Medical Oncology Unit, Medical Science Department, American SamoaST Bergamo Ovest, Treviglio (BG), Italy.
Cancer Center ASST Papa Giovanni XXIII, Bergamo, Italy.
JAMA Oncol. 2020 Apr 1;6(4):547-551. doi: 10.1001/jamaoncol.2019.6486.
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.
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).
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.
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.
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.
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.
ClinicalTrials.gov Identifier: NCT0064660.
在标准的基于氟尿嘧啶的 6 个月辅助化疗中加入奥沙利铂已经被报道可以降低复发风险，尽管它不会增加生存。三期或六期结肠癌辅助治疗（TOSCA）试验比较了 III 期结肠癌患者 3 个月和 6 个月的辅助氟嘧啶和奥沙利铂为基础的化疗。其效果仍不清楚。
评估高危 II 期结直肠癌患者在 TOSCA 试验中接受 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）辅助化疗 3 个月与 6 个月的非劣效性和毒性作用。
设计、地点和参与者：TOSCA 研究是一项非劣效性的三期随机临床试验，于 2007 年 6 月至 2013 年 3 月在 130 家意大利中心进行。纳入的患者有内镜下距肛门 12cm 或手术中腹膜反射以上的 II 期结直肠癌。在这项评估意向治疗人群的预先计划的研究中，对 1254 例高危 II 期结直肠癌患者进行了 5 年无复发生存率评估，这些患者接受了辅助 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。
患者最初在 TOSCA 试验中随机（1：1）接受 3 个月（实验组）或 6 个月（对照组）的标准剂量 FOLFOX 或 CAPOX，由治疗医生决定。
化疗组 3 个月和 6 个月之间的危险比至少为 1.2，以拒绝非劣效性的零假设。
共有 1254 例（平均[标准差]年龄 62.4[9.8]岁；565 名女性[45.1%]）有临床高危 II 期结直肠癌，中位随访时间为 62 个月（四分位距 53-71）。其中 301 例（24.0%）患者有 pT4N0M0 肿瘤，其余 953 例（76.0%）患者有高危 pT3N0M0 肿瘤；776 例（61.9%）患者接受 FOLFOX 治疗，478 例（38.1%）患者接受 CAPOX 治疗。3 个月组的 5 年无复发生存率为 82.2%，6 个月组为 88.2%，估计的危险比为 1.41（95%可信区间，1.05-1.89；非劣效性 P=0.86）。对于 CAPOX，两组的 5 年无复发生存率相似（差异为 0.76%，有利于 6 个月组；95%可信区间，-6.28%至 7.80%），而对于 FOLFOX，差异明显：有利于较长持续时间组 8.56%（95%可信区间，3.45%-13.67%）。然而，持续时间和方案之间的交互作用检验没有统计学意义。神经毒性在较短持续时间组中比在较长持续时间组中低约 5 倍。
在 3 个月组中，治疗的毒性明显低于 6 个月组。5 年无复发生存率未显示非劣效性。然而，观察到了可能的方案效应，这表明对于接受 II 期结直肠癌治疗的患者，无论是 3 个月的 CAPOX 还是 6 个月的 FOLFOX 治疗都可以使用奥沙利铂双药。
ClinicalTrials.gov 标识符：NCT0064660。
