomas are a histopathologically and clinically diverse group of solid 

tumors, and many of these tumor types affect both children and adults. Although 

sarcomas are relatively rare compared to many epithelial malignancies, they are 

significant causes of morbidity and mortality, as many patients with these cancers are 

not identified until the disease is advanced. Moreover, the rarity of sarcomas has 

made it difficult to conduct large, randomized treatment studies and has made this 

subgroup of solid tumors less attractive as a focus for drug development by 

pharmaceutical companies than more common epithelial malignancies. These are 

among the many compelling reasons for developing better in vitro and in vivo models 

of human sarcomas. 

Models of human sarcomas have a number of key requirements: 

• Models must recapitulate the in vivo disease as closely as possible. 

• The use of models should be reproducible in many laboratories for validation 

purposes, and the models should be relatively easy to work with. 

• Models should be amenable to the testing of potential therapeutic agents either 

alone or in combination. 

• Ideally, models should represent tumor recurrence or metastasis with clinically 

relevant mechanisms of drug resistance. 

Relevant models of sarcomas would permit experimental assessment of hypotheses 

derived from human clinical and epidemiological data, as well as the opportunity for 

preclinical testing that can accurately predict human clinical response to novel agents 

for these diseases. In particular, models will provide a means for investigators to 

develop and test new molecularly targeted approaches to treat sarcomas. 

Unfortunately, very few models of human sarcomas have been successfully designed 

for either biological or therapeutic investigations. 

Appendix B: Science-Centric Breakout Group Reports B-19 
Report of the Sarcoma Progress Review Group (PRG) 

PRIORITY 1. 

sarcoma models. 

Establish a mechanism to create a repository of viable tissue for developing 

Rationale 

Most of the current preclinical models of human sarcomas are inadequate for biology 

and therapy studies. While many human sarcoma cell lines are available for research 

purposes, a large proportion of these cell lines represent only a small subset of 

sarcomas, predominantly sarcomas that are more common in children. Additionally, 

the relevance of such cell lines to human tumors in vivo has been questioned, 

especially after multiple passages. Xenograft models of sarcomas, including 

orthotopic transplantation, have been used quite extensively in sarcoma research and 

have addressed some of these concerns. However, these systems still need to be 

rigorously validated for their relevance to human sarcomas, especially since most 

models use human sarcoma cell lines injected into murine hosts. 

Issues of Importance 

• A funding mechanism (e.g., request for applications [RFA]) should be initiated 

that will support research to generate in vitro and in vivo models of sarcomas for 

which very few or no models exist and to annotate and validate those models that 

currently exist. The development of new models will require a concerted effort 

to collect, annotate, and maintain viable tumor tissues that can be provided to 

researchers who are actively pursuing these aims. 

• Existing and newly developed models need to be annotated. Existing models 

should be better characterized with respect to the molecular and genetic 

definition of the tumor cells and assessment of the cells’ metastatic potential. 

Annotation of viable human tissues will require standardizing personal data (e.g., 

clinical data) collection, in addition to defining the same global biological 

characteristics as the existing models. 

• Cell lines will be optimized by expanding to three-dimensional culture systems 

grown under physiological conditions (e.g., varying oxygen and nutrient 

content). Three-dimensional culture systems will enable cell cultures to be a 

closer representation of in vivo conditions. Growing cells on MatrigelTM or 

similar supports also enables studies to test the metastatic potential of cells, 

perform confocal microscopy, and examine the influence of additional cell types 

(e.g., fibroblasts) in the tumor microenvironment. 

• Tissue collection, storage, and annotation should not be exclusive to human 

tissue but should include collection from other animal species for validation 

purposes. Comparative genetic expression or proteomic studies between human 

and animal models (e.g., spontaneous sarcomas in canines) would further define 

the similarities and differences between these model systems to better validate 

the use of specific models for specific research purposes. 

Appendix B: Science-Centric Breakout Group Reports B-20 
Report of the Sarcoma Progress Review Group (PRG) 

PRIORITY 2. 

Establish an integrated preclinical testing program for human sarcomas. 

Rationale 

Currently, no integrated mechanism exists to test sarcomas for therapeutic response to 

drugs. 

Issues of Importance 

• An RFA should be initiated that supplements an existing program in preclinical 

drug screening to support the inclusion of adult sarcomas, or a screening 

program could be developed as a new initiative. 

• A proposal for a program already exists for preclinical drug screening in 

pediatric cancer (Pediatric Preclinical Testing Program). This program may be 

an intermediate step between in vitro studies and large animal studies and has 

been organized to examine drugs that have entered clinical trials or are likely 

candidates for clinical trials. The program uses a panel of distinct, diseasespecific in vitro and in vivo models to examine the potential for agents for which 

maximally tolerated doses have been defined. Examining a sarcoma model 

panel will add a layer of analysis to confirm the potential for success of a 

particular intervention before advancing to longer term, more expensive 

preclinical and clinical trials. The program is currently designed to study 

common childhood tumors; however, the establishment of adult sarcoma tissue 

models will enable this program to expand into other sarcomas. 

• Models should include, but not be limited to, cell lines, xenografts, orthotopic 

transplants, genetically engineered mice, and large animal models. Currently, 

the program, as developed for childhood cancers, relies mostly on xenograft 

models and some transgenic models. However, by supporting an infrastructure 

to develop novel cell models and animal models, these panels can be expanded. 

• The current preclinical testing program itself is a prototype that needs to be 

critically examined and optimized. In addition to providing data about selective 

drugs, the program needs to be tested using panels of models for different 

diseases. By expanding the preclinical testing program to include adult 

sarcomas, this program can continue to be optimized while simultaneously 

providing much-needed preclinical data for potential agents to target sarcomas. 

In addition, for more rare diseases like sarcomas, the more preliminary testing to 

validate a drug’s potential will improve the likelihood that partnerships will be 

developed with biopharmaceutical companies to advance the drug. 

PRIORITY 3. 

Focus on developing better models for metastatic sarcomas. 

Rationale 

Metastatic disease is the strongest prognostic factor for most human sarcomas. Most 

patients who die from sarcomas die from metastatic disease. Research in metastasis is 

mired by the dearth of models specifically addressing sarcoma metastasis. Fusion 

proteins are commonly associated with different sarcomas, and observed roles of 

fusion proteins in sarcomagenesis will offer a unique model in which to study 

mechanisms of tumor progression. 

Appendix B: Science-Centric Breakout Group Reports B-21 
Report of the Sarcoma Progress Review Group (PRG) 

Issues of Importance 

• Metastatic sarcoma cell lines and animal models need to be identified and/or 

established for subsequent biologic and preclinical studies. The availability of 

these reagents will permit detailed analysis of molecular pathways causally 

associated with metastasis, as well as provide a preclinical tool for assessment of 

the efficacy of novel therapeutic and preventive approaches. Metastatic cell 

lines should be derived from a variety of sources, including human, rodent, and 

large animal sarcoma. The identification and experimental analysis of metastatic 

cell lines would be facilitated through development of in vitro assays that are 

predictive of metastatic behavior in vivo. One example would be the use of 

invasion assays and other measures potentially related to metastatic capability of 

sarcoma cell lines. Cell lines to be used as metastatic models should be designed 

to incorporate imaging capability (e.g., luciferase, green fluorescent protein, and 

red fluorescent protein) to augment basic research efforts, as well as to expedite 

assessment of the efficacy of new therapeutic agents. 

• Sarcomas should be considered as representing useful models for studying other 

metastatic tumors. At least subtypes of sarcomas are hypothesized to result from 

fewer genetic abnormalities than many carcinomas, particularly translocationassociated sarcomas of childhood. Therefore, recapitulating metastatic disease in 

sarcoma models may be easier and more accurate than for more cytogenetically 

complex carcinoma-derived metastatic tumors. As such, sarcomas should be 

rigorously explored to understand basic metastatic biology. Additionally, 

targeted therapeutics may be better examined preclinically in a less complex 

metastatic tumor. The results of investigating sarcoma metastases can provide a 

foundation that can be applied to other cancers. 

CONCLUSION 

A repository that collects and maintains primary tissues to establish in vitro and in 

vivo model systems will accelerate the biological studies of sarcomas and 

investigations of the therapeutic potential of drugs to treat human sarcomas. Through 

technical expertise, a centralized repository will be able to efficiently process, 

annotate, and maintain viable tissues and, from those tumors, develop both in vitro 

and in vivo models. The existence and support of a well-maintained sarcoma 

repository will enable the broadest community of basic and clinical sarcoma 

researchers to develop an integrated preclinical testing program and conduct 

biological studies that define the molecular characteristics of sarcomas. Such a 

repository will also facilitate the generation and study of in vitro metastatic models 

and the generation and study of better animal models of primary and metastatic 

sarcomas. Novel models will be applied to study not only broad issues of biology and 

therapeutic potential of drugs but also specific diagnostic technologies of imaging and 

surrogate (intermediate) biomarker identification and validation. As the molecular 

characteristics of sarcomas are better understood and the needs of the preclinical 

testing field are refined for specific sarcomas, this information may influence the 

development of later generation models. 

