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

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

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