IMPORTANCE: The addition of oxaliplatin to the standard 6-month 
fluorouracil-based adjuvant chemotherapy in stage II colorectal cancer has been 
reported to reduce the risk of relapse although it does not increase survival. 
The Three or Six Colon Adjuvant (TOSCA) trial compared 3 months with 6 months of 
adjuvant fluoropyrimidine and oxaliplatin-based chemotherapy in patients with 
stage III colon cancer. The utility remains unknown.
OBJECTIVE: To assess the noninferiority and toxic effects of 3 vs 6 months of 
FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine plus 
oxaliplatin) adjunct chemotherapy among patients with high-risk stage II 
resected colorectal cancer enrolled in the TOSCA trial.
DESIGN, SETTING, AND PARTICIPANTS: The TOSCA study was a noninferiority phase 3 
randomized clinical trial conducted from June 2007 to March 2013 in 130 Italian 
centers. Included patients had resected colorectal cancer located 12 cm from the 
anal verge by endoscopy or above the peritoneal reflection at surgery. In this 
preplanned study assessing the per-protocol population, 5-year relapse-free 
survival was evaluated in 1254 patients with high-risk stage II resected 
colorectal cancer who had received adjuvant FOLFOX (fluorouracil, leucovorin, 
and oxaliplatin) or CAPOX (capecitabine plus oxaliplatin).
INTERVENTIONS: Patients were originally randomized (1:1) in the TOSCA trial to 
receive 3 months (experimental group) or 6 months (control) of standard doses of 
FOLFOX or CAPOX at the discretion of the treating physician.
MAIN OUTCOME AND MEASURES: A hazard ratio of at least 1.2 between the 3-month 
and 6-month chemotherapy groups was set to reject the null hypothesis of 
noninferiority.
RESULTS: Overall, 1254 patients (mean [SD] age, 62.4 [9.8] years; 565 women 
[45.1%]) with clinical high-risk stage II resected colorectal cancer were 
analyzed at a median follow-up of 62 months (interquartile range, 53-71) months. 
Of them, 301 patients (24.0%) had pT4N0M0 tumors, and the remaining 953 patients 
(76.0%) had high-risk pT3N0M0 tumors; 776 patients (61.9%) received FOLFOX and 
478 (38.1%) received CAPOX. The 5-year relapse-free survival was 82.2% for the 
3-month arm and 88.2% for the 6-month arm, with an estimated hazard ratio of 
1.41 (95% CI, 1.05-1.89; P = .86 for noninferiority). For CAPOX, the 5-year 
relapse-free survival was similar in the 2 arms (difference, 0.76% favoring the 
6-month arm; 95% CI, -6.28% to 7.80%), whereas for FOLFOX, the difference was 
pronounced: 8.56% in favor of the longer-duration arm (95% CI, 3.45%-13.67%). 
Nevertheless, the test for an interaction between duration and regimen was not 
statistically significant. Neurotoxicity was approximately 5 times lower in the 
shorter duration arm than in the longer duration arm.
CONCLUSIONS AND RELEVANCE: 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.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT0064660.