Oxaliplatin-Based Adjuvant Chemotherapy for Rectal Cancer after Preoperative Chemoradiotherapy (ADORE): Long-Term Results of an Open-Label, Multicentre, Phase 2, Randomised Controlled Trial

Abstract

Background: Oxaliplatin-based adjuvant chemotherapy for rectal cancer patients after preoperative chemoradiotherapy (CRT) is currently based on extrapolated results from colon cancer patients. We evaluated the role of oxaliplatin as adjuvant chemotherapy in rectal cancer patients who received preoperative CRT with fluoropyrimidine monotherapy and total mesorectal excision (TME). Methods: The ADORE is a multicentre, randomised trial in patients with postoperative ypStage II (ypT3-4N0) or III (ypTanyN1-2) rectal cancer after fluoropyrimidine-based preoperative CRT and TME. Patients were randomly assigned (1:1) to receive adjuvant chemotherapy either with FL (5-fluorouracil 380 mg/m², leucovorin 20 mg/m²) or FOLFOX (oxaliplatin 85 mg/m², leucovorin 200 mg/m², 5-fluorouracil bolus 400 mg/m² on day 1, 5-fluorouracil infusion 2400 mg/m² for 46 hours). Stratification factors included ypStage and participating centre. Investigators were not blinded to the group assignment. Primary endpoint was disease-free survival (DFS), analysed according to the intention-to-treat principle (ClinicalTrials.gov registration number: NCT00807911). Findings: A total of 321 patients were enrolled between November 19, 2008, and June 12, 2012. The 6-year DFS rates were 68·2% in the FOLFOX arm vs 56·8% in the FL arm, with a stratified hazard ratio (HR) of 0·63 (95% CI, 0·43-0·93, p=0·018) by intention-to-treat analysis. In the subgroup analysis for DFS, FOLFOX was favourable to FL in patients with ypStage III, ypN1b, ypN2, high-grade histology, minimally regressed tumour, and absence of lymphovascular or perineural invasion. The 6-year overall survival (OS) rate was 78·1% in the FOLFOX arm vs 76·4% in the FL arm (HR 0·73 [0·45-1·19], p=0·21). In the subgroup analysis for OS, FOLFOX was favourable to FL in patients with ypN2 and minimally regressed tumour. Interpretation: Adjuvant FOLFOX improved DFS in rectal cancer patients with ypStage II/III after preoperative CRT. Adjuvant FOLFOX should be chosen based on the postoperative pathologic stage in those received preoperative CRT and TME. Trial Registration Number: ClinicalTrials.gov registration number: NCT00807911 Funding: Sanofi-Aventis, Republic of Korea Declaration of Interest: TWK received research funding from Sanofi-Aventis, Taiho, and Roche. YSH received research funding from Bayer. All other authors have no conflicts of interest to declare. Ethical Approval: All patients provided written informed consent, and the study protocol was approved by the institutional review boards of all participating institutions.