Appendix B: Science-Centric Breakout Group Reports B-22 
Report of the Sarcoma Progress Review Group (PRG) 

BETTER PREVENTION 

Co-Chairs: 

Sharon E. Plon Louise C. Strong 

Participants: 

Tamara Barnes Alfred Knudson Asad Umar 

Matthew Freedman Mary Ellen Rybak David Viskochil 

Holcombe E. Grier 

INTRODUCTION 

Sarcomas are relatively rare and very heterogeneous and, hence, as a group lack a 

uniform approach and visibility in research and clinical studies. The etiology of 

sarcomas is probably similarly heterogeneous, and few precursor lesions are known. 

In general, prevention research focuses on primary prevention, identifying etiological 

factors that can be modified (e.g., smoking cessation for lung cancer), or on secondary 

prevention, identifying early or precursor lesions that can be removed or reversed to 

prevent progression to life-threatening cancer (e.g., screening for colon polyps that, if 

removed, reduce colon cancer risk). However, for sarcomas in general, neither clearly 

defined environmental risk factors nor precursor lesions exist. The results of this PRG 

must advance this work for sarcomas. 

The best-defined environmental risk factor for sarcoma is therapeutic radiation for 

both soft-tissue sarcoma and osteosarcoma, with young age at exposure associated 

with increased risk. Thus, one identifiable high-risk group is childhood cancer 

survivors treated with radiation therapy. Newer forms of more targeted radiation 

therapy with less exposure of the surrounding normal tissue reduce this risk. Other 

epidemiologic studies have suggested that some agricultural groups may be at 

increased risk of soft-tissue sarcoma. However, but the relative risk is not large, and 

no specific causal agents have been identified. In addition, increased incidence of 

sarcoma may follow exposure to Agent Orange but, again, the risk is not sufficiently 

high to provide a high-risk group on which to focus prevention research or 

intervention. All of NIH’s currently funded prevention research on sarcoma focuses 

on Kaposi’s sarcoma and human herpes virus 8. 

Additional considerations in prevention include understanding the basic biology of 

tumor development. Sarcomas are pathologically heterogeneous and include tumors 

attributable primarily to mutations in tumor suppressor genes; tumors attributable 

primarily to translocations, giving rise to new fusion oncoproteins; and tumors 

attributable to mutation, giving rise to constitutive activation of an oncogene. Hence, 

no single mechanism of tumor development exists on which to base prevention 

strategies. We suggest that different prevention strategies will be needed for these 

three mechanistic types of sarcoma development. 

Appendix B: Science-Centric Breakout Reports B-23 
Report of the Sarcoma Progress Review Group (PRG) 

A number of rare hereditary syndromes predispose to sarcoma, some to sarcoma in 

general, others to specific types of sarcoma. These are as follows: 

Hereditary Syndrome Sarcomas 

Li Fraumeni syndrome

Hereditary retinoblastoma 

Neurofibromatosis (NF1) 

Rothmund Thompson syndrome

Werner syndrome 

Hereditary multiple exostoses 

Lipomatosis

Paget’s disease 

Familial gastrointestinal stromal tumor 

(GIST) 

General 

General 

Malignant peripheral nerve sheath tumor 

Osteosarcoma 

Soft-tissue sarcomas 

Chondrosarcoma 

Liposarcoma 

Osteosarcoma 

GIST 

It is our judgment that prevention approaches using human studies for heterogeneous 

rare tumor type(s) must focus on very high-risk groups. Currently, for osteosarcoma 

and soft-tissue sarcoma, the only currently identifiable very high-risk groups are 

genetically susceptible individuals and long-term survivors of childhood cancer 

treated with therapeutic radiation. 

In addition, both spontaneous and engineered animal models for sarcoma development 

may provide new information and the ability to carry out preclinical trials relevant to 

prevention of human sarcoma. 

PRIORITY 1. 

Preclinical 

Develop, use, and validate preclinical models that mimic human high-risk genetic 

syndromes predisposing to sarcoma or spontaneous sarcoma, including 

recombinant mouse, dog (spontaneous), rat, cat, and zebrafish. 

models will be used to identify precursor lesions and genetic and environmental 

risk modifiers, and test preventive strategies. 

Rationale 

Animal models can be engineered to develop predictable patterns of sarcoma, 

including specific histologic subtypes attributable to defined molecular mechanisms. 

Given the predictably of the sarcomas, these model systems can be used to identify the 

genetic pathways and precursor lesions. Mouse models offer unique opportunities to 

identify modifiers of high-risk genes by varying the host background or environment. 

These models then provide the opportunity to identify host and environmental factors 

that also reduce risk. Spontaneous models, including dog models, also allow studies of 

specific environmental and genetic modifiers of sarcoma development. 

Issues of Importance 

• Significant resources are available to address this priority. Achievement of the 

priority will include interaction with established consortia, especially the NCIfunded Mouse Models of Cancer Consortia, which has significant infrastructure 

but will need to develop a focus on the issues of sarcoma prevention. 

• The needed focus will include collaboration between investigators of mouse 

models (or other model systems) and human cancer oncologists, prevention 

specialists, and geneticists. This effort requires validation of the mouse models’ 

relevance to human sarcoma, such as demonstrating the causal mutation(s), 

Appendix B: Science-Centric Breakout Reports B-24 
Report of the Sarcoma Progress Review Group (PRG) 

relevant histologic and molecular analysis, and biologic behavior. This model 

system may then be used not only to build models of tumor progression, but also 

to identify precursor lesions, demonstrate the relevant biologic imaging 

endpoints, and identify the relevant molecular changes that occur in cancer 

development that may be targets for intervention. These mouse (or other) 

validated models would be an ideal setting for initial “clinical prevention trials.” 

Model systems can be developed that include models for the sarcomas 

attributable to tumor-suppressor gene mutations, chromosome translocations that 

produce new fusion proteins, and mutations in oncogenes leading to constitutive 

activation. Common and distinct pathways may be identified for the various 

mechanisms through which sarcomas develop and for which distinct prevention 

strategies may be needed. 

• At present, mouse models seem to offer the greatest potential; however, the 

initiative would support development of other sarcoma-related model systems as 

well, particularly in organisms such as zebrafish. 

• In some instances, dogs may serve as a preferred model because some species 

are prone to spontaneous osteosarcomas. Veterinarians have developed cancer 

prevention efforts in dogs but these may not be sarcoma specific. Some species 

(wolfhounds) have a very high risk and in some lines, the tumor susceptibility 

appears to segregate as a recessive condition. Other than rapid growth in long 

bones, no sarcoma risk factors have been identified in dogs. The incidence of 

sarcoma in most dogs may not be high enough to enable them to serve as model 

systems, but high-risk species may serve as “sentinels” for response to exposure 

to suspected environmental agents. Resources may include the NCI 

Comparative Oncology Program and the Dog Genome Project at the National 

Human Genome Research Institute. 

PRIORITY 2. 

i

childhood. 

Identify a cohort of individuals at high risk for sarcoma for longitudinal 

prevention studies to identify precursor lesions and biomarkers associated with 

risk, test new imaging or early detection techniques, identify risk modifiers, and, 

ultimately, test preventive agents found through the preclinical studies. 

Identifiable high-risk indiv duals include those with hereditary cancer 

susceptibility syndromes and those with prior radiation therapy exposure in 

Rationale 

High-risk groups provide the greatest opportunity in humans to understand the 

molecular pathways that lead to sarcomas and identify the genetic mechanisms. They 

also provide the greatest opportunity to develop prevention studies, given their 

increased risk and the frequent identification of these individuals’ years before they 

are at greatest risk for developing sarcomas. Their increased risk significantly affects 

the risk/benefit analysis when designing human prevention trials. Given that the 

hereditary syndromes are rare, a variety of groups must be contacted to identify 

sufficient numbers of individuals willing to enroll in sarcoma studies. These groups 

may include the Cancer Genetics Network, NIH Office of Rare Diseases, National 

Organization of Rare Diseases (NORD), Childhood Cancer Survivor Study (CCSS), 

and Sarcoma Foundation of America. 

Appendix B: Science-Centric Breakout Reports B-25 
Report of the Sarcoma Progress Review Group (PRG) 

This cohort is a high-risk group for sarcoma that will allow the testing of hypotheses 

related to various genetic and environment risk modifiers, early or evolving 

biomarkers, effective diagnostic imaging, and chemoprevention. 

Issues of Importance 

• This defined cohort provides the best opportunity to develop strategies for 

prevention in humans. The findings from the mouse or other model systems 

described in Priority 1 should directly interact with and affect the study of the 

human hereditary cancer susceptibility syndromes. 

• A bank with biospecimens, including longitudinal plasma and serum samples, 

DNAs, and tissue (fibroblasts, other) for ongoing and future studies to identify 

changes prior to tumor development or to precursor lesions should be established 

from these high-risk patients. 

• This priority requires the collection of longitudinal data and samples to allow 

testing of new hypotheses. As in the mouse models system described earlier, the 

study of the high-risk tissue for the general and specific sarcomas may reveal 

common and distinct pathways for the various sarcomas. 

