Preoperative Chemoradiotherapy and Postoperative Chemotherapy with Capecitabine and Oxaliplatin Vs. Capecitabine Alone in Locally Advanced Rectal Cancer: Disease Free Survival at Interim Analysis

Abstract

Introduction: The PETACC‐6 trial investigates whether the addition of oxaliplatin to preoperative oral fluoropyrimidine‐based chemoradiation (CRT) followed by postoperative adjuvant fluoropyrimidine‐based chemotherapy (CT) improves disease‐free survival (DFS) in locally advanced rectal cancer. Methods: Between 11/2008 and 09/2011, patients with rectal adenocarcinoma within 12 cm from the anal verge, T3/4 and/or node‐positive, with no evidence of metastatic disease and considered either resectable at the time of entry or expected to become resectable, were randomly assigned to receive 5 weeks of preoperative CRT with capecitabine, followed by 6 cycles of adjuvant CT with capecitabine (arm 1) or capecitabine + oxaliplatin (arm 2) before and after surgery. DFS was defined as the time from randomization to the first event of: loco‐regional failure, distant failure, the appearance of a secondary cancer or death. Patients with R2 resection, a tumour that cannot be resected or distant metastases discovered at the time of surgery were considered as failures at the time of surgery. 440 DFS events were required to have 80% power to detect an improvement in 3‐year DFS from 65% with capecitabine alone to 72% with capecitabine + oxaliplatin (HR = 0.763) using a two‐sided alpha of 5% and owing for an interim analysis for early efficacy at 200 events. The primary analysis was intent‐to‐treat and adjusted for stratification factors (clinical T category, nodal status, distance from the tumor to the anal verge and method of locoregional staging) except the center. Results: 1094 patients were randomized (547 in each arm). 543 eligible patients in arm 1 and 528 in arm 2 started preoperative treatment (3/528 patients without oxaliplatin in arm 2), and 420/543 (77.3%) and 381/525 (72.6%) patients started postoperative chemotherapy within protocol. In arm 2, 45/381(11.8%) patients did not receive postoperative oxaliplatin. Major reasons for protocol discontinuation were progressive disease (3.9% in arm 1 vs. 3.8% in arm 2), toxicity (7.7% vs. 16.5%), surgery complication (8.7% vs. 9.1%), and patient's refusal (5.9% vs. 10.8%). At planned interim analysis, the independent data monitoring committee recommended the early release of the results. At a median follow‐up of 31months, 124 and 121 DFS events were observed in arm 1 and 2 (adjusted HR = 1.036, 95% CI: 0.806 ‐1.331, P = 0.781). 3‐year DFS was 74.5% (95% CI: 70.1% ‐ 78.3%) in arm 1, which is higher than anticipated vs. 73.9% (95% CI: 69.5% ‐ 77.8%) in arm 2; conditional power under HR = 0.763 is only 7%. Conclusion: Interim results at a median follow up of 2.6 y indicate no DFS‐benefit for the addition of oxaliplatin to preoperative Capecitabine based CRT and postoperative adjuvant CT. However, with actually only 245 out of the required 440 events, at least 2 further years follow‐up is required for final evaluation. (Table Presented).