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J Clin Oncol. 2018 May 20;36(15):1478-1485. doi: 10.1200/JCO.2017.76.2187. Epub 2018 Apr 5.

FOLFOX or CAPOX in Stage II to III Colon Cancer: Efficacy Results of the Italian Three or Six Colon Adjuvant Trial.

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Alberto Sobrero, IRCCS San Martino-IST, Genova; Sara Lonardi and Vittorina Zagonel, Istituto Oncologico Veneto-IRCCS, Padova; Gerardo Rosati, Ospedale San Carlo, Potenza; Maria Di Bartolomeo, Fondazione Istituto Nazionale Tumori-IRCCS; Monica Ronzoni, Ospedale San Raffaele-IRCCS; Maria Giulia Zampino, Istituto Europeo di Oncologia-IRCCS; Daris Ferrari, Azienda Ospedaliera San Paolo; and Eliana Rulli, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milano; Nicoletta Pella, Azienda Ospedaliero Universitaria Santa Maria della Misericordia, Udine; Mario Scartozzi, University Hospital and University of Cagliari, Cagliari; Maria Banzi, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia; Felice Pasini, Ospedale Santa Maria della Misericordia, Rovigo; Paolo Marchetti, Sant'Andrea Hospital, Sapienza University of Roma and IDI-IRCCS, Roma; Maurizio Cantore, Civico Hospital Carrara, Carrara; Alberto Zaniboni, Fondazione Poliambulanza, Brescia; Lorenza Rimassa, Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano; Libero Ciuffreda, Azienda Ospedaliero Universitaria San Giovanni Battista, Molinette, Torino; Evaristo Maiello, Hospital Casa Sollievo della Sofferenza-IRCCS, San Giovanni Rotondo; Sandro Barni, Treviglio-Caravaggio Hospital, Treviglio; and Roberto Labianca, Cancer Center ASST Papa Giovanni XXIII, Bergamo, Italy.


Purpose Given the cumulative neurotoxicity associated with oxaliplatin, a shorter duration of adjuvant therapy, if equally efficacious, would be advantageous for patients and health-care systems. Methods The Three or Six Colon Adjuvant trial is an open-label, phase III, multicenter, noninferiority trial randomizing patients with high-risk stage II or stage III colon cancer to receive 3 months or 6 months of FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine plus oxaliplatin). Primary end-point is relapse-free survival. Results 3,759 patients were accrued from 130 Italian sites, 64% receiving FOLFOX and 36% CAPOX. Two-thirds were stage III. The median time of follow up was 62 months and 772 relapses or deaths have been observed. The hazard ratio (HR) of the 3 months versus 6 months for relapse/death was 1.14 (95% CI, 0.99 to 1.32; P [for noninferiority] = .514) and the CI crossed the noninferiority limit of 1.20. However, the absolute difference in 3-year RFS was 1.9% (95% CI, -0.7% to 4.4%). Counter-intuitively, while the RFS curves were similar for stage III (HR, 1.07; 95% CI, 0.91 to 1.26) and for CAPOX treated patients (HR, 0.98; 95% CI, 0.77 to 1.26), they were not for stage II and for FOLFOX treated patients, with HR of 1.41 (95% CI, 1.05 to 1.89) and 1.23 (95% CI, 1.03 to 1.46), respectively, favoring the 6 months of treatment. Conclusion The Three or Six Colon Adjuvant trial failed to formally show noninferiority of 3 versus 6 months of treatment to the predefined margin of 20% relative increase. The results depended on the adjuvant regimen and risk. For CAPOX, 3 months were as good as 6 months; for FOLFOX, 6 months added extra benefit. Counter-intuitively, the low-risk patients benefitted more than the high-risk population from the 6-month duration. The choice of regimen and duration should depend on patient characteristics and be balanced against the extra toxicity of longer therapy.


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