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Randomized Controlled Trial of Reduced-Dose Bolus Fluorouracil Plus Leucovorin and Irinotecan or Infused Fluorouracil Plus Leucovorin and Oxaliplatin in Patients With Previously Untreated Metastatic Colorectal Cancer: A North American Intergroup Trial

Richard M. Goldberg, Daniel J. Sargent, Roscoe F. Morton, Charles S. Fuchs, Ramesh K. Ramanathan, Stephen K. Williamson, Brian P. Findlay, Henry C. Pitot, Steven Alberts

From the Division of Hematology and Oncology, University of North Carolina, Chapel Hill, NC; Divisions of Biostatistics and Medical Oncology, Mayo Clinic, Rochester, MN; Iowa Oncology Research Association Community Clinical Oncology Program, Des Moines, IA; Department of Oncology, Dana-Farber Cancer Center Institute, Boston, MA; Division of Medical Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA; Division of Hematology and Oncology, University of Kansas Medical Center, Kansas City, KS; and the National Cancer Institute of Canada, Saint Catherines, Ontario, Canada

Address reprint requests to Richard M. Goldberg, MD, Division of Hematology and Oncology, University of North Carolina at Chapel Hill, CB # 7305, 3009 Old Clinic Bldg, Chapel Hill, NC 27514; e-mail: Goldberg{at}med.unc.edu

PURPOSE: Previously, we reported results of Intergroup N9741, which compared standard bolus fluorouracil (FU), leucovorin, plus irinotecan (IFL) with infused FU, leucovorin, plus oxaliplatin (FOLFOX4) and irinotecan plus oxaliplatin in patients with untreated metastatic colorectal cancer. High rates of grade 3 toxicity on IFL (resulting in some deaths) led us to reduce the starting doses of both irinotecan and FU by 20% (rIFL). This article compares rIFL with FOLFOX4.

PATIENTS AND METHODS: The primary comparison was time to progression, with secondary end points of response rate (RR), overall survival, and toxicity.

RESULTS: Three hundred five patients were randomly assigned. The North Central Cancer Treatment Group Data Safety Monitoring Committee interrupted enrollment at a planned interim analysis when outcomes crossed predetermined stopping boundaries. The results were significantly superior for FOLFOX4 compared with rIFL for time to progression (9.7 v 5.5 months, respectively; P < .0001), RR (48% v 32%, respectively; P = .006), and overall survival (19.0 v 16.3 months, respectively; P = .026). Toxicity profiles were not significantly different between regimens for nausea, vomiting, diarrhea, febrile neutropenia, dehydration, or 60-day all-cause mortality. Sensory neuropathy and neutropenia were significantly more common with FOLFOX4. Approximately 75% of patients in both arms received second-line therapy; 58% of rIFL patients received oxaliplatin-based second-line therapy, and 55% of FOLFOX4 patients received irinotecan-based regimens as second-line therapy.

CONCLUSION: FOLFOX4 led to superior RR, time to progression, and overall survival compared with rIFL. The survival benefit for FOLFOX4 observed in the earlier stage of the study was preserved with equal use of either irinotecan or oxaliplatin as second-line therapy.

Supported by National Institutes of Health Grants No. CA25224, CA32102, CA38926, CA21115, and CA77202; Pharmacia Corporation (now Pfizer); and Sanofi-Synthelabo (now sanofi-aventis).

Presented at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004.

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

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