Statistical Analysis
death, Dukes’ B2 disease, toxicity, Dukes’ B3 and C disease, deaths, Dukes’ B3 or C, Dukes’ B3 and C colon cancer
RECURRENCE, ADVERSE EVENTS, DISEASE, SECONDARY, EVENTS, PRIMARY CANCER
The primary endpoint was to compare OS between arms A and B in patients with Dukes’ B3 and C colon cancer. The study was originally designed to detect a 9% difference in 5-year OS (60% versus 69%, 37% improvement in median OS) with 82% power, which required 800 patients with Dukes’ B3 and C colon cancer. Using data on pathologic staging, it was projected that 40% of all patients would be Dukes’ B3 or C, thus requiring a total accrual goal of 2000 patients to obtain the required 800 patients.Accrual to this study was slower than expected, mainly because of the increasingly complex logistics of perioperative chemotherapy administration, and it was terminated early with final accrual of 314 patients with Dukes’ B3 and C disease. The study design was then revised. In the revised design, with 314 patients with Dukes’ B3 and C disease, the study had 84% power to detect a 60% improvement in median OS (5-year OS: 66% versus 77%) with one-sided type I error rate of 5% (no interim analysis had been conducted before accrual termination) using log-rank test. The revised design included one interim analysis at about 2–3 years after study closure and one final analysis at 5 years after study closure.No formal treatment comparison was planned in the study design for patients with Dukes’ B2 disease, and there was no target accrual goal for this subgroup either. Efficacy analysis was conducted separately for patients with Dukes’ B3 and C disease and patients with Dukes’ B2 disease. Per protocol, the primary population for efficacy analyses was all eligible patients. However, because in recent years the standard for the conduct and reporting of phase III studies has shifted strongly in the direction of intent to treat (ITT) in all cases regardless of eligibility status, the primary population for all efficacy analyses in this report was all randomized patients regardless of eligibility status. Efficacy analyses in all eligible patients (per protocol) were conducted as sensitivity analysis. Analyses pertaining to adverse events (AEs) were based on all patients who received at least one dose of protocol therapy and had toxicity data. The trial was not registered, since the study was done in 1993 there was no regulation that trials be registered at that time.OS was defined as time from randomization to death from any cause, censoring patients who had not died at the date last known alive. Disease-free survival (DFS) was a secondary endpoint, defined as time from randomization to recurrence, second invasive primary cancer, or deaths, whichever occurred first. Patients who were still alive and had no DFS events were censored at the last known follow-up disease assessment date. Patients without any follow-up data were censored at random assignment.The distributions of DFS and OS were estimated using the Kaplan–Meier method (1958),For the primary endpoint (OS in patients with Dukes’ B3 and C disease), the overall significance level was one-sided 0.05 per protocol, the nominal significance level at the final analysis was 0.048 for one-sided log rank test adjusting for the one interim analysis conducted in 2002. The significance level was set at 0.05 for two-sided tests for all other analyses.