• Available resources include an international NF1 database with voluntary 

participation. The CCSS includes some 15,000 five-year survivors of childhood 

cancer treated between 1970 and 1986, who are well characterized by radiation 

and chemotherapy and (to some extent) family history of cancer. These 

individuals have been followed longitudinally for late effects of cancer, 

including additional malignant neoplasms. This group could be targeted for 

collection of samples for proteomics, markers of risk, imaging studies, etc. 

Hereditary retinoblastoma cohorts have been developed for the study of 

additional malignant neoplasms that perhaps could be recruited for these studies. 

A number of individual investigators are studying some of the hereditary cancer 

syndromes. In addition, recruitment could proceed through the patient advocacy 

groups, including the Sarcoma Foundation of America, Life Raft Group, and 

NORD. 

• Identification of the genetic high-risk groups may provide additional information 

on risk factors for sarcoma in the general population. To date, studies of genetic 

high-risk groups suggest that they may be at increased risk following exposure to 

agents that cause sarcoma in the general population (e.g., therapeutic radiation). 

Hence, they may be able to provide evidence for environmental risk factors. For 

example, the risk of sarcoma could be determined in genetic high-risk groups 

residing in agricultural areas. 

• The hereditary syndromes cited are experienced primarily by individuals at high 

risk of sarcoma attributable to mutations in tumor suppressor genes (not 

including familial GIST) and hence may not be relevant to prevention strategies 

for the translocation-based sarcomas described in Priority 3. 

Appendix B: Science-Centric Breakout Reports B-26 
Report of the Sarcoma Progress Review Group (PRG) 

PRIORITY 3. 

tissue bank registry. 

Include epidemiologic, ethnic, and family history of cancer data in the sarcoma 

Rationale 

This registry could facilitate a better understanding of etiology at the molecular, 

cellular, and epidemiologic level to develop prevention strategies. Sarcomas of 

different etiologies may have different molecular signatures, different expression 

profiles, etc. Investigators should consider stratifying tumors by etiologic factors. We 

are further motivated to consider opportunities to understand sarcoma etiology when 

extreme differences in exposure groups or ethnic groups are observed. Specifically, 

highly significant differences in the incidence of Ewing’s sarcoma exist in African 

Americans and others; Ewing’s sarcoma represents one of the tumors attributable to 

chromosome translocations. In the African American population, specific DNA 

sequences might be resistant to the specific Ewing’s translocation. Further, 

epidemiologic studies indicate that agricultural exposure may be associated with 

increased risk of soft-tissue sarcoma, and sarcoma shows an increased incidence in the 

farming belt in the middle of the United States. Research (expression profiling, etc.) 

that classified these tumors by exposure might provide new clues to etiology that 

might lead to the identification of specific carcinogens and, ultimately, to primary 

prevention by reducing the exposure. 

If epidemiology information is not included in the sarcoma registry, these studies will 

be essentially prohibited. 

Issues of Importance 

• An epidemiologic questionnaire and database must be developed to characterize 

the specimens in the tissue bank. Epidemiologic studies in general would be 

facilitated by consistent coding developed to capture sarcomas currently coded to 

site of origin. 

CONCLUSION 

We have outlined a set of priorities to develop the knowledge on etiology and 

mechanisms required for the development of programs in prevention of sarcoma. 

These include collaborating with animal models groups to focus on sarcoma 

prevention, developing a cohort of high-risk individuals based on genetic 

susceptibility or environmental exposure, and characterizing the proposed sarcoma 

tissue bank by genetic and epidemiologic risk factors. These studies, when combined, 

should greatly advance the possibility of sarcoma prevention. 

Appendix B: Science-Centric Breakout Reports B-27 
Report of the Sarcoma Progress Review Group (PRG) 

BETTER DIAGNOSIS AND PROGNOSTICATION 

Co-Chairs: 

Frederic G. Barr Sharon W. Weiss 

Participants: 

Laurence H. Baker Paul S. Meltzer Abraham Sunshine 

Charles D. Blanke Andrew E. Rosenberg Timothy S. Triche 

Howard D. Dorfman 

INTRODUCTION 

Better diagnosis of bone and soft-tissue sarcomas implies both an improvement in the 

traditional morphologic diagnosis as well as development and implementation of 

novel markers to enhance diagnosis and predict behavior. 

Traditionally, the morphologic diagnosis of sarcomas has been problematic. This is 

due to several interrelated factors including the rarity of the disease, limited 

experience of most pathologists, increasingly smaller biopsy specimens (e.g., core 

needle biopsy), and lack of consensus among pathologists themselves concerning both 

the classification and grading of sarcomas. These issues are underscored by the fact 

that a 30 percent error rate is found in the diagnosis of sarcomas referred to clinical 

protocols and approximately 40-70 percent of surgical pathology reports lack 

information critical to patient staging (e.g., size, and grade). 

Although without a doubt immunohistochemistry has improved the accuracy of 

sarcoma diagnosis, it has largely addressed the identification of structural cytoplasmic 

proteins, in an attempt to classify sarcomas more precisely. Few, if any, current 

markers are totally specific for any one tumor type, and there are essentially no 

prognostic or predictive markers used in daily practice. Thus, there is both a need and 

mandate to utilize new technologies to identify diagnostic, prognostic, and predictive 

markers. 

Development of such markers would take advantage of advances in the field of 

molecular genetics and high-throughput technologies. The observations of 

chromosomal translocation, point mutations, and tumor-specific proteins have served 

as the source of “first-generation markers” in sarcomas. Application of these 

molecular assays can impact the diagnosis and management of sarcomas at several 

levels. The consistent presence of unique gene fusions within specific sarcoma types 

provides valuable markers for diagnosis and in some cases the presence of alternative 

gene fusions resulting from variant translocations offers the promise of defining 

subsets with distinct outcomes. Finally, the ability of polymerase chain reactionbased technology to detect rare fusion-positive cells has provided approaches for highsensitivity detection of submicroscopic disease, such as metastatic spread to the bone 

marrow. 

Despite the promise of the “first-generation markers” there remains a large category 

of sarcomas that to date have no diagnostic or prognostic markers (e.g., malignant 

fibrous histiocytoma or undifferentiated pleomorphic sarcomas of adults). Newer 

approaches that take advantage of high-throughput screening methodologies offer the 

best promise of marker identification. 

Appendix B: Science-Centric Breakout Reports B-28 
Report of the Sarcoma Progress Review Group (PRG) 

PRIORITY 1. 

Develop and promote best practice pathology guidelines. It is recommended that

such guidelines be developed by a group of pathology experts working in close 

conjunction with appropriate organizations (e.g., College of American 

Pathologists) to encourage acceptance and dissemination of this information. 

Rationale 

There is a need to establish and/or endorse the following: 

• Clinical and imaging information essential for pathologic interpretation. 

• Minimum diagnostic criteria for certain sarcoma types. 

• Appropriate allocation of tissues for diagnosis, research, and tissue banking. 

• Grading system and its applicability or nonapplicability to needle biopsy

specimens. 

• Definitions of margin status (e.g., positive margin). 

• Criteria for evaluating treatment effects. 

• Algorithmic decision-making process for application of immunohistochemistry. 

A discussion of problems related to immunohistochemical methods may comprise a 

part of these deliberations. 

Issues of Importance 

A critical issue will be to define an “expert” pathologist and appoint an appropriate 

group of such individuals to work constructively and objectively with various 

constituencies. 

Development of standards for application of immunohistochemistry will be 

challenging since it infringes on the practice of large commercial laboratories who 

typically perform numerous immunostains largely for profit. 

PRIORITY 2. 

appropriate subsets of sarcoma cases. 

Studies need to be developed to test the diagnostic, prognostic, and/or 

predictive utility of recognized and novel molecular markers on large numbers of 

Rationale 

Studies of translocation-associated sarcomas have in several tumor categories detected 

one or more variant translocations as well as tumors without detectable translocations. 

Similarly, recent studies of gastrointestinal stromal tumors have provided evidence 

that KIT point mutations in different exons and point mutations in other tyrosine 

kinases (PDGFRA) are associated with different treatment outcomes. These findings 

provide evidence of molecular heterogeneity among cases with histologic 

homogeneity and that this molecular heterogeneity results in the presence of 

significant phenotypic heterogeneity. Therefore, these and other molecular markers 

provide the opportunity to identify unappreciated biological subsets within these 

sarcoma categories. 

Appendix B: Science-Centric Breakout Reports B-29 
Report of the Sarcoma Progress Review Group (PRG) 

In addition, numerous studies of various molecular markers, most notably gene 

fusions in leukemias, have demonstrated the potential of sensitive molecular assays to 

detect these signposts of tumor cells even when the tumor cells are present in only the 

minority within a cellular population. Therefore, these assays provide the potential to 

monitor the presence of tumor cells at distal sites and at various time points during a 

patient’s clinical course. Such analysis will have potential utility as a tool for 

molecular staging at the time of diagnosis, for monitoring response to therapy, and for 

assessing relapse. 

Issues of Importance 

These studies are contingent on the availability of a bank(s) of well-categorized, 

clinically annotated samples. These samples should include tissue from the primary 

tumor, sites of metastasis, and biological fluids. 

