Improved Survival with Adjuvant FOLFOX vs Fluorouracil/Leucovorin After Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer
In a Korean phase II trial reported in The Lancet Oncology, Hong et al found that adjuvant FOLFOX (oxaliplatin, fluorouracil [5-FU], leucovorin) prolonged progression-free survival and overall survival vs 5-FU/leucovorin in patients with locally advanced rectal cancer who had received neoadjuvant chemoradiotherapy and total mesorectal excision.
Study Details
In the open-label, randomized, multicenter ADORE trial, 321 patients with postoperative pathologic stage II or III rectal cancer were randomly assigned between November 2008 and June 2012 to receive FOLFOX (n = 160) or 5-FU/leucovorin (n = 161) after preoperative fluoropyrimidine-based chemoradiotherapy and total mesorectal excision. 5-FU/leucovorin was given for four cycles as 5-FU 380 mg/m² and leucovorin 20 mg/m² on days 1 to 5 every 4 weeks; FOLFOX was given for eight cycles as oxaliplatin 85 mg/m², leucovorin 200 mg/m², and 5-FU bolus 400 mg/m² on day 1, and 5-FU infusion of 2,400 mg/m² for 46 hours every 2 weeks. Randomization was stratified by pathologic stage and center. The primary endpoint was 3-year disease-free survival analyzed by intention to treat.
Improved Disease-Free Survival in Stage III Disease
All planned cycles of treatment were completed in 97% of FOLFOX patients and 95% of 5-FU/leucovorin patients. Median follow-up was 38.2 months. Three-year disease-free survival was 71.6% (95% confidence interval [CI] = 64.6–78.6) in the FOLFOX group vs 62.9% (95% CI = 55.4–70.4) in the 5-FU/leucovorin group (hazard ratio [HR] = 0.657, P = .047). After adjustment for stratification factors, the hazard ratio was 0.630 (P = .032).The improvement in disease-free survival was significant among patients with stage III disease (n = 102 vs 96, HR = 0.602, P = .040), but not among those with stage II disease (n = 58 vs 65, HR = 0.744, P = .47).
Among all patients, 3-year overall survival was significantly prolonged with FOLFOX (95.0% vs 85.7%, HR = 0.456, P = .036).
Adverse Events
Any grades of sensory neuropathy (71% vs 5%), neutropenia (70% vs 46%), nausea (53% vs 38%), fatigue (28% vs 17%), and thrombocytopenia (26% vs 2%) were significantly more common in the FOLFOX group (all P < .05). There were no significant differences between groups in rates of specific grade 3 or 4 adverse events. The most common grade 3 or 4 adverse events were neutropenia (36% vs 26%), leukopenia (8% vs 5%), febrile neutropenia (< 1% vs 3%), diarrhea (1% vs 3%), and nausea 1% vs < 1%).
The investigators concluded: “Adjuvant FOLFOX improves disease-free survival compared with [5-FU] plus leucovorin in patients with locally advanced rectal cancer after preoperative chemoradiotherapy and total mesorectal excision, and warrants further investigation.”
Tae Won Kim, MD of University of Ulsan College of Medicine, Seoul, is the corresponding author for The Lancet Oncology article.
The study was funded by the South Korean Ministry of Health and Welfare. Dr. Kim has received research funding from Sanofi-Aventis, Taiho, Bayer, and Roche, and has served as a consultant and advisory board member for AbbVie.
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