Assessment of Duration and Effects of 3 vs 6 Months of Adjuvant Chemotherapy in High-Risk Stage II Colorectal Cancer: A Subgroup Analysis of the TOSCA Randomized Clinical Trial

Abstract

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Labianca reported receiving grants from Agenzia Italiana del Farmaco (AIFA) during the conduct of the study and receiving personal fees from Roche, Merck & Co, and Servier outside the submitted work. Dr Zaniboni reported receiving grants from Bayer, Eli Lilly and Company, Saboti, and Servier outside the submitted work. Dr Lonardi reported being a paid consultant and receiving research funding from Amge; being a paid consultant, receiving research funding, and serving on the speakers bureau for Merck Serono; being a paid consultant, and serving on the speakers bureau for Eli Lilly and Company; and serving on the speakers bureau for Roche, Bristol-Myers Squibb, and Servier. Drs Galli and Rulli reported receiving grants from AIFA during the conduct of the study. Dr Zagonel reported receiving personal fees and nonfinancial support from Bristol-Myers Squibb; personal fees and nonfinancial support from Merck & Co, Celgene; Bayer, and Roche; and receiving personal fees from Janssen and from Pfizer outside the submitted work. Dr Rimassa reported receiving personal fees from AbbVie, Amgen, AstraZeneca, Bayer, Baxter, Celgene, Eisai Co Ltd, Eli Lilly and Company, Exelixis, Gilead Sciences Inc, Hengrui Therapeutics, Incyte, Italfarmaco SpA, Merck Sharp & Dohme Corp, Roche, and Sanofi outside the submitted work; and receiving personal fees and nonfinancial support from Arqule and from Ipsen outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. CONSORT Study Flow Diagram of the TOSCA Patient Subgroup

The per-protocol population analyzed was defined as all randomized patients who had no major violations of eligibility criteria or study conduct, and who received at least 1 dose of treatment. TOSCA indicates the Three or Six Colon Adjuvant randomized clinical trial.

Figure 2.. Kaplan-Meier Curves for Relapse-Free Survival by Treatment Duration

FOLFOX/CAPOX indicates fluorouracil, leucovorin, and oxaliplatin/capecitabine plus oxaliplatin.

Figure 3.. Forest Plot for Relapse-Free Survival Within the Per-Protocol Population

CAPOX indicates capecitabine plus oxaliplatin; FOLFOX, fluorouracil, leucovorin, and oxaliplatin; ECOG PS, Eastern Cooperative Oncology Group performance status; and HR, hazard ratio. Dashed line indicates predefined noninferiority boundary (HR, 1.2).