Adult Sarcomas: A Missed Opportunity for Sustained Cooperative Group Translational and Clinical Research

ABSTRACT: Preclinical advances offer an opportunity to further reduce morbidity and mortality from sarcomas over the next decade. Since no single institution or North American cooperative oncology group has the expertise or patient resources for histology-specific clinical and translational research on adult sarcomas, efforts have been made to develop funding from the National Cancer Institute (NCI). One such initiative was the Intergroup Coalition Against Sarcomas (ICAS), which, building upon the strengths of the multimodality cooperative oncology groups, provided an infrastructure for broad participation by investigators from all treatment disciplines in protocol development and patient entry. However, despite an excellent evaluation in formal peer review, the Division of Cancer Treatment of NCI has ended this initiative claiming insufficient available funds—to the detriment of adult sarcoma patients now and in the future.

Based upon the Surveillance, Epidemiology, and End Results (SEER) database, approximately 15,000 new cases of sarcomas of bone and soft tissues are diagnosed in the United States on an annual basis. This places sarcoma incidence within the same order of magnitude as myeloma, cervical carcinomas, gliomas, and carcinomas of the esophagus and makes it more frequent than testicular carcinomas or Hodgkin's disease. The effectiveness of imatinib mesylate (Gleevec) in treating gastrointestinal stromal tumors (GIST) has demonstrated over the past 5 years how studies of soft-tissue sarcoma can enhance the understanding of cancer biology and development of targeted therapeutics. This realization has been long overdue.

Early Research

Sarcoma research over the past 3 decades, particularly in the clinical arena, has benefited from sporadic initiatives by the cooperative groups and a few institutions of excellence. These efforts have been primarily responsible for advances in clinical and translational sarcoma research.[1] Progress in the treatment of adult soft-tissue sarcomas from 1970 to 2000 included improvements in pathologic definition through identification of trans-locations, increased use of immunohistochemistry, introduction of new imaging modalities, refinements in prognosis and staging, use of radiotherapy as an adjunct to other modalities, surgical advances in functional preservation, and the definition of doxorubicin and ifosfamide as active drugs in this setting.[1-5]

Progress in the treatment of pediatric sarcomas through the Children's Oncology Group and its predecessors has established a model for successful interinstitutional collaboration for multidisciplinary management of specific sarcoma types in the younger patient. Thus, an effort was made during this era to interest the National Cancer Institute (NCI) in a coordinated program for research on the more common adult sarcomas. This proposal, however, was rebuffed.

Leaders in pathologic and clinical sarcoma research realized that the 21st century was going to offer a new opportunity to further improve outcomes for sarcoma patients (Table 1). The use of small molecules with a known oncogenic target, whether resulting from a mutation or translocation, could be a base for entirely new approaches to the treatment of sarcomas. In the fall of 2000, a core group of medical oncologists and biostatisticians with a history of good interactions began discussing a new structure for cooperative group sarcoma research. Since only the Southwest Oncology Group (SWOG) had a peer-reviewed and approved sarcoma committee, this was viewed as a base from which to begin new intergroup collaborations-an initiative that evolved into the Intergroup Coalition Against Sarcomas (ICAS).

GIST Paradigm

With the needed phase III evaluation of phase II results of imatinib in GIST, the discussions for intergroup collaboration facilitated an agreement for the first North American phase III trial of the agent in this setting, chaired by a Cancer and Leukemia Group B (CALGB) member, with clinical operations and biostatistics handled through SWOG, and funding through NCI. This intergroup trial was immediately successful, with over 700 metastatic GIST patients enrolled in 9 months, a third of the expected accrual time.

It seemed probable that the GIST paradigm would stimulate pharmaceutical and investigator development of other targeted therapeutics that would likely be active in only specific sarcoma histologies. The need for study of specific histologies of soft-tissue sarcomas represented a marked departure from prior studies in adult sarcomas (although the success of this approach had been pioneered and affirmed by the pediatric oncology groups beginning more than 2 decades earlier). Since no single group would likely have the investigator expertise or patient resources for histology-specific sarcoma trials, the ICAS was formed and competed successfully through peer review for NCI funding, with a score of "excellent."

