• Alberto Sobrero, Sara Lonardi, Gerardo Rosati, Maria Di Bartolomeo, Monica Ronzoni, Nicoletta Pella, Mario Scartozzi, Maria Banzi, Maria Giulia Zampino, Felice Pasini, Paolo Marchetti, Maurizio Cantore, Alberto Zaniboni, Lorenza Rimassa, Libero Ciuffreda, Daris Ferrari, Vittorina Zagonel, Evaristo Maiello, Sandro Barni, Eliana Rulli, Roberto Labianca, and TOSCA Investigators.
• 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.
• J. Clin. Oncol. 2018 May 20; 36 (15): 1478-1485.

AbstractPurpose 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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