© 1996 by Oxford University Press
Journal of the National Cancer Institute, Vol. 88, No. 10, 668-674,
May 15, 1996
© 1996 Oxford University Press
Phase III Study of Bolus Versus Infusion Fluorouracil With or Without Cisplatin in Advanced Colorectal Cancer
Waukesha Memorial Hospital WI
Dana-Farber Cancer Institute Boston, MA
Medical College of Wisconsin Milwaukee
Northwestern University School of Medicine Chicago, IL
University of Pennsylvania Cancer Center Philadelphia
AMC Cancer Research Center Denver, CO
Correspondence to: Richard M. Hansen, M.D., The Regional Cancer Center, Waukesha Memorial Hospital, 725 American Ave., Waukesha, WI 53188.
BACKGROUND:: Phase II studies of fluorouracil (5-FU) administered by protracted intravenous infusion have suggested an improved response rate and decreased toxicity profile when compared with 5-FU given by bolus injection in patients with metastatic colorectal cancer. Additional studies have suggested further enhancement of infusion 5-FU activity when it is combined with low-dose weekly cisplatin administration.
PURPOSE:: This phase III study in adults with metastatic colorectal cancer was planned as a comparison of objective response rates, toxicity, and survival in patients receiving bolus versus protracted-infusion 5-FU with or without cisplatin.
METHODS:: Four hundred ninety-seven previously untreated patients with advanced, measurable metastatic colorectal cancer were randomly assigned to receive treatment A (bolus 5-FU at 500 mg/m2 for 5 days followed in 2 weeks by weekly bolus 5-FU at 600 mg/m2), treatment B (bolus 5-FU at 500 mg/m2 for 5 days followed in 2 weeks by weekly bolus 5-FU at 600 mg/m2, plus weekly cisplatin at 20 mg/m2), treatment C (5-FU at 300 mg/m2 per day by continuous infusion), or treatment D (5-FU at 300 mg/m2 per day by continuous infusion plus weekly cisplatin at 20 mg/m2). All drugs were administered intravenously. Enrollment in the trial occurred from August 1987 through December 1990, and follow-up was through September 1995. The Kaplan-Meier method was used to estimate overall and disease-free survival, and Cox regression models were used to assess the effects of patient characteristics on survival. All P values resulted from two-sided tests.
RESULTS:: Objective tumor response was observed in 28 (18%) of 153 patients receiving treatment A, in 45 (28%) of 159 patients receiving treatment C (C versus A; P = .045), and in 47 (31%) of 153 patients receiving treatment D (D versus A; P = .016). Because of excessive toxicity, treatment B was discontinued after only 12 patients had begun treatment. Median time to disease progression was 5.1 months for patients in arm A compared with 6.2 and 6.5 months for patients in arms C and D, respectively (C versus A, P = .007; D versus A, P = .017). Patterns of toxic effects differed substantially among the treatment arms. Forty-five percent of the patients receiving bolus 5-FU alone (A) experienced grade 3–4 leukopenia, with two sepsis-related deaths. Hand-foot syndrome and mucositis were the major treatment-limiting toxic effects for patients in the two treatment arms involving infusion. Despite the improvement in response rates and time to disease progression with infusion 5-FU with or without cisplatin (C and D, respectively) (P = .003), the overall survival for the three groups (A, C, and D) was similar (P = .307). This may have been due in part to a longer median survival time of 10.4 months for patients in arm A, compared with an anticipated survival of 7 months.
CONCLUSION:: 5-FU given as a continuous infusion produced a higher objective response rate, a modest prolongation in time to disease progression, and less life-threatening myelosuppression in patients than bolus 5-FU. Concomitant treatment with low-dose cisplatin caused added toxicity and complexity of treatment and did not provide a major clinical benefit. No statistically significant survival differences were observed among the three treatment groups. [J Natl Cancer Inst 1996;88:668–74]
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