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. doi: 10.1200/JCO.2017.76.2187. Epub 2018 Apr 5.
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.
目的 鉴于奥沙利铂相关的累积神经毒性，如果辅助治疗时间更短且同样有效，对患者和医疗保健系统将更为有利。
方法 Three or Six Colon Adjuvant 试验是一项开放标签、III 期、多中心、非劣效性试验，将高危 II 期或 III 期结肠癌患者随机分配接受 3 个月或 6 个月的 FOLFOX（氟尿嘧啶、亚叶酸钙和奥沙利铂）或 CAPOX（卡培他滨加奥沙利铂）治疗。主要终点是无复发生存。
结果 该试验从 130 个意大利站点招募了 3759 名患者，其中 64%接受 FOLFOX 治疗，36%接受 CAPOX 治疗。三分之二的患者为 III 期。中位随访时间为 62 个月，观察到 772 例复发或死亡。3 个月与 6 个月的复发/死亡风险比为 1.14（95%CI，0.99 至 1.32；P[非劣效性] =.514），且 CI 超过了 1.20 的非劣效性界限。然而，3 年 RFS 的绝对差异为 1.9%（95%CI，-0.7%至 4.4%）。出乎意料的是，虽然 III 期（HR，1.07；95%CI，0.91 至 1.26）和 CAPOX 治疗患者（HR，0.98；95%CI，0.77 至 1.26）的 RFS 曲线相似，但 II 期和 FOLFOX 治疗患者的 RFS 曲线却不同，其 HR 分别为 1.41（95%CI，1.05 至 1.89）和 1.23（95%CI，1.03 至 1.46），这表明 6 个月的治疗更有利。
结论 Three or Six Colon Adjuvant 试验未能正式证明 3 个月与 6 个月治疗在预先设定的 20%相对增加的边界内具有非劣效性。结果取决于辅助治疗方案和风险。对于 CAPOX，3 个月与 6 个月一样有效；对于 FOLFOX，6 个月的治疗额外增加了获益。出乎意料的是，低危患者比高危人群从 6 个月的治疗中获益更多。治疗方案和持续时间的选择应取决于患者特征，并与更长治疗时间的额外毒性相平衡。
