Importance In patients with colorectal cancer and unresectable liver-only metastases (CRLM), treatment with folinic acid, fluorouracil, and oxaliplatin (FOLFOX) plus irinotecan (FOLFOXIRI) and bevacizumab vs FOLFOX/folinic acid, fluorouracil, and irinotecan (FOLFIRI) plus bevacizumab increased progression-free survival, response, and R0/R1 resection/ablation rates, as well as toxic effects in RAS/BRAFV600E-variant and/or right-sided tumors. FOLFOX/FOLFIRI-panitumumab vs FOLFOX/FOLFIRI-bevacizumab increased response at the cost of more toxic effects in RAS/BRAFV600E wild-type, left-sided tumors. Objective To present long-term outcomes of treatment with FOLFOXIRI plus bevacizumab vs FOLFOX/FOLFIRI plus bevacizumab and FOLFOX/FOLFIRI plus panitumumab vs FOLFOX/FOLFIRI + bevacizumab. Design, Setting, and Participants The randomized phase 3 CAIRO5 trial included patients with initially unresectable CRLM in 46 Dutch centers and 1 Belgian center between November 2014 and January 2022. A liver expert panel repeatedly evaluated resectability. Intervention Patients with RAS/BRAFV600E-variant and/or right-sided tumors randomly received FOLFOX/FOLFIRI-bevacizumab (group 1) or FOLFOXIRI-bevacizumab (group 2), and those with RAS/BRAFV600E wild-type, left-sided tumors received FOLFOX/FOLFIRI-bevacizumab (group 3) or FOLFOX/FOLFIRI-panitumumab (group 4). Adjuvant chemotherapy (ACT) after complete local treatment was recommended but not standard. Main Outcomes and Measures Overall survival (OS) was analyzed as a secondary outcome. Other outcomes were post hoc analyses. Results A total of 530 patients (327 male [62%] and 203 female individuals [38%]; median age, 62 [IQR, 54-69] years) were randomized: 148 in group 1, 146 in group 2, 118 in group 3, and 118 in group 4. The median OS in group 1 was 23.6 (95% CI, 20.1-27.5) vs 24.1 (95% CI, 21.0-30.9) months in group 2 (hazard ratio [HR], 0.90; 95% CI, 0.70-1.17; P = .44), and 39.9 (95% CI, 30.7-44.6) in group 3 vs 38.3 (95% CI, 35.3-51.3) months in group 4 (HR, 0.95; 95% CI, 0.68-1.32; P = .75). OS was longest after complete local treatment without early (≤6 months) recurrence (64.3 months; 95% CI, 57.6 to not reached) and salvage local treatment options after early recurrence (58.9; 95% CI, 47.3 to not reached), followed by patients without salvage local treatment after early recurrence (30.5; 95% CI, 24.4-33.4) and with incomplete local treatment (28.7; 95% CI, 25.9-38.3), and worst in patients with continued unresectability (18.3; 95% CI, 15.7-20.0). After confounder adjustment, ACT was associated with longer OS (HR, 0.66; 95% CI, 0.44-0.98) and relapse-free survival (HR, 0.65; 95% CI, 0.48-0.88) and less early recurrence without salvage local treatment (odds ratio, 0.46; 95% CI, 0.25-0.85). Conclusions and Relevance These results support using FOLFOX/FOLFIRI-bevacizumab for patients with initially unresectable CRLM irrespective of RAS/BRAFV600E status and tumor sidedness. Patients with complete local liver treatment with salvage local treatment in case of early recurrence had the longest OS. ACT might be considered for these patients. Trial Registration ClinicalTrials.gov NCT02162563.

中文翻译：

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最初不可切除的结直肠肝转移的一线全身治疗：CAIRO5 随机临床试验的事后分析。


重要性 对于结直肠癌和不可切除的仅肝转移 （CRLM） 患者，亚叶酸、氟尿嘧啶和奥沙利铂 （FOLFOX） 加伊立替康 （FOLFOXIRI） 和贝伐珠单抗治疗与 FOLFOX/亚叶酸、氟尿嘧啶和伊立替康 （FOLFIRI） 联合贝伐珠单抗治疗增加了无进展生存期、反应和 R0/R1 切除/消融率，以及对 RAS/BRAFV600E 变异和/或右侧肿瘤的毒性作用。FOLFOX/FOLFIRI-帕尼单抗与 FOLFOX/FOLFIRI-贝伐珠单抗在 RAS/BRAFV600E 野生型左侧肿瘤中以更多毒性作用为代价增加了反应。目的 介绍 FOLFOXIRI 加贝伐珠单抗 vs FOLFOX/FOLFIRI 加贝伐珠单抗和 FOLFOX/FOLFIRI 加帕尼单抗 vs FOLFOX/FOLFIRI + 贝伐珠单抗治疗的长期结果。设计、设置和参与者 随机 3 期 CAIRO5 试验包括 2014 年 11 月至 2022 年 1 月期间在 46 个荷兰中心和 1 个比利时中心接受的初始不可切除的 CRLM 患者。肝脏专家小组反复评估了可切除性。干预 RAS/BRAFV600E 变异型和/或右侧肿瘤患者随机接受 FOLFOX/FOLFIRI-贝伐珠单抗 （第 1 组） 或 FOLFOXIRI-贝伐珠单抗 （第 2 组），RAS/BRAFV600E野生型左侧肿瘤患者接受 FOLFOX/FOLFIRI-贝伐珠单抗 （第 3 组） 或 FOLFOX/FOLFIRI-帕尼单抗 （第 4 组）。建议在完全局部治疗后进行辅助化疗 （ACT），但不是标准的。主要结局和指标 总生存期 （OS） 作为次要结局进行分析。其他结局为事后分析。结果 共有 530 例患者 （327 例男性 [62%] 和 203 例女性 [38%];中位年龄 62 [IQR，54-69] 岁） 被随机分配： 第 1 组 148 例，第 2 组 146 例，第 3 组 118 例，第 4 组 118 例。 第 1 组的中位 OS 为 23.6 （95% CI，20.1-27.5） 比第 2 组 24.1 （95% CI，21.0-30.9） 个月 （风险比 [HR]，0.90;95% CI，0.70-1.17;P = .44），第 3 组为 39.9 （95% CI，30.7-44.6），第 4 组为 38.3 （95% CI，35.3-51.3） 个月 （HR，0.95;95% CI，0.68-1.32;P = .75）。完全局部治疗无早期（≤6 个月）复发（64.3 个月;95% CI，57.6 至未达到）和早期复发后挽救性局部治疗方案（58.9;95% CI，47.3 至未达到）的 OS 最长，其次是早期复发后未进行挽救性局部治疗的患者（30.5;95% CI，24.4-33.4）和局部治疗不完全（28.7;95% CI， 25.9-38.3），在持续无法切除的患者中最差 （18.3;95% CI，15.7-20.0）。在混杂因素调整后，ACT 与较长的 OS （HR，0.66;95% CI，0.44-0.98） 和无复发生存期 （HR，0.65;95% CI，0.48-0.88） 和较少的早期复发相关，无需挽救性局部治疗 （比值比，0.46;95% CI，0.25-0.85）。结论和相关性这些结果支持将 FOLFOX/FOLFIRI-贝伐珠单抗用于最初不可切除的 CRLM 患者，无论 RAS/BRAFV600E 状态和肿瘤偏侧如何。在早期复发的情况下，完全局部肝脏治疗和挽救性局部治疗的患者具有最长的 OS。试验注册 ClinicalTrials.gov NCT02162563.