As reported in JAMA Oncology by Petrelli et al, noninferiority in relapse-free survival for 3 vs 6 months of adjuvant chemotherapy was not established among patients with resected high-risk stage II colorectal cancer in the Italian phase III TOSCA trial. A potential regimen effect was observed, raising the possibility that 3 months of capecitabine plus oxaliplatin (CAPOX) may be suitable as adjuvant therapy.
The previously reported primary analysis from TOSCA in patients with stage III disease showed that the hazard ratio for relapse-free survival numerically favored 6 months of adjuvant chemotherapy; noninferiority of 3 months of treatment was not established.
Study Details
The multicenter trial, conducted from June 2007 to March 2013, included 1,254 patients (per-protocol population) with high-risk stage II disease who were randomly assigned to receive 3 months (n = 621) or 6 months (n = 633) of standard FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX at investigator discretion. Overall, 776 patients (61.9%) received FOLFOX and 478 (38.1%) received CAPOX.
Among all patients, 24.0% had pT4N0M0 tumors and 76.0% had high-risk pT3N0M0 tumors. The primary outcome measure was 5-year relapse-free survival in the per-protocol population.
Relapse-Free Survival
Median follow-up was 62 months. Five-year relapse-free survival was 82.2% in the 3-month group vs 88.2% in the 6-month group (hazard ratio [HR] = 1.41, 95% confidence interval [CI] = 1.05–1.89; P = .86 for noninferiority).
Among patients receiving CAPOX, 5-year relapse-free survival was 84.6% vs 85.4% (95% CI = -6.3%–7.8%; noninferiority margin for 5-year difference = 2.8%), with a hazard ratio of 1.13 (95% CI = 0.70–1.84). Among patients receiving FOLFOX, 5-year rates were 81.1% vs 89.6% (95% CI = 3.4%–13.7%; noninferiority margin = 3.3%), with a hazard ratio of 1.58 (95% CI = 1.09–2.28). The test for interaction between duration and regimen, however, was not statistically significant.
Adverse Events
The toxicity profiles of the 3- and 6-month regimens were reported previously. Overall, rates of severe adverse events were higher in the 6-month group, including neutropenia (27.6% vs 20.7%, P < .001), diarrhea (6.4% vs 5.0%, P < .001), and allergic reactions (2.0% vs 0.5%, P < .001). The rate of grade 3 or 4 neuropathy was also higher in the 6-month group (8.4% vs 1.3%, P < .001).
The investigators concluded, “In the 3-month arm, the treatment was significantly less toxic than in the 6-month arm. Noninferiority was not shown for 5-year relapse-free survival. However, a possible regimen effect was observed, suggesting that either 3 months of CAPOX or 6 months of FOLFOX therapy can be used whenever an oxaliplatin doublet is indicated for treatment of patients with stage II colorectal cancer.”
Fausto Petrelli, MD, of the Medical Science Department, ASST Bergamo Ovest, Piazzale Ospedale 1, Treviglio, is the corresponding author for the JAMA Oncology article.
Disclosure: The study was sponsored by the Italian Group for the Study of Digestive Tract Cancers Foundation and supported by a grant from Agenzia Italiana del Farmaco. For full disclosures of the study authors, visit jamanetwork.com.
