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CALGB 50th: Tomorrow's Cancer Treatments Today |
Authors' Affiliations: 1 Cancer and Leukemia Group B, Central Office of the Chairman and University of Chicago, Chicago, Illinois; 2 Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire; 3 Mt. Sinai Hospital and Medical Center, New York, New York; and 4 Dana-Farber Cancer Institute, Boston, Massachusetts
Requests for reprints: Richard L. Schilsky, Cancer and Leukemia Group B, Central Office of the Chairman, 230 West Monroe Street, Suite 2050, Chicago, IL 60606. Phone: 773-702-9171; Fax: 312-345-0117; E-mail: rs27{at}uchicago.edu.
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A formal NCI Clinical Trials Cooperative Group Program was conceived in 1955 when Dr. Sidney Farber, Mary Lasker, and others approached Congress with a proposal to increase support for studies of chemotherapy of cancer. In response, Congress awarded US$5 million to NCI to establish the Chemotherapy National Service Center. When Tom Frei joined NCI in 1955, a formal interinstitutional protocol comparing continuous to interrupted combination chemotherapy for treatment of acute leukemia was begun. The entire protocol document was eight pages long and described a collaborative effort among three institutions: the NCI (Frei and Richard Silver), RPMI (Holland), and the Children's Hospital in Buffalo, NY (Selkirk). The study was a comparative trial of continuous versus intermittent methotrexate in combination with daily 6-mercaptopurine for treatment of acute leukemia. Remarkably, this first multicenter cancer clinical trial included clearly stated eligibility and exclusion criteria, required prestudy tests, a description of the treatment plan, and a plan for randomization, as well as provisions for central morphology review, a description of anticipated toxicities, recommended supportive care measures (steroids, transfusions, and antibiotics) and, importantly, detailed criteria for response evaluation. The protocol was intended for all patients with all forms of acute leukemia, both newly diagnosed and relapsed; thus, the eligibility criteria were essentially limited to the following requirement: "an unequivocal diagnosis of acute leukemia." Patients were stratified by type of acute leukemia, age, history of prior therapy, and duration of prior therapy resulting in 28 possible strata and, within each stratum, new patients were randomized, "using a sealed envelope technique," to continuous or intermittent therapy with methotrexate (the variable) and 6-mercaptopurine (given at a fixed dose daily). Patients received therapy for 35 days followed by the same drugs given at twice the dose for another 35 days unless toxicity prevented dosage escalation. The protocol schema is shown in Fig. 1 .
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In 1956, the group was designated the Acute Leukemia Group B by the Chemotherapy National Service Center Clinical Studies Panel, and Frei was elected chairman. The Group expanded to national and even international membership during the ensuing years, and its research programs embraced the entire spectrum of hematologic neoplasia in children and adults.
Tom Frei resigned as Group Chair in 1962, and Holland was elected chairman. Under his leadership over the ensuing 18 years, pediatric neoplasms other than leukemia came under study; for example, multimodality treatment involving surgery, radiotherapy, and chemotherapy for Wilm's tumor began in 1965. Studies of metastatic carcinoma in adults were initiated in 1968, and trials assessing adjuvant chemotherapy for breast cancer began in 1974. Because of the increasing scope of the research program, the focus on solid tumors and hematologic malignancies, and the recruitment of other oncologic specialists, the Group voted in 1976 to change its name to the CALGB. A formal disease committee structure, including committees on Breast Cancer, Respiratory Cancer, GI Cancer, and Other Tumors, was put in place at that time.
In 1979, the pediatric division of CALGB was disapproved in peer review. The bulk of that membership joined with the former pediatric members of the Southwest Oncology Group to form the Pediatric Oncology Group. Many of the fundamental principles of chemotherapy and the groundbreaking studies that showed the curability of childhood acute leukemia were accomplished by ALGB. In a coherent and inter-related series of studies spanning 25 years, the Group first showed the importance of combination chemotherapy for ALL, the value of maintenance chemotherapy after remission induction, the role of vincristine and prednisone for remission induction, the importance of methotrexate dose scheduling, the use of intrathecal methotrexate, and the importance of timing in the scheduling of asparaginase. These observations and principles provided the foundation for combination chemotherapy studies of solid tumors and the framework for conducting multicenter clinical trials. Indeed, the founders of CALGB and the other cooperative groups invented many of the standard clinical trial procedures used today. Eligibility criteria, toxicity grading, response criteria, uniform data collection tools, quality assurance measures, and the fundamental principles of statistical analysis of clinical trials can all trace their origins to early cooperative group studies.
