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Brief Report
February 13, 2020

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

Author Affiliations
  • 1Medical Oncology Unit, Medical Science Department, American SamoaST Bergamo Ovest, Treviglio (BG), Italy
  • 2Cancer Center ASST Papa Giovanni XXIII, Bergamo, Italy
  • 3Medical Oncology Unit, Fondazione Poliambulanza, Brescia, Italy
  • 4Medical Oncology Unit 1, Istituto Oncologico Veneto–IRCCS, Padova, Italy
  • 5Laboratory of Clinical Research Methodology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy
  • 6Medical Oncology Unit, Ospedale San Carlo, Potenza, Italy
  • 7Medical Oncology Unit, Fondazione Istituto Nazionale Tumori–IRCCS, Milano, Italy
  • 8Medical Oncology Unit, Ospedale San Raffaele–IRCCS, Milano, Italy
  • 9Medical Oncology Unit, Azienda Ospedaliero Universitaria Santa Maria della Misericordia, Udine, Italy
  • 10Medical Oncology Unit, Azienda Ospedaliera Santa Croce, Fano, Italy
  • 11Medical Oncology Unit Massa Carrara, Azienda Toscana Nordovest, Italy
  • 12Medical Oncology Unit, Azienda Ospedaliero Universitaria San Giovanni Battista, Molinette, Torino, Italy
  • 13Medical Oncology Unit, AUSL-IRCCS, Reggio Emilia, Italy
  • 14Medical Oncology, University Hospital and University of Cagliari, Cagliari, Italy
  • 15Medical Oncology Unit, Hospital Casa Sollievo della Sofferenza–IRCCS, San Giovanni Rotondo, Italy
  • 16Gastrointestinal Medical Oncology Unit and Neuroendocrine Tumors, Istituto Europeo di Oncologia–IRCCS, Milano, Italy
  • 17Medical Oncology Unit, Sant’Andrea Hospital, Sapienza University of Rome and IDI-IRCCS, Roma, Italy
  • 18Medical Oncology Unit Azienda Ospedaliera San Giovanni Calibita Fatebenefratelli Roma, Italy
  • 19Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center-IRCCS, Rozzano (Milano), Italy
  • 20Medical Oncology Unit, Ospedale di Summa A. Perrino Brindisi, Italy
  • 21Medical Oncology Unit, IRCCS San Martino-IST, Genova, Italy
JAMA Oncol. Published online February 13, 2020. doi:10.1001/jamaoncol.2019.6486
Key Points

Question  What is the optimal duration of oxaliplatin-based adjuvant chemotherapy with capecitabine plus oxaliplatin (CAPOX) or fluorouracil, leucovorin, and oxaliplatin (FOLFOX) for patients with high-risk stage II resected colorectal cancer?

Findings  In this subgroup analysis of a randomized clinical trial of 1254 patients with high-risk stage II resected colorectal cancer, 5-year relapse-free survival was 82.2% for the 3-month arm and 88.2% for the 6-month arm, with noninferiority not shown. Differences in favor of 6-month administration for CAPOX were 0.76% and were 8.56% for FOLFOX although in the 3-month arm, the treatment was significantly less toxic.

Meaning  Although noninferiority of the 3-month arm was not shown, a 3-month CAPOX regimen or a 6-month FOLFOX regimen can be selected when choosing adjuvant chemotherapy in stage II colorectal cancer.


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

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