Advisory Committee Members participating in the teleconference:
Andrew von Eschenbach, M.D., Director, National Cancer Institute (Chair)
Frederick R. Appelbaum, M.D., Fred Hutchinson Cancer Research Center (Board of Scientific Advisors)
LaSalle D. Leffall, Jr., M.D., Howard University School of Medicine (President's Cancer Panel)
Barbara LeStage, American Cancer Society (Chair, Director's Consumer Liaison Group)
John Niederhuber, M.D., University of Wisconsin (National Cancer Advisory Board)

Ex Officio Members present:
Paulette Gray, Ph.D., Acting Director, Division of Extramural Activities, National Cancer Institute
Alan Rabson, M.D., Deputy Director, National Cancer Institute

Executive Secretary:
Cherie Nichols, M.B.A., Director, Office of Science Planning and Assessment, National Cancer Institute

PRG Leadership
Karen Antman, M.D., Co-Chair, National Cancer Institute Sarcoma Progress Review Group
Todd Golub, M.D., Co-Chair, National Cancer Institute Sarcoma Progress Review Group
Lee Helman, M.D., Executive Director, National Cancer Institute Sarcoma Progress Review Group

NCI Staff
Margaret Ames, Ph.D., Office of Science Planning and Assessment, National Cancer Institute
Mary Leveck, Ph.D., Office of Science Planning and Assessment, National Cancer Institute
Lisa Stevens, Ph.D., Office of Science Planning and Assessment, National Cancer Institute
Kathleen Schlom, Special Assistant to the Director, National Cancer Institute

Other participants:
Nancy Volkers, Science Writer
Cathy Hall, Science Applications International Corporation (SAIC)

The purpose of this teleconference was to present to the Advisory Committee to the Director (ACD), for its discussion and acceptance, the draft report of the Sarcoma Progress Review Group (PRG). The ACD must formally accept the report to enable NCI to develop an implementation plan based on the report's recommendations. Dr. Andrew von Eschenbach welcomed those in attendance, and thanked Drs. Antman, Golub, and Helman for their collective leadership in developing the scientific program and presenting the report.

Cherie Nichols reminded attendees of the purpose of the teleconference, and noted that the meeting was open to the public. It was determined that the ACD members had no conflicts related to the matters being discussed.

Dr. Helman thanked attendees for their time. One of the greatest difficulties for those who diagnose and treat sarcomas is that they are rare and difficult to diagnose. Scientists now realize that "sarcoma" is a heterogeneous group of diseases, making clinical studies more difficult to conduct in defined categories. Therefore, sarcoma studies have received a lower priority in the cooperative group structure, giving way to research on more common epithelial tumors. Diagnoses of sarcoma are frequently delayed as patients present with "lumps and bumps" and are referred to general surgeons who are often inexperienced with sarcomas. Patients may not be referred for additional follow-up. Deciphering statistics under the diagnostic coding system is problematic as related to sarcomas; the diagnostic coding system is organized by location, but sarcomas are not site specific. For example, one can infer that a malignancy listed as a "bone tumor" is an osteosarcoma, but it may be a different type of sarcoma of the bone.

Sarcomas are rare, with an incidence of 11,600 per year and a death rate of 5,800 per year. As compared to other rare cancers, such as Hodgkin's Disease (7,400 incidence; 1,300 deaths) and testicular cancer (7,200 incidence; 400 deaths), the sarcoma death rate is poor, and much work is needed to improve outcomes. More common epithelial tumors understandably receive the greatest amount of funding, and sarcoma receives approximately the same level of funding as the more uncommon stomach, kidney/bladder, and esophageal cancers. However, current funding statistics are not an accurate reflection of actual sarcoma funding. Half of the funding that is reported for sarcoma is devoted to Kaposi sarcoma, which became increasingly prevalent during the AIDS epidemic. Funding for sarcoma has since dropped, and with the introduction of Highly Active Retroviral Therapy (HART), the incidence and prevalence of Kaposi's sarcoma will decline. Thus, the funding for other types of sarcoma is much lower than the statistics indicate.