Immunotherapy studies, focused on the use of the methanol extractable residue of Bacillus Calmette-Guerin, were initiated by CALGB in 1975. This agent was studied in detail across multiple disease areas, and the correlative studies that accompanied the clinical trials led to the formation of an Immunology Committee with expertise in immunodiagnosis and monitoring of immune function. Under the leadership of Clara Bloomfield, this committee evolved over time to become the Immunology and Cytogenetics Committee, the forerunner of the Corrrelative Science for Leukemia and Lymphoma Committee and the current Leukemia Correlative Science Committee.
A Psychiatry Committee was formed under the leadership of Jimmie C. Holland in 1976 to bring quantitative assessment to important aspects of cancer therapy, such as quality of life, symptom management, and patient compliance. Pathology was also established as a modality committee in 1976, and the Group adopted a new Constitution and By Laws in 1978 that affirmed the primacy of multidisciplinary research in CALGB and the key role of modality committees in the scientific leadership of the Group.
In 1980, Tom Frei was again elected Group Chair and put in place the scientific and administrative structure that supports CALGB to this day. Oliver Glidewell was succeeded by Jim Anderson as Group Statistician; Brad Patterson was appointed Chief of Staff in the Central Office; and Karen Antman, now Dean of the Boston University School of Medicine, served as Assistant to the Chairman, a role analogous to that of Executive Officer today.
Since then, the CALGB research program has become even more diverse and multidisciplinary. In 1990, Ross McIntyre was elected Chairman, and in the next 5 years, he organized the Solid Tumor Correlative Science, Surgery, and Prostate Cancer Committees. He also conducted a national search for a new Group Statistician and Statistical Center that led to the appointment of Stephen George as Group Statistician and the relocation of the CALGB Statistical Center to Duke University. Since 1995, under Schilsky's leadership, the CALGB has continued to diversify; now involving experts in molecular biology, pharmacogenetics, geriatrics, imaging, economics, health outcomes, and cancer prevention in CALGB activities.
The pioneering efforts of the Group's founders, the substantial financial contributions of the NCI, foundations, and the pharmaceutical industry coupled with the contributions of other cooperative groups and research centers have allowed progress in cancer treatment that could scarcely have been imagined 50 years ago. The CALGB is proud of its record of achievement. In the articles that follow, current CALGB leaders summarize the accomplishments of CALGB in specific disease and modality areas over the last 50 years and describe how the work of the Group has introduced new therapies, changed treatment paradigms, improved quality of life and survival, and provided important insights into cancer biology that are the foundation for the next 50 years of progress in the fight against cancer.
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Acknowledgments |
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Baptist Cancer Institute CCOP, Memphis, TN–Lee S. Schwartzberg, MD, supported by CA71323; CALGB Central Office of the Chair, Chicago, IL–Richard L. Schilsky, MD, supported by CA31946; CALGB Statistical Center, Durham, NC–Stephen George, Ph.D., supported by CA33601; CALGB CCOP Research Base grant CA37447; CALGB Surgery Committee grant CA59594; Cancer Centers of the Carolinas, Greenville, SC–Jeffrey K. Giguere, M.D, supported by CA29165; Cedars-Sinai Medical Center, Los Angeles, CA–Alan T. Lefor; Christiana Care Health Services, Inc. CCOP, Wilmington, DE–Stephen Grubbs, MD., supported by CA45418; Community Hospital -Syracuse CCOP, Syracuse, NY–Jeffrey Kirshner, MD, supported by CA45389; Dana Farber Partners, Boston, MA–George P Canellos, MD, supported by CA32291; Dartmouth Medical School - Norris Cotton Cancer Center, Lebanon, NH–Marc S. Ernstoff, MD, supported by CA04326; Duke University Medical Center, Durham, NC–Jeffrey Crawford, MD, supported by CA47577; Evanston Northwestern Healthcare CCOP, Evanston, IL–Gershon Y. Locker, MD; Georgetown University Medical Center, Washington, DC, Edward Gelmann, MD, supported