Even though retrospectively collected tissue will permit focused studies of specific 

diagnostic issues, in many cases these tissues will not have annotated clinical data 

because of lack of appropriate informed consent necessitating delinking of the patient 

and much of the clinical data. In addition, in many cases, patients will be pooled from 

different sources; thus, the dataset will suffer from a lack of uniform treatment and 

clinical care. It is envisioned that, following institution of appropriate informed 

consent mechanisms, prospective collection of tissue, preferably from a cohort of 

uniformly treated patients, with the accompanying collection of clinical follow-up 

data will provide the optimal data for these studies. 

PRIORITY 3. 

Efforts need to be coordinated to apply high-throughput discovery approaches 

(including expression profiling, array comparative genomic hybridization, 

mutation screening, and proteomics) on selected subsets of sarcomas. 

Rationale 

New markers need to be identified that will enhance diagnostic, prognostic, and 

predictive capabilities. For various sarcoma subsets, analyses will provide data that 

will either confirm the homogeneity of these categories or detect unappreciated 

heterogeneity in these categories. In the case of homogeneous categories, the data 

will provide potential surrogate diagnostic markers that can be tested in subsequent 

directed studies. In the cases of heterogeneous categories, the data will provide 

markers that will enable novel subsets to be distinguished and the properties of these 

subsets to be compared in subsequent studies in which these markers of prognosis can 

be directly tested. Finally, based on the hypothesis that some aspects for the 

capability for eventual metastasis can be predicted from the properties of the primary 

tumor, it is believed that in some categories, markers that are associated with the 

propensity for metastasis may be identified. 

Issues of Importance 

The availability of tissue samples is crucial to the success of these ventures, at the 

levels of both the number of samples of a particular type of sarcoma as well as the 

amount of tissue of each sample. Therefore, judicious choices must be made 

concerning the specific studies for each tissue sample to maximize the benefit of 

limited tissue resources. 

Appendix B: Science-Centric Breakout Reports B-30 
Report of the Sarcoma Progress Review Group (PRG) 

Based on the cost of the high-throughput approaches, consideration must also be made 

concerning the likely utility of each high-throughput approach to maximize the benefit 

of limited financial resources. 

As in the previous priority, tissue collected retrospectively will provide only limited 

utility because of the likely absence of a full set of annotated clinical data. Therefore, 

it is likely that the most fruitful studies will be those that use tissues collected in a 

prospective manner from patients who are appropriately approached with informed 

consent in order to accumulate the full range of clinical follow-up data. 

For several of these approaches, the availability of matched normal tissue from the 

patients will provide valuable controls for the precancerous genomic state of the 

patient. 

CONCLUSION 

Accurate pathologic diagnosis of sarcomas represents the cornerstone for subsequent 

scientific discovery and innovative clinical trials. Efforts to address issues related to 

inconsistent and incomplete reporting of sarcomas should be addressed immediately 

by knowledgeable individuals capable of interfacing with appropriate national and 

international organizations. Despite efforts on development of current markers, there 

remains significant work to definitively establish their role in clinical diagnosis and 

management. New methodologies represent the most promising means to identify 

urgently needed diagnostic, prognostic, and predictive markers. All of these efforts 

are contingent upon the availability of collections of well-annotated and uniformly 

diagnosed tissues. 

Appendix B: Science-Centric Breakout Reports B-31 
Report of the Sarcoma Progress Review Group (PRG) 

BETTER IMAGING 

Co-Chairs: 

Ernest U. Conrad III Janet F. Eary Robert B. Marcus, Jr. 

Participants: 

John S. J. Brooks Elizabeth L. Layne Mary S. Tobin 

Deborah R. Jaffe Lynne S. Steinbach Annick D. Van de Abbeele 

INTRODUCTION 

Sarcoma tumors derived from mesenchymal tissue elements have traditionally been 

imaged using standard radiological techniques such as plain film, computed 

tomography (CT) scanning, and magnetic resonance imaging (MRI). More recently, 

positron emission tomography (PET) scanning has added significant functional 

information in a noninvasive and quantitative manner that correlates with 

histopathologic findings and clinical outcome. These imaging modalities can specify 

the tumor diagnosis based on anatomic and functional imaging information and 

correlation with histopathological data. In some sarcoma subtypes, the anatomic 

image may be pathognomonic for a specific tumor. However, these modalities have 

varying sensitivity to specific clinical information regarding the extent of disease, 

response to chemotherapy/radiotherapy, and diagnosis of recurrence. 

Recently, PET imaging of tumor metabolism (and limited use of more specific 

biological tracers) has been explored and is becoming an important complement to 

conventional anatomic imaging and histopathological techniques in patient diagnosis 

and treatment planning. In limited studies, PET scanning has been shown to be useful 

in determining diagnostic biopsy site, assessing tumor grade, characterizing response 

to neoadjuvant/radiotherapy and site-directed drugs, and predicting patient outcome. 

PET scanning of a variety of tumors is also being investigated by a number of groups 

for use in treatment planning in conjunction with anatomic imaging data in radiation 

oncology. 

Combined imaging modality use has demonstrated significant utility in identifying 

treatment response in experimental therapy protocols. However, sarcoma biological 

and experimental therapy research and clinical care still have not exploited the full 

capabilities of imaging to contribute to improved patient survival. Imaging is 

underused and often not performed properly at the basic science, translational, and 

clinical research levels. Properly designed imaging studies need to be incorporated 

into all levels of research to provide noninvasive, real-time biological data on tumor 

biology, effectiveness of new treatment strategies in animal models, and clinical trial 

design. 

Imaging is often underused and sometimes overused in everyday clinical care due to 

the widespread lack of knowledge of imaging techniques and recommendations for 

imaging sarcoma patients, as well as the lack of recognition by third-party payers that 

patients with sarcoma have the same imaging requirements for their diagnosis, 

treatment planning, and response evaluation as patients with other cancer histologies. 

The information that can be provided by including appropriate imaging techniques in 

prospective studies and clinical care can significantly contribute to answering a wide 

array of questions regarding how to increase the survival of patients with sarcoma. 

Appendix B: Science-Centric Breakout Reports B-32 
Report of the Sarcoma Progress Review Group (PRG) 

Barriers to the widespread use of imaging techniques in basic biology studies, animal 

studies, translational clinical studies, and larger scale clinical trials design include the 

following: 

• Lack of input from imaging experts to study protocols at all levels of 

investigation. 

• Underuse of functional and anatomic imaging techniques in patient diagnosis, 

treatment planning, and treatment response assessment. 

• Lack of hypothesis-driven imaging studies in sarcoma. 

• Lack of insurance reimbursement for functional imaging studies of proven 

clinical utility. 

• Resources needed to achieve the priorities are as follows: 

• Inclusion of imaging experts at all levels of investigation, with a demand for 

hypothesis-driven studies. 

• Provision of adequate funding to include imaging in existing studies. 

• Inclusion of anatomic and functional imaging modalities in prospective studies to 

justify Centers for Medicare and Medicaid Services and third-party 

reimbursement. 

• Opportunities for stand-alone studies on the efficacy of imaging and new 

imaging techniques to determine treatment response and patient outcome. 

PRIORITY 1. 

Reg y sarcoma centers must include the following imaging 

resources: 

• 

• 

• 

• 

• 

• 

• 

Dedicated imaging coordinator 

and a dedicated PET scanner. 

Patient care coordinator. 

Access to clinical outcome data. 

Access to tissue samples and validation studies. 

practices. 

ional multidisciplinar

State-of-the-art hardware, including a high-field MRI (1.0 Tesla or above) 

Data analysis and imaging processing (information technology) capability. 

Ability to access intramural images and receive extramural images for 

interpretation and analysis. 

Regional sarcoma centers should establish imaging guidelines to define best 

Rationale 

Anatomic and functional imaging is a critical component of a high standard of care 

and specialized capability for sarcoma diagnosis, evaluation, treatment, and research. 

Issues of Importance 

• Imaging capabilities must be a component of qualification for designation of a 

regional sarcoma center of expertise. 

Appendix B: Science-Centric Breakout Reports B-33 
Report of the Sarcoma Progress Review Group (PRG) 

PRIORITY 2. 

Imaging 

translation). 

design of the study. 

Provide imaging input into clinical trial design and care planning. 

should be involved in all phases of trials (preclinical; phases I, II, and III; and 

Imaging data analysis should be integrated into the statistical 

Rationale 

Imaging is underused and not always completed properly. Existing imaging 

techniques, including anatomic and functional imaging modalities, can make 

significant contributions to all levels of research. Considerable imaging data are 

acquired but not analyzed in trial results. 

Issues of Importance 

• Study budgets must include funding for imaging and image analyses, as well as 

support for an imaging expert to conduct these studies. 

PRIORITY 3. 

• 

• 

• 

• 

Prospective validated imaging studies. 

y 

planning. 

• 

and effectiveness of therapy. 

appropriate new technology, and supply more funding. 

Identify imaging research issues in sarcoma, including the following: 

Identification of surrogate endpoints using imaging. 

Development of new imaging agents and imaging modalities. 

Incorporation of innovative uses of imaging protocols in radiation therap

Participation in preclinical studies examining the mechanism of response 

Institute collaboration among academia, the pharmaceutical industry, the 

private sector, and NCI to share knowledge, provide advice on the use of 

Rationale 

Imaging data can provide surrogate endpoints that will increase the speed of 

development and significance of current and new therapies. Use of validated imaging 

techniques can also increase the speed of clinical trial outcome analysis. 

