Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: A randomized controlled trial

Context: Chemoradiation as definitive therapy is the preferred primary therapy for patients with anal canal carcinoma; however, the 5-year disease-free survival rate from concurrent fluorouracil/mitomycin and radiation is only approximately 65%. Objective: To compare the efficacy of cisplatin-based (experimental) therapy vs mitomycin-based (standard) therapy in treatment of anal canal carcinoma. Design, Setting, and Participants: US Gastrointestinal Intergroup trial RTOG 98-11, a multicenter, phase 3, randomized controlled trial comparing treatment with fluorouracil plus mitomycin and radiotherapy vs treatment with fluorouracil plus cisplatin and radiotherapy in 682 patients with anal canal carcinoma enrolled between October 31, 1998, and June 27, 2005. Stratifications included sex, clinical nodal status, and tumor diameter. Intervention: Participants were randomly assigned to 1 of 2 intervention groups: (1) the mitomycin-based group (n=341), who received fluorouracil (1000 mg/m² on days 1-4 and 29-32) plus mitomycin (10 mg/m² on days 1 and 29) and radiotherapy (45-59 Gy) or (2) the cisplatin-based group (n=341), who received fluorouracil (1000 mg/m² on days 1-4, 29-32, 57-60, and 85-88) plus cisplatin (75 mg/m² on days 1, 29, 57, and 85) and radiotherapy (45-59 Gy; start day=day 57). Main Outcome Measures: The primary end point was 5-year disease-free survival; secondary end points were overall survival and time to relapse. Results A total of 644 patients were assessable. The median follow-up for all patients was 2.51 years. Median age was 55 years, 69% were women, 27% had a tumor diameter greater than 5 cm, and 26% had clinically positive nodes. The 5-year disease-free survival rate was 60% (95% confidence interval [CI], 53%-67%) in the mitomycin-based group and 54% (95% CI, 46%-60%) in the cisplatin-based group (P=.17). The 5-year overall survival rate was75%(95% CI, 67%-81%) in the mitomycin-based group and 70% (95% CI, 63%-76%) in the cisplatin-based group (P=.10). The 5-year local-regional recurrence and distant metastasis rates were 25% (95% CI, 20%-30%) and 15% (95% CI, 10%-20%), respectively, for mitomycin-based treatment and33%(95% CI, 27%-40%) and19%(95% CI, 14%-24%), respectively, for cisplatinbased treatment. The cumulative rate of colostomy was significantly better for mitomycinbased than cisplatin-based treatment (10% vs 19%; P=.02). Severe hematologic toxicity was worse with mitomycin-based treatment (P<.001). Conclusions: In this population of patients with anal canal carcinoma, cisplatinbased therapy failed to improve disease-free-survival compared with mitomycinbased therapy, but cisplatin-based therapy resulted in a significantly worse colostomy rate. These findings do not support the use of cisplatin in place of mitomycin in combination with fluorouracil and radiotherapy in the treatment of anal canal carcinoma. Trial Registration: clinicaltrials.gov Identifier: NCT00003596.