Researchers have made tremendous progress in understanding the biology of sarcomas. Genetic studies demonstrate that sarcomas segregate into two distinctive categories: those with tumor-specific recurrent chromosomal translocations and simple karyotypes and those without specific chromosomal alterations and complex karyotypes. When diseases are defined by specific genetic characteristics, patient numbers may increase dramatically and clinical studies may become more robust and easier to perform. For example, significant progress has been made over last five years in the treatment of gastrointestinal stromal tumors. Researchers defined a point mutation, which led to a tremendous increase in cases of these tumors and the dramatic, successful therapeutic introduction of Gleevec. As researchers more carefully stratify these tumors, more effective therapies and more rapid studies can be achieved. The PRG is of the opinion that establishing a new way of dealing with this set of diseases could accelerate the pace of progress in the treatment of sarcomas and serve as model for many other rare diseases.

Dr. Golub noted that the PRG addressed two fundamental issues in its deliberations: delivery of standard clinical care for sarcoma patients and the performance of sarcoma research. Currently, these activities are fractured and exist in separate, small-scale efforts in multiple centers across the country to the detriment of the delivery of routine patient care and innovative research. Research is particularly difficult with rare tumors because, in the absence of an organized, concerted effort, the critical mass necessary to conduct clinical research is difficult to achieve. There is a tension between this decentralized clinical care and research state of affairs at one extreme versus an entirely centralized, coordinated effort that can become elitist and exclusionary. The PRG recommends as a first priority the creation of a coordinating Sarcoma Research Consortium (SRC)-a dedicated, sarcoma-specific organizational structure which would serve both as a focal point for sarcoma clinical trials and related research and also to enhance networks of investigators and centers committed to sarcoma research. One challenge in sarcoma patient care and research is the lack of a centralized body of individuals to address issues. A national, multi-disciplinary group of investigators is needed to provide leadership to basic and clinical research and to guide delivery of patient care. SRC leadership would comprise investigators from Sarcoma Centers of Excellence (SCE), as well as biologists, patient advocates, non-sarcoma researchers, and anyone else interested in playing a leadership role in sarcoma research.

Another important component of the SRC are the SCEs. The SRC would designate 10-20 such centers, which it has sanctioned as having the requisite multi-disciplinary expertise to care for sarcoma patients and sufficient numbers of patients to be a referral center. The SRC would recommend that patients be seen at the SCE nearest them. Because this would not always be possible, a main activity of the SRC would be the generation of standard of care practice guidelines for treatment of sarcoma patients and dissemination of such guidelines to community physicians and surgeons. Clinical trials would be performed predominantly at SCEs, and the leadership body of the SRC would set a clinical trials agenda in order to expeditiously conduct clinical research.

Wet laboratories and biostatistics reference laboratories to facilitate research would be a key activity of the SRC, although the SRC would make use of existing efforts in these areas. For example, the SRC may employ a biostatistics unit used by other cooperative groups, or SRC may determine that a separate biostatistics unit is warranted. The PRG recognized that national tumor banking efforts, such as the National Biospecimen Network (NBN), might be a solution to the current tissue banking problem. Pooling resources for these rare tumors is very important. Tissues, most of which would be obtained from clinical research trials through the SCEs, would be made available to sarcoma researchers through a simple application process. Patient advocates have voiced their desire to establish a mechanism whereby patients could arrange to have their tissues or tumor material made available to tissue banks. Lastly, a sarcoma information resource would be a source of online information for three constituents: the research community, patients, and community physicians who may be treating sarcoma patients outside of SCEs. The SRC would be an umbrella organization that would make decisions regarding delivery of care and research and determine the best solutions for tissue banks and reference laboratories.

Dr. Leffall asked whether community physicians would receive any incentive or remuneration for referring patients to SCEs, other than assuring them that the patients will get best care. Physicians are concerned about losing patients.

Dr. Antman noted that about half of sarcoma patients have had a "shelling out" procedure, which has been known to be the incorrect procedure for sarcoma since the 1940s. If physicians need to go to the Internet to find treatment recommendations, they should not be treating sarcoma patients. The cases are so rare that referral of sarcoma patients to an SCE would not impact a community physician's practice. In addition, few physicians know that the chemotherapy is very different for each type of sarcoma.