Issues of Importance 

• An imaging research agenda for sarcoma is needed that leads to hypothesisdriven prospective studies at all levels. 

• Patients with sarcoma are ideal research imaging subjects, as the majority of their 

tumors are in the extremities and thus easily accessible for early clinical 

evaluation of new imaging technologies. 

Appendix B: Science-Centric Breakout Reports B-34 
Report of the Sarcoma Progress Review Group (PRG) 

CONCLUSION 

The development of regional multidisciplinary sarcoma centers will provide a high 

standard of care and specialized capability for sarcoma diagnosis, evaluation, 

treatment, and research. Inclusion of anatomic and functional imaging in clinical trial 

design is essential to evaluate the role and cost-effectiveness of these techniques as 

surrogate markers of response to therapy and as prognostic markers. Imaging data 

may help speed the development and clinical application of new therapeutic agents 

and determine the effectiveness of current therapeutic protocols. 

Appendix B: Science-Centric Breakout Reports B-35 
Report of the Sarcoma Progress Review Group (PRG) 

Co-Chairs: 

Robert S. Benjamin 

Participants: 

Vivien H.C. Bramwell 

George D. Demetri 

Philip A. Leider 

Paul A. Meyers 

BETTER CLINICAL STUDIES 

Herman D. Suit 

Perry D. Nisen 

Alberto Pappo 

Vernon K. Sondak 

Peter F. Thall 

Katherine Loy Stadler 

Margaret von Mehren 

Jay Wunder 

INTRODUCTION 

The management of patients with sarcomas requires a multidisciplinary team that 

specializes in basic and translational research on sarcomas and the care of patients 

with this group of tumors. The multidisciplinary expertise at the special sarcoma 

centers recommended by the Sarcoma PRG is expected to provide higher success rates 

in diagnosis, surgery, medical/pediatric oncology, and radiation oncology. 

The efficacy of surgery and radiation therapy has strong potential for improvement, 

resulting in higher likelihood of local tumor control and reduced frequency and 

severity of late treatment-associated morbidity, which remains a serious problem for 

sarcomas at many anatomic sites and for certain sarcoma types. Even though local 

control can be achieved, the late sequelae often constitute serious problems for 

patients and their physicians. 

Despite many important advances, the majority of deaths in patients with sarcoma is 

due to metastatic disease because currently available chemotherapeutic and other 

systemic agents are not uniformly successful in eradicating microscopic or 

macroscopic metastatic disease. Chemotherapeutic studies have been limited by the 

small numbers of patients with particular sarcoma subtypes, the lack of widely 

accepted diagnostic criteria for sarcomas, and the small number of patients seen in 

centers other than those specializing in sarcomas. These factors severely lessen the 

experience with sarcomas of the oncologists at most institutions. 

The current U.S. adult cooperative groups have been very effective at conducting 

studies in common tumors, but have not had similar success for sarcomas. This may 

be due to the following: 

• The fact that sarcomas make up a small portion of all cancers treated by these 

groups and, hence, are not given sufficiently high priority for clinical study. 

• The lack of sufficient expertise and/or interest in these tumors among group 

members. 

• The fact that sarcomas have not been given high priority by the NCI Cancer 

Therapy Evaluation Program.

The Intergroup mechanism is unlikely to provide greater success because it shares the 

bottlenecks and problems experienced by the cooperative groups that are part of it. 

Because all soft-tissue sarcomas are typically lumped together in chemotherapy trials, 

most studies have failed to identify the drugs or combinations of drugs that are active 

in particular sarcoma subtypes. For example, myxoid liposarcomas are highly 

Appendix B: Science-Centric Breakout Reports B-36 
Report of the Sarcoma Progress Review Group (PRG) 

responsive to doxorubicin and ifosfamide, while gastrointestinal stromal tumors 

(GISTs) have been found to be unresponsive. The high prevalence of GIST in 

previous metastatic sarcoma trials has heretofore diluted the overall effects of the 

regimens tried. The best regimen for synovial sarcoma may not be the best regimen 

for leiomyosarcoma, and the best regimen for angiosarcoma may be entirely different. 

The best currently available regimens for Ewing’s sarcoma are different from the best 

regimens for osteosarcoma, and these tumors are never lumped together in studies. 

Certainly, the best regimen for GIST is different from those for other sarcomas. 

For effective studies to be mounted in specific sarcomas, specific diagnoses are 

required, and these can be made reliably only by expert sarcoma pathologists. 

Consequently, patients must be diagnosed at centers with sufficient expertise in the 

pathology of these rare tumors. Alternatively, a few referral centers should be 

established for the smaller centers, and pathologists at referring hospitals must be 

willing to share sufficient material for diagnosis and, hopefully, additional studies. 

Specifically, this means that physicians at smaller centers need to submit blocks or 

multiple unstained slides. 

The diverse group of diseases known as “soft-tissue sarcomas” includes several 

subtypes that may be optimal for approaches of targeted therapy because they have 

specific translocations. To study these tumors effectively, cytogenetic studies or, 

preferably, molecular genetic studies must be performed to ensure correct target 

identification. 

To study these diseases in scientifically reliable clinical trials, patients must be 

brought to the experts across North America for national trials. Trials should also be 

performed internationally to identify the best therapies for specific sarcomas and then 

strategies must be devised to test the integration of these therapies into 

multidisciplinary therapy. 

Standard clinical trial designs requiring large numbers of patients, such as 

conventional phase III trials, are not well suited to dealing with a rare disease having 

multiple subtypes. New strategies must therefore be devised, and reliable 

intermediate therapeutic outcomes must be developed for assessing the activity of new 

treatments. Imaging has come a long way since current response criteria were 

developed and, ideally, should provide such outcomes. Functional imaging adds a 

new dimension, but due to the small numbers of patients, the database is inadequate 

for Medicare reimbursement for positron emission tomography. 

At present, an international multidisciplinary forum for sarcomas exists but is not 

funded as a clinical trials organization. Interestingly, European investigators are 

organized to conduct sarcoma studies; cooperative groups exist in Scandinavia, Italy, 

Spain, and France that are specifically focused on sarcomas. The European 

Organization for Research and Treatment of Cancer (EORTC) has a specific and very 

strong soft-tissue and bone group, and members of this group are the only ones who 

perform EORTC studies of sarcomas. Both North American and European 

investigators would like to see a group coordinating multicenter North American or, 

better still, international trials. However, the obstacles for European participation in 

U.S. trials, especially those related to ethical issues, need to be resolved to have true, 

international collaboration. 

In the United States, a small group of investigators has come together to form a 

consortium that includes some of the major sarcoma centers in the country. Other 

centers with an interest in sarcomas, including European investigators, would like to 

Appendix B: Science-Centric Breakout Reports B-37 
Report of the Sarcoma Progress Review Group (PRG) 

participate in studies if an international sarcoma trial consortium with adequate 

funding were developed. The advantages of such a strategy would be multiple: 

• Since only investigators with a major interest in sarcomas would participate in 

the consortium, internal competition with studies of more common tumors would 

be prevented and studies of high priority to investigators in the field could be 

conducted. 

• Exceptionally rare tumors, such as alveolar soft part sarcoma, that could never be 

studied at a single institution could be studied with international cooperation. If 

North American investigators joined forces with European investigators, the 

number of patients available for study would be doubled. 

• Only investigators interested in studying sarcoma would participate in an 

international sarcoma trial consortium. This would ensure a high level of 

expertise in sarcoma management and a focus on sarcoma biology that does not 

exist in the current adult cooperative groups. New trial designs addressing 

accrual of small numbers of patients could be used. Multidisciplinary studies 

could be performed because the membership would be multidisciplinary. Since 

the consortium would offer a forum for basic scientists as well as clinicians, 

translational studies would be encouraged. 

PRIORITY 1. 

Form a sarcoma-specific group to organize clinical trials that will be integrated 

into a multidisciplinary society focused on sarcomas that will conduct 

diagnostic, therapeutic, basic, and translational research. 

• Dissociate from existing adult cooperative groups. 

• Prioritize and facilitate translation of new approaches. 

• Establish representation at FDA and NCI. 

Rationale 

Previous cooperative group mechanisms have worked well for common tumors but 

have not served the sarcoma community effectively. 

Issues of Importance 

• Facilitate rapid recruitment, efficient trial conduct, and rapid translation of 

innovative therapies. 

• Concentrate patients into a single clinical trial group focused on sarcomas. 

• Bring clinicians of different disciplines and basic scientists into a single forum to 

facilitate translational research. 

• Provide a mechanism for international participation in collaborative clinical 

trials. 

Appendix B: Science-Centric Breakout Reports B-38 
Report of the Sarcoma Progress Review Group (PRG) 

PRIORITY 2. 

Use innovative clinical trial designs. 

Rationale 

• Sarcoma research is poorly served by traditional statistical paradigms for clinical 

trial design and conduct. 

• Many sarcoma subtypes exist, some of which are quite rare. 

• Rapidly emerging technologies are producing new experimental treatments at an 

ever-increasing rate. 

