A randomised comparison between 6 months of bolus fluorouracil/leucovorin and 12 weeks of protracted venous infusion fluorouracil as adjuvant treatment in colorectal cancer

Chau, I., Norman, A.R., Cunningham, D., Tait, D., Ross, P.J., Iveson, T., Hill, M., Hickish, T., Lofts, F., Jodrell, D., Webb, A. and Oates, J.R. (2005) A randomised comparison between 6 months of bolus fluorouracil/leucovorin and 12 weeks of protracted venous infusion fluorouracil as adjuvant treatment in colorectal cancer. Annals of Oncology, 16 (4), 549-557. (doi:10.1093/annonc/mdi116).

Abstract

Background: We performed a multicentre randomised trial to compare the efficacy and toxicity of 12 weeks of protracted venous infusion (PVI) 5-fluorouracil (5-FU) against the standard bolus monthly regimen of 5-FU/leucovorin (LV) given for 6 months as adjuvant treatment in colorectal cancer (CRC).
Patients and methods: Patients with curatively resected stage II and III CRC were randomly assigned to 5-FU/LV [5-FU 425 mg/m2 intravenously (i.v.) and LV 20 mg/m2 i.v. bolus days 1–5 every 28 days for 6 months] or to PVI 5-FU (300 mg/m2/day for 12 weeks).
Results: Between 1993 and 2003, 801 eligible patients were randomised to 5-FU/LV (n=404) or PVI 5-FU (n=397). With a median follow-up of 5.3 years, 231 relapses and 220 deaths have been observed. Five-year relapse-free survival (RFS) was 66.7% [95% confidence interval (CI) 61.6% to 71.3%] and 73.3% (95% CI 68.4% to 77.6%) with bolus 5-FU/LV and PVI 5-FU, respectively [hazard ratio (HR) 0.8; 95% CI 0.62–1.04; P=0.10]. Five-year overall survival (OS) was 71.5% (95% CI 66.4% to 75.9%) and 75.7% (95% CI 70.8% to 79.9%) with bolus 5-FU/LV and PVI 5-FU, respectively (HR 0.79; 95% CI 0.61–1.03; P=0.083). There was a significant survival advantage for patients starting adjuvant chemotherapy within 8 weeks (P=0.044). Significantly less diarrhoea, stomatitis, nausea and vomiting, alopecia, lethargy, and neutropenia (all with P <0.0001) were seen with PVI 5-FU.
Conclusions: There was no OS difference between the two arms, although PVI 5-FU was associated with a trend towards better RFS and OS compared with bolus 5-FU/LV, as well as significantly less toxicity. Based on our results, the probability of 12 weeks of PVI 5-FU being inferior to 6 months of bolus 5-FU/LV is extremely low (P <0.005), and therefore shorter duration of adjuvant treatment should be explored further.

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Contributors

Author: T. Iveson

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