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Phase III Study of Fluorouracil, Leucovorin, and Levamisole in High-Risk Stage II and III Colon Cancer: Final Report of Intergroup 0089

From the University of Pennsylvania, Philadelphia, PA; Dana-Farber Cancer Institute, Department of Biostatistics, Boston, MA; St Vincent's Hospital and Medical Center, New York, NY; Cancer Centers of the Carolinas-Eastside, Greenville, SC; Dean Medical Center, Madison, WI; and Ashville Hematology and Oncology, Asheville, NC

Address reprint requests to Daniel G. Haller, MD, 16 Penn Tower, 3400 Spruce St, Philadelphia, PA 19014; e-mail: daniel.haller{at}uphs.upenn.edu

PURPOSE: In 1990, fluorouracil (FU) plus levamisole for 1 year became standard adjuvant treatment for patients with high-risk stages II and III colon cancer. Intergroup (INT) 0089 assessed the relative contributions of leucovorin and levamisole in such patients.

PATIENTS AND METHODS: From 1988 to 1992, 3,794 patients were randomly assigned. Experimental treatment consisted of one of three chemotherapy regimens: the low-dose leucovorin plus FU (Mayo Clinic; LDLV) regimen, the high-dose leucovorin plus FU (Roswell Park; HDLV) regimen, and the low-dose leucovorin plus levamisole plus FU (LDLV plus LEV) regimen, each administered for 30 to 32 weeks. The control arm was levamisole plus FU (LEV) for 1 year.

RESULTS: After a median follow-up of 10 years, of 3,561 eligible patients, 1,691 (47%) have died and 1,330 (37%) have experienced disease recurrence; 137 (10%) of those experiencing recurrence are still alive. A total of 481 patients (13%) died without evidence of recurrence, and 1,723 (48%) are alive and disease free. Although there were toxicity differences among the four arms, none was statistically superior in disease-free or overall survival.

CONCLUSION: The 6- to 8-month regimens of LDLV and HDLV without levamisole used in this trial, rather than the previous standard regimen of 12 months of LEV, have become widely used. INT-0089 has long-term follow-up of the largest clinical trial of patients with high-risk colon cancer, documenting not only the durability of the treatment effects, but also the natural history of patients with high-risk colon cancer, and analyses of treatment based on age, race, and comorbid conditions such as obesity, diabetes, and second primary cancers.

Supported in part by Public Health Service Grants No. CA23318, CA66636, CA21115, CA32291, and CA15488, and from the National Cancer Institute, National Institutes of Health and the Department of Health and Human Services.

Presented in part at the 33rd Annual Meeting of the American Society of Clinical Oncology, Denver, CO, May 20, 1997.

Study contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. This study was coordinated by the Eastern Cooperative Oncology Group (Robert L. Comis, MD).

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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