• Actual medical treatment is sequentially adaptive, with multiple stages. 

• Patient outcome typically is complex. 

• Translational science and imaging studies should be incorporated into trial 

design whenever feasible. 

Issues of Importance 

• Use adaptive decision rules. 

• Use Bayesian hierarchical models and regression methods to borrow strength 

across patient subgroups and between clinical trials. 

• Account for complex treatment-outcome structure. 

• Account for multiple sources of variability. 

• Conduct many small-to-moderate-scale trials instead of a few large-scale trials. 

• Conduct long-term follow-up to assess late morbidities and survival. 

PRIORITY 3. 

Implement high-quality information systems. 

Rationale 

• To optimize the reliability of the data that are the basis for statistical analyses 

and medical decision making. 

• To optimize the linkage between statistical software, user interfaces, and 

databases. 

Issues of Importance 

• Database design and management, including data from clinical trials, genomics, 

proteomics, and other translational research studies. 

• User-friendly interfaces. 

• Statistical software development. 

Appendix B: Science-Centric Breakout Reports B-39 
Report of the Sarcoma Progress Review Group (PRG) 

CONCLUSION 

To enhance the ability to conduct better clinical trials in this group of rare tumors, a 

sarcoma-specific collaborative group is essential. It might be possible to base such a 

group on an already-established voluntary collaboration. 

Innovative clinical trial designs maximizing the information from small numbers of 

patients are also required. The methodologies developed for these sarcoma trials 

could then be applied to other rare diseases. 

Achieving these priorities requires dedicated funding for the proposed collaborative 

group with the responsibility for conducting the proposed clinical trials. This funding 

could be appropriately obtained by redistributing the funding for the existing 

cooperative groups to a newly formed sarcoma-specific collaborative group. 

Appendix B: Science-Centric Breakout Reports B-40 
Report of the Sarcoma Progress Review Group (PRG) 

BETTER COMMUNICATION AND OUTCOMES 

Co-Chairs: 

Karen O. Anderson Brian O’Sullivan Leonard Wexler 

Judith K. Jones 

Participants: 

Karen H. Albritton William G. Kraybill Dempsey S. Springfield 

Mark C. Gebhardt Anna T. Meadows Jerome W. Yates 

Anne E. Kazak Scott Saxman 

INTRODUCTION 

Sarcomas are rare neoplasms and, given the current fragmentation of care for these 

uncommon and diverse tumors, information about their management and outcomes is 

not readily accessible. At the time of initial diagnosis, many clinicians often are not 

knowledgeable about appropriate referrals, optimal management, and the need for 

follow-up care. Many treated patients, even those enrolled in clinical trials, have 

unknown outcomes. Treatment practices are poorly defined and have unclear 

relationships to outcomes. The ability to obtain long-term information, other than 

vital status and/or local control, is hindered by a mobile population, lack of access to 

medical records, and a gap in patients’ self-knowledge about the details of their 

diagnoses and subsequent treatments, particularly among long-term survivors of 

childhood cancers. Appropriate short, intermediate, and long-term outcomes, as well 

as the tools for their measurement, are not standardized. Mechanisms for follow-up 

need definition, as do methods for managing barriers such as Health Insurance 

Portability and Accountability Act regulations. 

Researchers, medical providers, patients, and others lack knowledge due to 

communication barriers. In particular, researchers do not share with each other 

relevant sarcoma research activities. Physicians who make the initial diagnosis often 

seem unaware of opportunities for referral for both optimal initial management 

(including radiologic assessment, diagnostic accuracy, and surgical management) and 

for tumor banking and evaluation of eligibility for clinical trials. Pathologists and/or 

diagnostic radiologists often do not recognize the importance and value of their role as 

facilitators of referrals to regional centers of excellence. Physicians who follow 

patients after completion of therapy typically are not familiar with guidelines for 

follow-up of late effects. Patients lack access to comprehensive information 

concerning their tumors, treatment, and critically important long-term follow-up. 

Third-party payers, the public, and legislators lack information regarding the disease 

and its care. 

In NCI’s current portfolio, approximately 20 projects and 4 clinical trials address 

survivorship, outcomes research, and cancer-control issues related to sarcomas. The 

majority of these studies focus on Kaposi’s sarcoma, and only four projects and four 

clinical trials focus on bone sarcoma and/or soft-tissue sarcomas. One observational 

outcome study is evaluating the late effects of prior treatment for pediatric sarcoma. 

Additionally, one communication project is directed at children with solid tumors 

including, but not limited to, sarcomas. No projects directly address communication 

issues related specifically to sarcomas. 

Appendix B: Science-Centric Breakout Reports B-41 
Report of the Sarcoma Progress Review Group (PRG) 

In terms of outcomes, effective multimodal treatments have improved the prognosis of 

many sarcomas in children, adolescents, and adults. The newer surgical techniques 

for sarcomas focus on preserving tissue and limb function; thus, amputations are 

performed less frequently. However, these preservation techniques are usually 

associated with the need for radiotherapy and potential late morbidity, including 

second cancers. Longer follow-up of these patients is needed to assess both medical 

risks and functional and psychological sequelae of local resection or amputation. The 

intensity of treatments required for most sarcomas is associated with the potential for 

increased toxicities. Patients typically experience multiple symptoms and impaired 

quality of life during the treatment phase. Effective communication with patients and 

their families is critical to minimize symptom distress and provide the necessary 

supportive care. 

For sarcoma survivors, the late effects of treatment can include second malignancies 

and functional musculoskeletal impairment, as well as cardiac, gonadal, renal, 

metabolic, and immune dysfunction. Depending on the site of involvement, specific 

problems relating to deformity, risk of bone fracture, tissue fibrosis, and edema also 

may result. In addition to the medical sequelae, many children, adolescents, and 

adults must cope with long-term effects relating to education, occupation, and 

multiple other psychosocial changes. Sarcoma survivors may report chronic 

symptoms such as pain, fatigue, sleep disturbance, or emotional distress. 

Clinical research on late effects and other outcomes experienced by sarcoma survivors 

has focused on incidences of significant medical outcomes such as second 

malignancies and cardiac toxicities. Some studies have addressed the physical, 

functional, and occupational outcomes associated with sarcomas and their treatment. 

Very little research has focused on quality of life or other psychosocial outcomes that 

affect survivors and their families, and very few patients have been followed for more 

than 20 years. 

Despite the fact that survivors of sarcoma appear to be at great risk for adverse health 

outcomes over the long term, few outcomes models exist. Among them is that of the 

Pediatric Brain Tumor Consortium, which studies second tumors in childhood cancer 

survivors. The Childhood Cancer Survivor Study[1] recently focused on adult 

survivors of childhood cancer to determine their health status. Further opportunities 

exist to gain an understanding of some short- and long-term outcomes and patterns of 

care using administrative data, such as Medicaid, Medicare, third-party payer data, 

and Canadian provincial health databases. 

Finally, the young mobile population of survivors with a multitude of possible 

outcomes, often manifested many years later, presents prodigious barriers to outcome 

capture and assessment. As recommended subsequently, as many sarcoma patients as 

possible should be enrolled in a long-term registry that, in its best form, would play 

several roles. For those in the registry contributing tissue specimens, the registry 

would allow exploration of underlying biologic processes, different treatment 

modalities, and long-term outcomes. Furthermore, such a registry could provide a 

formal process for long-term research and serve as a repository of sarcoma treatment 

details. This registry also would provide an accessible medical record resource for 

patients, who could then share this information with their future care providers to 

support their management over the longer term. 

Appendix B: Science-Centric Breakout Reports B-42 
Report of the Sarcoma Progress Review Group (PRG) 

PRIORITY 1. 

Evaluate patterns of care, including short- and long-term outcomes, in 

retrospective data on sarcoma patients in population-based studies. 

Rationale 

Information is lacking on the natural history of sarcoma diagnosis, initial treatment 

(and modalities), portals of care, physician specialty, cancer treatment, center types, 

short- and long-term management, and outcomes. 

Issues of Importance 

• Reliable data on short-term processes and outcomes are needed, including 

baseline imaging, accuracy of histologic diagnosis and grading, open biopsy 

versus fine needle aspiration, definitive primary resection versus need for reexcision, marginal resection versus negative margins, referral for radiotherapy, 

enrollment in clinical trials and follow-up, and submission of tissue to 

repositories. 

• Information is also needed on long-term follow-up of treated sarcoma patients 

with respect to process of care, occurrence of late toxicity (e.g., cardiotoxicity), 

and secondary tumors. 

• Determinations are needed of whether disparities in care exist by geographic 

region, ethnic and social group, age, and/or sarcoma type, and whether any 

disparities translate into differences in outcomes. 

PRIORITY 2. 

Prospectively register all newly diagnosed patients and compare short- and longterm outcomes of those treated at community hospitals and those treated at 

sarcoma centers of excellence. 

Rationale 

It must be demonstrated that patients can be registered and followed for short- and 

long-term outcomes to determine whether a relationship exists between outcomes and 

specific care interventions. This registry is also needed to allow correlation of 

pathological specimens collected at the time of registration with long-term follow-up 

and prognosis of patients. 

