Preoperative radiation (Preop RT) in rectal cancer: Effect and timing of additional chemotherapy (CT) 5-year results of the EORTC 22921 trial

Abstract

3505 Background: This 2 x 2 factorial trial evaluates the addition of CT to preop RT and that of postop CT vs nil on overall survival (primary end-point) and progression-free survival (secondary end-point). Methods: Eligibility: age<80 y, WHO PS 0–1. Arm 1: preop RT 45 Gy in 5 weeks (w). Arm 2: preop RT + two 5 day CT courses (5-FU 350 mg/m2/d; LV: 20 mg/m2/d), the 1st and 5th w of RT. Arm 3: preop RT + four postop CT courses. Arm 4: preop RT-CT + postop CT. We analyzed surgical results, compliance to postop CT and 5-year outcome. The study was planned to detect a mortality hazard ratio of.0.73 (2-sided Logrank test, a=5%, 80% power). Results: 1011 patients entered the trial: median age 63 y; male/female 73.1%/27.9%. T. distance from anal verge: < 5 cm:49.8%; 6–10 cm:43.6%; >10 cm: 6.6 %. T stage: T3: 90%; T4:10%. The median Fup is 5.4 years. Conservative resection was 55.6% vs 52.4% with preop RT-CT and preop RT, respectively (p = 0.05). One patient in four did not start postop CT due to various reasons. Among those who started, 58.5% received planned CT. 5 y OS Results: Preop RT-CT vs preop RT: 65.6% vs 64.8% (P=0.798). Postop CT vs nil: 67.1% vs 63.2% (P=0.132); the curves diverge after 4 years. 5 y PFS Results: Preop RT-CT vs preop RT: 56.0% vs 54.4% (P=0.545). Postop CT vs nil: 58.1% vs 52.2% (P=0.145); the curves diverge after 2 years. 5-y local failure: The assumption of no interaction is not validated. Local failure rates decreased in the 3 groups with chemotherapy: 8.8%, 9.6% and 8.0% with either preop, postop. or both, respectively vs 17.1% without (P=0.002). Conclusion: Some form of CT benefit to local control. The results do not indicate the best timing and do not suggest a benefit of both preop and postop CT. In view of the benefit of preop CT on conservative surgery and the bad compliance to postop CT, preop CT-RT might be preferred. The data shows no significant effect of CT (pre and postop) on OS nor on PFS. More follow up is needed to confirm the suggested late divergence of PFS and OS in favour of adjuvant CT. Supported in part by a grant from the French Research Ministry (PHRC 1992) and by NCI grants 2U10-CA11488–22 through 5U10-CA11488–34. No significant financial relationships to disclose.