Goals of ICAS

The focus of ICAS has been on histology-specific trials with molecularly targeted therapeutics. Leadership came from (and trials were conducted across) the CALGB, Eastern Cooperative Oncology Group (ECOG), National Cancer Institute of Canada (NCIC), and SWOG (Table 2). Specific aims and hypotheses for ICAS were refined and developed at an NCI-sponsored meeting in the summer of 2002 (Table 3). This meeting also addressed needs for additional molecular and pathologic definition of histologic subtypes, and for improvements in primary management with a particular emphasis on imaging.[1]

ICAS has operated with an Executive Committee that met semiannually with intervening teleconferences (Table 3). The semiannual meetings, which reviewed the status of current protocols and new investigator-initiated ideas, were open to members of any cooperative group with an interest. To further facilitate participation and registration of patients, almost all active studies (including phase II trials) were opened for registration through the Clinical Trials Support Unit (CTSU) of the Cancer Treatment and Evaluation Program of NCI. In many ways, ICAS developed as a paradigm for what the NCI recently proposed as a new structure for disease-oriented clinical research-the Clinical Trials Working Groups.

The goal of this series of articles is to provide the rationale and background of the ICAS program, and to stimulate ideas for future research directions in sarcomas. Central review of tissues will ensure uniform outcomes and facilitate research in pathogenesis. Methods for extraction of RNA and DNA from paraffin blocks will further the definition of genes with aberrant expression.

Much more remains to be done if the promise of molecular definitions and imaging are to be fully developed to reduce morbidity and mortality from sarcomas. Of course, morbidity and mortality would also be further decreased if we continue to educate our colleagues in primary care of the importance of biopsy of any mass that is enlarging, tender, or greater than 3 to 5 cm in size. Broad participation by cooperative group members will ensure reductions in morbidity and mortality from adult sarcomas, as has resulted from the efforts of pediatric oncology colleagues. As the articles in this series will illustrate, the ideas and opportunities exist.

Need for Funding

Despite these ideas and infrastructure for a national program for clinical research on adults with metastatic or recurrent sarcomas, funding through the NCI has now been precipitously terminated. Shortfalls in the NCI budget have resulted in the elimination of financial support for ICAS beginning in 2007. Ten active or planned studies-which could have opened new therapeutic directions in adult patients with new diagnoses of sarcoma-will not be completed. Two trials will remain open through the American College of Surgeons Oncology Group (ACOSOG) and Radiation Therapy Oncology Group (RTOG), for patients at the time of initial diagnosis of GIST or low-grade sarcomas, respectively. The Children's Oncology Group will continue to receive funding for its work on pediatric sarcomas-which differ almost entirely from the sarcomas of adults.

The ICAS Executive Committee is considering options to address this unsatisfactory state of affairs and will develop a plan for consideration of ways to continue the precepts, science, and patient goals upon which ICAS was based. For the near to intermediate term, however, there will be no NCI-funded sarcoma committees in SWOG, ECOG, or CALGB-the adult cooperative groups focused on drug development-to the detriment of adult patients with the most aggressive forms of sarcoma.

Disclosures:

The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Borden EC, Baker LH, Bell RS, et al: Soft tissue sarcomas of adults: State of the translational science. Clin Cancer Res 9:1941-1956, 2003.

2. Singer S, Demetri GD, Baldini EH, et al: Management of soft-tissue sarcomas: an overview and update. Curr Surg 60:20-24, 2003.

3. Cormier JN, Langstein HN, Pisters PW: Preoperative therapy for soft tissue sarcoma. Cancer Treat Res 120:43-63, 2004.

4. O'Sullivan B, Pisters PW: Combined-modality treatment of localized soft tissue sarcomas of the extremities Surg Oncol Clin North Am 12:355-368, 2003.

5. Kattan MW, Leung DH, Brennan MF: Postoperative nomogram for 12-year sarcoma-specific death. J Clin Oncol 20:791-796, 2002.