Issues of Importance 

• The development of this registry would provide an opportunity to develop a 

consensus on standard definitions of sarcomas and short- and long-term

outcomes. 

• The development of this registry would provide an important foundation for a 

database for research as well as summaries of patient treatment and outcomes. 

The latter function would be important for research, but could also serve as a 

resource for patients to access, via password, their own medical record of 

treatment for their long-term care. 

• This registry would also be linked to pathological specimen data, if collected, 

and would allow linkage of biological studies to long-term outcomes. 

Appendix B: Science-Centric Breakout Reports B-43 
Report of the Sarcoma Progress Review Group (PRG) 

PRIORITY 3. 

Target a communication campaign to diagnostic radiologists and pathologists to 

ensure an optimal portal of entry to multidisciplinary centers. 

Rationale 

These two types of specialists provide initial diagnostic information and are thus 

uniquely positioned to facilitate optimal care. 

Issues of Importance 

• Diagnostic radiologists and pathologists may not be aware of their critical role in 

facilitating appropriate patient referrals and educating referring physicians. 

CONCLUSION 

Population-based studies of sarcoma patients and the development of a sarcoma 

patient registry are recommended strategies for meeting the urgent need for increased 

outcomes research. Additionally, increasing effective communication with 

community pathologists and diagnostic radiologists is critical for increasing referrals 

to multidisciplinary sarcoma treatment centers. 

The current state of sarcoma outcome assessment remains unsatisfactory due to the 

rarity, diverse histology, and clinical behavior of these tumors; the numerous 

interventions required; the varied practitioners who provide care for these patients; 

and the overall fragmentation of care. The process of care from the time of diagnosis 

to that of ultimate follow-up is inherently susceptible to aberrant and disjointed 

practice. 

Unfortunately, many patients are not referred to centers of excellence, and their 

outcomes remain largely unknown. More effective communication between 

diagnostic gatekeepers, such as pathologists and diagnostic radiologists, and sarcoma 

specialists, the medical community, and the broader public is needed to improve 

access to optimal care in specialized centers of excellence, increase tumor specimen 

acquisition, and increase enrollment in clinical trials. 

Therefore, the extent of fragmentation in care delivery and communication to patients 

diagnosed with sarcomas must be understood. The medical community must begin to 

assess the feasibility of registration and data collection for established sarcoma centers 

of excellence and community practice. 

REFERENCE 

1. Hudson M, Mertens A, Yasui Y, et al. Health status of adult long-term 

survivors of childhood cancer. JAMA. 2003. 290-12:1583-92. 

Appendix B: Science-Centric Breakout Reports B-44 
Report of the Sarcoma Progress Review Group (PRG) 

Appendix C 

About the NCI’s Progress Review Groups 

Appendix C: About the NCI’s Progress Review Groups C-1 
Report of the Sarcoma Progress Review Group (PRG) 

INTRODUCTION 

The NCI supports basic, clinical, and population-based research to elucidate the 

biology; etiology; prevention; early detection, diagnosis, and prognosis; cancer 

control, survivorship, and outcomes; treatment; and scientific model systems of 

cancers of various organ sites. These research efforts have produced a substantial 

base of knowledge that provides a wealth of new scientific opportunities for further 

advancing our knowledge and progress against these diseases, but this plentitude has 

also dictated that the Institute focus on the best use of its resources. 

To help ensure the wise use of resources, NCI has established Progress Review 

Groups (PRGs) to assist in assessing the state of knowledge, reviewing the Institute’s 

research portfolio, and identifying scientific priorities and needs for its large, sitespecific research programs. 

CHARGE TO THE PRGS 

Each PRG is charged with the following: 

• Identify and prioritize scientific research opportunities and needs to advance 

medical progress against the cancer(s) under review. 

• Define the scientific resources needed to address these opportunities and needs. 

• Compare and contrast these priorities with the current NCI research portfolio. 

• Prepare a written report that describes findings and recommendations. 

• Discuss a plan of action with NCI leaders to ensure that the priority areas are 

addressed. 

The subsequent section details the process used to execute these charges. 

THE PRG PROCESS 

PRG members are selected from prominent members of industry and the scientific, 

medical, and advocacy communities to represent the full spectrum of scientific 

expertise required to make comprehensive recommendations for the NCI’s cancer 

research agenda. The membership is also selected for its ability to take a broad view 

in identifying and prioritizing scientific needs and opportunities that are critical to 

advancing the field of cancer research. 

The leadership of each PRG finalizes an agenda and process for a PRG Planning 

Meeting. At the planning meeting, participants are identified to take part in a 

subsequent Roundtable meeting. Topics are identified for Roundtable breakout 

sessions to which participants will be assigned and for which the PRG members will 

serve as co-chairs. 

A PRG Roundtable brings together in an open forum approximately 100–180 leading 

members of the relevant cancer research, medical, industry, and advocacy 

communities to formulate key scientific questions and priorities for the next 5–10 

years of research on specific cancers. As part of the process, the NCI provides the 

PRG Roundtable with an analysis of its portfolio of cancer research in the relevant 

organ site. This analysis is intended to enable the Roundtable to compare and contrast 

identified scientific priorities with the research currently being done under the 

Institute’s auspices. Input from the Roundtable is used by the PRG in delineating and 

prioritizing recommendations for research, related scientific questions, and resource 

and infrastructure needs. At its discretion, the PRG may solicit additional input from 

Appendix C: About the NCI’s Progress Review Groups C-2 
Report of the Sarcoma Progress Review Group (PRG) 

the research and advocacy communities through workshops and ad hoc groups or by 

other means. The PRG also may consider the deliberations of previously convened 

expert groups that have provided relevant cancer research information. 

THE PRG REPORT 

After the Roundtable, the PRG’s recommendations are documented in a draft report, 

multiple iterations of which are reviewed by the PRG leadership and PRG members. 

The final draft report is then submitted for deliberation and acceptance by the NCI 

Advisory Committee to the Director. After the report is accepted, the PRG meets with 

the NCI Director to discuss the Institute’s response to the report, which is widely 

disseminated and integrated into the Institute’s planning activities. At this meeting, 

the PRG and the NCI identify the research priorities that ongoing NCI initiatives and 

projects do not address. Then the PRG and NCI discuss a plan for implementing the 

highest research priorities of the PRG. This plan becomes a blueprint for tracking and 

hastening progress against the relevant cancer. 

PRG reports on breast cancer; prostate cancer; colorectal cancer; pancreatic cancer; 

lung cancer; brain tumors; leukemia, lymphoma, and myeloma; gynecologic cancers; 

kidney/bladder cancers, and stomach/esophageal cancers, in addition to this PRG 

report on sarcoma are available online at http://planning.cancer.gov. 

Appendix C: About the NCI’s Progress Review Groups C-3 
Report of the Sarcoma Progress Review Group (PRG) 

Appendix D 

Sarcoma PRG Membership Roster 

Appendix D: Sarcoma PRG Membership Roster D-1 
Report of the Sarcoma Progress Review Group (PRG) 

Karen Antman, M.D. 

PRG Co-Chair 

Columbia University, College of 

Physicians & Surgeons 

Todd R. Golub, M.D. 

PRG Co-Chair 

Dana-Farber Cancer Institute, 

Whitehead Institute Center for 

Genome Research 

Lee J. Helman, M.D. 

PRG Executive Director 

National Institutes of Health, National 

Cancer Institute 

Karen O. Anderson, Ph.D. 

The University of Texas M.D. 

Anderson Cancer Center 

Laurence H. Baker, D.O. 

University of Michigan 

Comprehensive Cancer Center 

Robert S. Benjamin, M.D. 

The University of Texas M.D. 

Anderson Cancer Center 

Vivien Bramwell, Ph.D., M.B.B.S., 

F.R.C.P.C. 

Tom Baker Cancer Centre 

George D. Demetri, M.D. 

Dana-Farber Cancer Institute/Harvard 

Medical School 

Christopher Denny, M.D. 

UCLA School of Medicine 

Janet F. Eary, M.D. 

University of Washington 

Jonathan A. Fletcher, M.D. 

Harvard Medical School 

Judith K. Jones, M.D., Ph.D. 

The Degge Group, Ltd. 

William G. Kraybill, M.D. 

Roswell Park Cancer Institute 

Marc Ladanyi, M.D. 

Memorial Sloan-Kettering Cancer 

Center 

Crystal Mackall, M.D. 

National Institutes of Health, National 

Cancer Institute 

Robert B. Marcus, M.D. 

Emory Clinic 

Paul Meltzer, M.D., Ph.D. 

National Human Genome Research 

Institute 

Glenn Merlino, Ph.D. 

National Institutes of Health, National 

Cancer Institute 

Paul Meyers, M.D. 

Memorial Sloan-Kettering Cancer 

Center 

Cheryl Nichols, M.B.A. 

National Institutes of Health, National 

Cancer Institute 

Perry Nisen, M.D., Ph.D. 

Abbott Laboratories 

Norman J. Scherzer 

Life Raft Group 

Poul Sorensen, M.D., Ph.D. 

University of British Columbia 

Louise C. Strong, M.D. 

The University of Texas M.D. 

Anderson Cancer Center 

Herman Suit, M.D., D.Phil. 