by CA77597; Grand Rapids Clinical Oncology Program, Grand Rapids, MI–Kathleen J. Yost, MD; Green Mountain Oncology Group CCOP, Bennington, VT–L. Herbert Maurer, MD, supported by CA35091; Illinois Oncology Research Assoc, Peoria, IL, John W. Kugler, MD, supported by CA35113; Kaiser Permanente CCOP, San Diego, CA–Jonathan A. Polikoff, MD, supported by CA45374; Kansas City Community Clinical Oncology Program CCOP, Kansas City, MO–Jorge C. Paradelo, MD; Massachusetts General Hospital, Boston, MA–Michael L. Grossbard, MD, supported by CA12449; McGill University, Montreal, QC–Gerald Batist, MD; Medical University of South Carolina, Charleston, SC–Mark Green, MD, supported by CA03927; Missouri Baptist Medical Center CCOP, St. Louis, MO–Alan P Lyss, MD CA114558; Memorial Sloan-Kettering Cancer Center, New York, NY, Clifford Hudis, MD, supported by CA77651; Mount Sinai Medical Center, Miami, FL–Rogerio Lilenbaum, MD, supported by CA45564; Mount Sinai School of Medicine, New York, NY–Lewis R. Silverman, MD, supported by CA04457; North Shore - Long Island Jewish Medical Center, Manhasset, NY–Daniel R Budman, MD, supported by CA35279; Northern Indiana Cancer Research Consortium CCOP, South Bend, IN–Rafat Ansari, MD, supported by CA86726; Rhode Island Hospital, Providence, RI–William Sikov, MD, supported by CA08025; Roswell Park Cancer Institute, Buffalo, NY–Ellis Levine, MD, supported by CA02599; Southeast Cancer Control Consortium Inc. CCOP, Goldsboro, NC–James N. Atkins, MD, supported by CA45808; Southern Nevada Cancer Research Foundation CCOP, Las Vegas, NV–John Ellerton, MD, supported by CA35421; State University of New York Upstate Medical University, Syracuse, NY–Stephen L. Graziano, MD, supported by CA21060; Syracuse Hematology-Oncology Assoc. CCOP, Syracuse, NY–Jeffrey Kirshner, MD, supported by CA45389; The Ohio State University Medical Center, Columbus, OH–Clara D Bloomfield, MD, supported by CA77658; University of Alabama Birmingham, Birmingham, AL–Robert Diasio, MD, supported by CA47545; University of California at San Diego, San Diego, CA–Joanne Mortimer, MD, supported by CA11789; University of California at San Francisco, San Francisco, CA–Alan P. Venook, MD, supported by CA60138; University of Chicago, Chicago, IL–Gini Fleming, MD, supported by CA41287; University of Illinois MBCCOP, Chicago, IL–Lawrence E. Feldman, MD, supported by CA74811; University of Iowa, Iowa City, IA–Gerald Clamon, MD, supported by CA47642; University of Maryland Greenebaum Cancer Center, Baltimore, MD–Martin Edelman, MD, supported by CA31983; University of Massachusetts Medical School, Worcester, MA–William V. Walsh, MD, supported by CA37135; University of Minnesota, Minneapolis, MN–Bruce A Peterson, MD, supported by CA16450; University of Missouri/Ellis Fischel Cancer Center, Columbia, MO–Michael C Perry, MD, supported by CA12046; University of Nebraska Medical Center, Omaha, NE–Anne Kessinger, MD, supported by CA77298; University of North Carolina at Chapel Hill, Chapel Hill, NC–Thomas C. Shea, MD, supported by CA47559; University of Tennessee Memphis, Memphis, TN–Harvey B. Niell, MD, supported by CA47555; University of Texas Southwestern Medical Center, Dallas, TX–Debasish Tripathy, MD; Vermont Cancer Center, Burlington, VT–Hyman B. Muss, MD, supported by CA77406; Virginia Commonwealth University Massey Cancer Center CCOP, Richmond, VA–John D. Roberts, MD, supported by CA52784; Wake Forest University School of Medicine, Winston-Salem, NC–David D Hurd, MD, supported by CA03927; Walter Reed Army Medical Center, Washington, DC–Thomas Reid, MD, supported by CA26806; Washington University School of Medicine, St. Louis, MO–Nancy Bartlett, MD, supported by CA77440; Weill Medical College of Cornell University, New York, NY–Scott Wadler, MD, supported by CA07968; Western Pennsylvania Cancer Institute, Pittsburgh, PA–Richard K. Shadduck, MD; The Leukemia Committee has also been supported in part by National Cancer Institute grant CA101140; The Leukemia Correlative Science Committee has also been supported in part by National Cancer Institute grants CA101140; CA16058, and The Coleman Leukemia Research Foundation. The Pharmacology and Experimental Therapeutics Committee has also been supported in part by National Cancer Institute grant CA44691.
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