Importance The role of primary tumor resection (PTR) in synchronous patients with metastatic colorectal cancer (mCRC) who had unresectable metastases and few or absent symptoms of their primary tumor is unclear. Studying subgroups with low postoperative mortality may identify patients who potentially benefit from PTR.

Objective To determine the difference in 60-day mortality between patients randomized to systemic treatment only vs PTR followed by systemic treatment, and to explore risk factors associated with 60-day mortality.

Design, Setting, and Participants CAIRO4 is a randomized phase 3 trial initiated in 2012 in which patients with mCRC were randomized to systemic treatment only or PTR followed by systemic treatment with palliative intent. This multicenter study was conducted by the Danish and Dutch Colorectal Cancer Group in general and academic hospitals in Denmark and the Netherlands. Patients included between August 2012 and December 2019 with histologically proven colorectal cancer, unresectable metastases, and a primary tumor with few or absent symptoms were eligible.

Interventions Systemic treatment, consisting of fluoropyrimidine-based chemotherapy with bevacizumab vs PTR followed by fluoropyrimidine-based chemotherapy with bevacizumab.

Main Outcomes and Measures The aim of the current analysis was to compare 60-day mortality rates in both treatment arms. A secondary aim was the identification of risk factors for 60-day mortality in the treatment arms. These aims were not predefined in the study protocol.

Results A total of 196 patients were included in the intention-to-treat analysis (112 [57%] men; median [IQR] age, 65 [59-70] years). Sixty-day mortality was 3% (95% CI, 1%-9%) in the systemic treatment arm and 11% (95% CI, 6%-19%) in the PTR arm (P = .03). In a per-protocol analysis, 60-day mortality was 2% (95% CI, 1%-7%) vs 10% (95% CI, 5%-18%; P = .048). Patients with elevated serum levels of lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, and/or neutrophils who were randomized to PTR had a significantly higher 60-day mortality than patients without these characteristics.

Conclusions and Relevance Patients with mCRC who were randomized to PTR followed by systemic treatment had a higher 60-day mortality than patients randomized to systemic treatment. Especially patients randomized to the PTR arm with elevated serum levels of lactate dehydrogenase, neutrophils, aspartate aminotransferase, and/or alanine aminotransferase were at high risk of postoperative mortality. Final study results on overall survival have to be awaited.

Trial Registration ClinicalTrials.gov Identifier: NCT01606098

重要性 原发性肿瘤切除术 (PTR) 在转移性结直肠癌 (mCRC) 同步患者中的作用，这些患者有不可切除的转移灶且原发性肿瘤的症状很少或没有症状，目前尚不清楚。研究术后死亡率低的亚组可能会识别出可能从 PTR 中受益的患者。

目的 确定随机接受仅全身治疗与 PTR 继以全身治疗的患者在 60 天死亡率方面的差异，并探讨与 60 天死亡率相关的危险因素。

设计、设置和参与者 CAIRO4 是一项于 2012 年启动的随机 3 期试验，其中 mCRC 患者被随机分配至仅全身治疗或 PTR，然后进行全身性姑息治疗。这项多中心研究由丹麦和荷兰结直肠癌小组在丹麦和荷兰的综合医院和学术医院进行。纳入 2012 年 8 月至 2019 年 12 月期间经组织学证实为结直肠癌、无法切除的转移灶以及很少或没有症状的原发肿瘤的患者符合条件。

干预 全身治疗，包括基于氟嘧啶的贝伐单抗化疗 vs PTR，然后是基于氟嘧啶的贝伐单抗化疗。

主要结果和措施 当前分析的目的是比较两个治疗组的 60 天死亡率。次要目标是确定治疗组 60 天死亡率的危险因素。这些目标没有在研究方案中预先定义。

结果 共有 196 名患者被纳入意向治疗分析（112 [57%] 男性；中位 [IQR] 年龄，65 [59-70] 岁）。全身治疗组的 60 天死亡率为 3%（95% CI，1%-9%），PTR 组为 11%（95% CI，6%-19%）（P  = .03）。在符合方案分析中，60 天死亡率分别为 2%（95% CI，1%-7%）和 10%（95% CI，5%-18%；P  = .048）。血清乳酸脱氢酶、天冬氨酸氨基转移酶、丙氨酸氨基转移酶和/或中性粒细胞水平升高的患者被随机分配到 PTR 组，其 60 天死亡率显着高于没有这些特征的患者。

结论和相关性 随机接受 PTR 继以全身治疗的 mCRC 患者的 60 天死亡率高于随机接受全身治疗的患者。尤其是随机分配到 PTR 组的患者，其血清乳酸脱氢酶、中性粒细胞、天冬氨酸氨基转移酶和/或丙氨酸氨基转移酶水平升高，术后死亡率高。必须等待关于总生存期的最终研究结果。

试验注册 ClinicalTrials.gov 标识符：NCT01606098