Massachusetts General Hospital 

Mark O. Thornton, M.D., Ph.D. 

The Sarcoma Foundation of America 

Matt van de Rijn, M.D., Ph.D. 

Stanford University 

Appendix D: Sarcoma PRG Membership Roster D-2 
Report of the Sarcoma Progress Review Group (PRG) 

Appendix E 

Sarcoma PRG Roundtable Participants Roster 

Appendix E: Sarcoma PRG Roundtable Participants Roster E-1 
Report of the Sarcoma Progress Review Group (PRG) 

Iqbal Ahmed 

Karen H. Albritton, M.D. 

Huntsman Cancer Institute 

Barry Anderson, M.D., Ph.D. 

National Institutes of Health, National 

Cancer Institute 

Karen O. Anderson, Ph.D. 

The University of Texas M.D. 

Anderson Cancer Center 

Karen Antman, M.D. 

Columbia University, College of 

Physicians & Surgeons 

Laurence H. Baker, D.O. 

University of Michigan 

Comprehensive Cancer Center 

Tamara Barnes, R.N.,C.N.S., 

A.O.C.N. 

The University of Texas M.D. 

Anderson Cancer Center 

Frederic G. Barr, M.D., Ph.D. 

University of Pennsylvania 

Robert S. Benjamin, M.D. 

The University of Texas M.D. 

Anderson Cancer Center 

Charles D. Blanke, M.D., F.A.C.P. 

OHSU Cancer Institute 

Vivien Bramwell, Ph.D., M.B.B.S., 

F.R.C.P.C. 

Tom Baker Cancer Centre 

John S.J. Brooks, M.D. 

Hospital of University of Pennsylvania 

Jerry W. Call 

Life Raft Group 

Ernest U. Conrad, M.D., F.A.C.S. 

University of Washington 

Jody Cummings, M.P.H. 

The Sarcoma Foundation of America 

George D. Demetri, M.D. 

Dana-Farber Cancer Institute/Harvard 

Medical School 

Christopher Denny, M.D. 

UCLA School of Medicine 

Howard D. Dorfman, M.D. 

Montefiore Medical Center, Albert 

Einstein College of Medicine 

Janet F. Eary, M.D. 

University of Washington 

Jonathan A. Fletcher, M.D. 

Harvard Medical School 

Matthew Freedman, M.D. 

Massachusetts General Hospital, 

Whitehead Institute Center for 

Genome Research 

Gilles J. Frydman 

Association of Cancer Online 

Resources 

Mark C. Gebhardt, M.D. 

Beth Israel Deaconess Medical Center 

Mikhail L. Gishizky, Ph.D. 

SUGEN/Pfizer 

Todd R. Golub, M.D. 

Dana-Farber Cancer Institute, 

Whitehead Institute Center for 

Genome Research 

Holcombe E. Grier, M.D. 

Dana-Farber Cancer Institute 

Gerard C. Grosveld, Ph.D. 

St. Jude Children’s Research Hospital 

James Hadley, M.A. 

National Institutes of Health, National 

Cancer Institute 

Elisabeth Handley, M.P.A. 

National Institutes of Health, National 

Cancer Institute 

Appendix E: Sarcoma PRG Roundtable Participants Roster E-2 
Report of the Sarcoma Progress Review Group (PRG) 

Michael C. Heinrich, M.D. 

Oregon Health & Science University 

Lee J. Helman, M.D. 

National Institutes of Health, National 

Cancer Institute 

Peter J. Houghton, Ph.D. 

St. Jude Children’s Research Hospital 

Robert L. Ilaria, M.D. 

University of Texas Southwestern 

Medical Center 

Mark A. Israel 

M.D. Dartmouth Medical School 

Deborah R. Jaffe, Ph.D. 

National Institutes of Health, National 

Cancer Institute 

Judith K. Jones, M.D., Ph.D. 

The Degge Group, Ltd. 

Carl H. June, M.D. 

University of Pennsylvania 

Howard L. Kaufman, M.D. 

Columbia University 

Anne E. Kazak, Ph.D., A.B.P.P. 

University of Pennsylvania 

Chand Khanna, D.V.M., Ph.D. 

Comparative Oncology Program 

Alfred Knudson, M.D., Ph.D. 

Fox Chase Cancer Center 

William G. Kraybill, M.D. 

Roswell Park Cancer Institute 

Lora Kutkat 

National Institutes of Health 

Marc Ladanyi, M.D. 

Memorial Sloan-Kettering Cancer 

Center 

Ching C. Lau, M.D., Ph.D. 

Baylor College of Medicine 

Elizabeth L. Layne, D.D.S., M.S.D. 

Alliance for Lung Cancer Advocacy, 

Support and Education 

Philip A. Leider, M.A., J.D. 

The Sarcoma Alliance 

Stephen L. Lessnick, M.D., Ph.D. 

Dana-Farber Cancer Institute 

Hyam I. Levitsky, M.D. 

Johns Hopkins University School of 

Medicine 

Crystal Mackall, M.D. 

National Institutes of Health, National 

Cancer Institute 

Robert Maki, M.D., Ph.D. 

Memorial Hospital 

Robert B. Marcus, M.D. 

Emory Clinic 

Anna T. Meadows, M.D. 

Children’s Hospital of Philadelphia 

Paul S. Meltzer, M.D., Ph.D. 

National Human Genome Research 

Institute 

Glenn Merlino, Ph.D. 

National Institutes of Health, National 

Cancer Institute 

Paul A. Meyers, M.D. 

Memorial Sloan-Kettering Cancer 

Center 

Charles E. Nearburg 

Charles and Dara Nearburg Foundation 

Cheryl Nichols, M.B.A. 

National Institutes of Health, National 

Cancer Institute 

Perry D. Nisen, M.D., Ph.D. 

Abbott Laboratories 

Rachel Nosowsky, Esq. 

University of Michigan 

Appendix E: Sarcoma PRG Roundtable Participants Roster E-3 
Report of the Sarcoma Progress Review Group (PRG) 

Richard J. O’Reilly, M.D. 

Memorial Sloan-Kettering Cancer 

Center 

Brian O’Sullivan, M.D., F.R.C.P.C. 

University of Toronto 

Alberto Pappo, M.D. 

Hospital for Sick Children 

Sharon E. Plon, M.D., Ph.D. 

Baylor College of Medicine 

Angela L. Riepel, Ph.D. 

Stanford University 

Andrew E. Rosenberg, Dr. 

Massachusetts General Hospital 

Harvard Medical School 

Brian Rubin, M.D. Ph.D. 

University of Washington Medical 

Center 

Mary Ellen Rybak, M.D. 

Johnson & Johnson Pharmaceutical 

Research & Development 

Scott Saxman, M.D. 

National Institutes of Health, National 

Cancer Institute 

Norman Scherzer 

Life Raft Group 

Julie A. Schneider, D.Phil. 

National Institutes of Health, National 

Cancer Institute 

Stephen X. Skapek, M.D. 

St. Jude Children’s Research Hospital 

Vernon K. Sondak, M.D. 

University of Michigan 

Poul Sorensen, M.D., Ph.D. 

University of British Columbia 

Dempsey Springfield, M.D. 

Mount Sinai School of Medicine 

Katherine Loy Stadler 

Bone Cancer International Inc. 

Lynne S. Steinbach, M.D. 

University of California, San 

Francisco 

Louise C. Strong, M.D. 

The University of Texas M.D. 

Anderson Cancer Center 

Herman D. Suit, M.D., D.Phil. 

Massachusetts General Hospital 

Abraham Sunshine, M.D. 

New York University School of 

Medicine 

Stephen J. Tapscott, M.D., Ph.D. 

Fred Hutchinson Cancer Research 

Center 

Peter F. Thall, Ph.D. 

The University of Texas M.D. 

Anderson Cancer Center 

Mark O. Thornton, M.D., Ph.D. 

The Sarcoma Foundation of America 

Marny S. Tobin, R.D.C.S. 

The Sarcoma Foundation of America 

Timothy J. Triche, M.D., Ph.D. 

Children’s Hospital Los Angeles 

Asad Umar, D.V.M., Ph.D. 

National Institutes of Health, National 

Cancer Institute 

Matt van de Rijn, M.D., Ph.D. 

Stanford University 

Annick D. Van den Abbeele, M.D. 

Dana-Farber Cancer Institute/Harvard 

Medical School 

David H. Viskochil, M.D., Ph.D. 

University of Utah 

Appendix E: Sarcoma PRG Roundtable Participants Roster E-4 
Report of the Sarcoma Progress Review Group (PRG) 

Margaret von Mehren, M.D. 

Fox Chase Cancer Center 

Sharon W. Weiss, M.D. 

Emory University School of Medicine 

Leonard Wexler, M.D. 

Memorial Sloan-Kettering Cancer 

Center 

Richard B. Womer, M.D. 

Children’s Hospital of Philadelphia 

Jay Wunder, M.D. 

Mount Sinai Hospital, Toronto 

Jerome W. Yates, M.D., M.P.H. 

American Cancer Society 

Appendix E: Sarcoma PRG Roundtable Participants Roster E-5 
January 2004 

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES 

Public Health Service 

National Institutes of Health