Ms. LeStage suggested that the PRG consider putting the practice guidelines into an information resource center so that patients could access the information as well as physicians. Drs. Antman and Golub agreed that this would be an important objective once such guidelines were developed.

Dr. von Eschenbach asked about the governance of the proposed SRC and how the organization would be empowered and function to oversee clinical trials, clinical care, practice guidelines, etc. For example, would the SRC decide which trials are conducted, and would they have any impact on monitoring adherence to the practice guidelines?

Dr. Golub said that inherent in the organizational structure is the notion that existing sarcoma clinical trials activity would come out of existing cooperative groups and move into the SRC. It is a grass roots effort on the part of the sarcoma research community to organize, rather than a "top-down" mandate. The inclusion of non-sarcoma researchers and clinicians is necessary because there are few sarcoma experts. The SRC would not enforce the standard of care but would generate practice guidelines and have some ability to monitor quality of care through SRC's ability to designate centers of excellence.

Dr. Antman added that there are two models for such organizations: the Brain Tumor Consortia and the European sarcoma model. The Brain Tumor Consortia, which addresses a similarly rare disease, has been very successful, and the European sarcoma research community has centralized efforts to the benefit of European sarcoma research.

Dr. Golub noted that the Children's Oncology Group is another example of a successful centralized effort.

ACD members had some questions about why the cooperative groups have been unable to collaborate to advance sarcoma research, given the small number of patients and researchers. Dr. Antman said that since the 1980s, it has been increasingly difficult to get a sequence of sarcoma studies through the cooperative groups (with the exception of the Gleevec study that was based on a promising drug). Sarcoma research is not a priority in cooperative groups. The structure does not need to be reinvented. The existing mechanisms and infrastructure can be utilized, but some organization is needed to prioritize sarcoma research.

Dr. Golub continued, listing the second and third priorities of the PRG. The second priority is to fund and foster sarcoma biology research, taking advantage of the similarities between leukemia genetics and sarcoma genetics. The importance of signaling pathways in sarcoma is clear, as efforts to systematically investigate mutated and activated kinases in sarcoma show. Whereas the chromosome transmutations associated with sarcomas have been located for 10 years or more, the downstream effects remain unknown. Lastly, there are important research priorities that are not sarcoma specific, such as understanding cell death, pathways, and immunobiological aspects of cancer. There has been little effort to address these areas in a sarcoma context.

The PRG's third priority is to expand the number of sarcoma animal models, of which there are very few. This should be a highly feasible objective since the genetic events and chromosomal translocations are known for many sarcomas. It is important to move biological studies beyond cell culture experiments, using animal models to further biological understanding and to serve as pre-clinical development tools. Individual investigators are currently conducting much of this activity, but the SRC may elect to contract out research efforts deemed to be of general benefit to the sarcoma research community. For example, the SRC could establish new sarcoma cell lines and make them available or contract out the sequencing of kinases and make the information available.

Dr. Antman stated that the fourth PRG priority was to fund and foster comprehensive approaches to sarcoma profiling and target discovery. This has been done in a rudimentary fashion, and the results are interesting: sarcomas are separated into different groups depending on the genetics of the disease and the translocations are similar to those in leukemias and lymphomas. Basic sarcoma profiling is needed, including genome, transcriptome, and proteome profiling. High-throughput screens and functional genomic approaches are needed to identify therapeutic targets. The goal is to identify novel therapeutic targets; critical pathways regulating sarcoma growth and survival; and markers for diagnosis, susceptibility, and prognosis to predict treatment response and define intermediate endpoints. Sarcoma profiling is currently fragmented and focuses largely on expression profiling. Because targeted screening of specific pathways is limited by current knowledge of sarcoma biology, screening (compounds, RNAi, and functional genomics) may identify novel targets associated with pathways not currently implicated in sarcomagenesis. Both the NCI and NIH recognize molecular profiling and targeted therapeutic interventions as integral to future research and highlight them in their strategic plans and roadmaps.

