Adjuvant Chemotherapy with Uracil–Tegafur for Pathological Stage III Rectal Cancer after Mesorectal Excision with Selective Lateral Pelvic Lymphadenectomy: A Multicenter Randomized Controlled Trial*

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Abstract
Background: Although adjuvant radiotherapy was proved to be effective for local control of rectal cancer even after standardized mesorectal excision, the role of adjuvant chemotherapy after such standardized surgery remains to be clarified. We aimed to assess the efficacy of a combination of uracil and tegafur for pathological stage III rectal cancer treated by standardized mesorectal excision with selective lateral pelvic lymphadenectomy. Methods: We randomly assigned patients with completely resected stage III rectal cancer, who underwent standardized mesorectal excision with selective lateral pelvic lymphadenectomy, to receive either oral uracil–tegafur (400 mg/m2 tegafur per day) for one year or no treatment. Standardization and quality control of the surgery and pathological techniques were ensured by use of the guidelines of the Japanese Society for Cancer of the Colon and Rectum. The primary endpoint was relapse-free survival. The secondary endpoint was overall survival. Results: We enrolled and randomized 276 patients. Excluding two ineligible patients, 274 were included in the analysis. Planned interim analysis 2 years after accrual termination revealed significant prolongation of relapse-free survival (P = 0.001) and overall survival (P = 0.005) in the uracil–tegafur group. The 3-year relapse-free survival and overall survival rates were 78 and 91% in the chemotherapy group and 60 and 81% in the surgery-alone group, respectively. Local recurrence rates were low in both groups. Grade 3 events occurred in 17% of the chemotherapy patients, but no grade 4 or more events occurred. Conclusion: Adjuvant chemotherapy with uracil–tegafur improves survival of patients with stage III rectal cancer after standardized mesorectal excision with selective lateral pelvic lymphadenectomy.