The fifth PRG priority is to develop a centrally available sarcoma "research toolkit" of core reagents, including cell lines, model systems, annotated tissue banks, biomarkers, and imaging, as well as promote access to technology platforms for interested researchers. The toolkit would enable new technology to define novel and valid biomarkers, imaging, and surrogate markers to take advantage of the unique biology of sarcoma subsets; it would also encourage rational, targeted, and timely clinical development. The NIH Roadmap highlights the need for a "toolbox" that consists of technologies, databases, and other scientific resources. In addition, NCI's Strategic Priorities include a regional network of high-throughput laboratories for existing and emerging cancer risk biomarkers to facilitate collaborative development of national, regulatory-compliant, privacy-protected, standardized, and annotated biological samples.

Dr. Golub added that these resources exist in two groups: limited resources (patient derived tumors) and unlimited resources (cell lines, DNA samples). Even unlimited resources are difficult to access. The PRG recommended that there be a mechanism to ensure these non-precious resources are disseminated to the research community more expeditiously.

Dr. Antman continued, stating that PRG's sixth priority is to design prospective clinical trials, which would have a principal objective of comparing early surrogate (intermediate) markers to conventional endpoints. This has been accomplished in the pilot phase, where Gleevec was investigated in a number of sarcomas using novel statistical methodologies. The biostatistics were conducted on a Bayesian model, so that the study accrued patients depending on the number of sarcomas that responded in each of the histological subsets. Thus, the number of patients exposed to a drug in a clinical trial was minimized. Such innovative practices might allow more rapid conduct of clinical trials, which would be attractive to the pharmaceutical industry. NCI has identified as a Strategic Priority the development, validation, and approval of surrogate markers as endpoints in order to shorten the time necessary for conducting clinical trials. Also, the NIH Roadmap highlights the need for improved assessment of clinical outcomes. On behalf of the PRG, Dr. Antman thanked Dr. Ames, Ms. Hall, and SAIC for their support throughout the process of developing the report.

Ms. LeStage expressed concern that the report advocates the development of a central IRB and asked whether that was in addition to NCI's central IRB. Dr. Antman clarified that studies would utilize the IRB that exists; given limited resources, using entities and resources that are already in place would be key.

Dr. Niederhuber mentioned that the success of the PRG report depends on the priority of forming the SRC. Many have had frustrations trying to work with the larger cooperative groups with the lumbering process of moving through review committees, etc. Since surgeons are often on the "front line" of sarcoma diagnosis and treatment and the education of surgeons is an objective, perhaps sarcoma research would find a natural and supportive home in the American College of Surgeons Oncology Group (ACOSOG). ACOSOG has experience with early stage disease and has ample access to tissue. The infrastructure could provide a center of operations for the sarcoma group. Dr. Antman expressed concern that medical oncologists are not a part of ACOSOG. Some sarcoma studies are based there; however, a critical mass of sarcoma specific radiation therapists and medical oncologists is lacking. Dr. Niederhuber stated that finding financial support for a separate organization would be difficult. Dr. Helman noted that the objective is to get the few sarcoma researchers, surgeons, biologists, pediatric oncologists, and medical oncologists working together. More money is not necessarily required, but whatever money is currently allotted to sarcoma needs to be coordinated, using existing resources.

Dr. von Eschenbach asked how the PRG would manage the division between pediatric and adult sarcomas. Dr. Helman stated that there is better precedent for cooperation between pediatric oncology groups and the medical and surgical oncology groups. Insofar as there are diseases that span the age range from childhood to adulthood, ongoing studies that involve both pediatric and adult oncology groups will continue.

Dr. von Eschenbach recommended that the ACD consider the report, and if it accepts the concept, then these difficult implementation issues can be addressed. These are themes that are not unique to this proposed report.

Ms. LeStage reiterated her concern about the report recommending the formation of a national IRB, when such a central IRB already exists at NCI. Dr. Antman said that the report does not intend to develop a national IRB but rather intends to use the existing central IRB. At Ms. Nichols' suggestion, Ms. LeStage agreed to e-mail her suggested changes to the ACD. After some discussion, it was determined that the section in question was part of a "breakout report," which is not part of the final accepted report.

ACD members voted unanimously to accept the draft report of the PRG. The report itself will be posted to the NCI Web site, and an internal NCI working group will now develop an implementation plan to address PRG recommendations. The implementation plan will come back to the PRG for further discussion. Dr. von Eschenbach thanked PRG members and staff for their efforts.

The teleconference adjourned at 1:40 p.m.