Perioperative systemic therapy versus surgery alone for resectable colorectal peritoneal-only metastases (CAIRO6): a randomised, open-label, phase 3 trial.

This trial aimed to compare the efficacy of perioperative systemic therapy versus surgery alone in this population.

该试验旨在比较围手术期系统治疗与单纯手术在这一人群中的疗效。

Methods

This randomised, open-label, phase 3 trial was done at all nine Dutch tertiary centres and one Belgian tertiary centre.

这是一项在所有九个荷兰三级中心和一个比利时三级中心进行的随机、开放标签、III期试验。

Eligible patients were aged 18 years or older with a WHO performance status of 0 or 1 and pathologically proven resectable peritoneal-only metastases of a colorectal adenocarcinoma who did not receive systemic therapy for at least 6 months.

符合条件的患者年龄在18岁或以上，WHO表现状态为0或1，且经病理证实为可切除的仅限腹膜转移的结直肠腺癌，这些患者至少6个月内未接受全身治疗。

Enrolled patients were randomly assigned (1:1) to perioperative systemic therapy and cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC; perioperative systemic therapy group) or upfront CRS-HIPEC alone (surgery alone group) using a web-based system with minimisation stratified by previous systemic therapy, synchronous or metachronous peritoneal metastases, peritoneal cancer index 0-10 or 11-20, and mitomycin C-based or oxaliplatin-based HIPEC.

入组患者被随机分配（1:1）到围手术期系统治疗和细胞减灭术联合腹腔热灌注化疗（CRS-HIPEC; 围手术期系统治疗组）或仅先行CRS-HIPEC（仅手术组），使用基于网络的系统进行最小化分层，根据先前的系统治疗、同步或异时性腹膜转移、腹膜癌指数0-10或11-20，以及基于丝裂霉素C或奥沙利铂的HIPEC进行分层。

At investigator's choice, perioperative systemic therapy comprised either four 3-week neoadjuvant and adjuvant cycles of CAPOX (intravenous oxaliplatin 130 mg/m2 followed by oral capecitabine 1000 mg/m2 twice per day on days 1-14), six 2-week neoadjuvant and adjuvant cycles of FOLFOX (intravenous oxaliplatin 85 mg/m2 with intravenous leucovorin 400 mg/m2, followed by bolus intravenous 5-fluorouracil 400 mg/m2, and continuous intravenous 5-fluorouracil 2400 mg/m2 for 48 h), or six 2-week neoadjuvant cycles of FOLFIRI (intravenous irinotecan 180 mg/m2 with intravenous leucovorin 400 mg/m2, followed by bolus intravenous 5-fluorouracil 400 mg/m2, and continuous intravenous 5-fluorouracil 2400 mg/m2 for 48 h) followed by either four 3-week adjuvant cycles of oral capecitabine (1000 mg/m2 twice per day on days 1-14) or six 2-week adjuvant cycles of 5-fluorouracil and leucovorin (intravenous leucovorin 400 mg/m2, followed by bolus intravenous 5-fluorouracil 400 mg/m2, and continuous intravenous 5-fluorouracil 2400 mg/m2 for 48 h).

根据研究者的选择，围手术期系统治疗包括以下方案之一：CAPOX方案（静脉注射奥沙利铂130 mg/m2，随后口服卡培他滨1000 mg/m2，每日两次，持续14天）的四个3周新辅助和辅助周期；FOLFOX方案（静脉注射奥沙利铂85 mg/m2，随后静脉注射亚叶酸钙400 mg/m2，接着是静脉注射5-氟尿嘧啶400 mg/m2的冲击剂量，以及连续静脉注射5-氟尿嘧啶2400 mg/m2，持续48小时）的六个2周新辅助和辅助周期；或者FOLFIRI方案（静脉注射伊立替康180 mg/m2，随后静脉注射亚叶酸钙400 mg/m2，接着是静脉注射5-氟尿嘧啶400 mg/m2的冲击剂量，以及连续静脉注射5-氟尿嘧啶2400 mg/m2，持续48小时）的六个2周新辅助周期，随后是卡培他滨（口服，1000 mg/m2，每日两次，持续14天）的四个3周辅助周期，或者5-氟尿嘧啶和亚叶酸钙（静脉注射亚叶酸钙400 mg/m2，随后是静脉注射5-氟尿嘧啶400 mg/m2的冲击剂量，以及连续静脉注射5-氟尿嘧啶2400 mg/m2，持续48小时）的六个2周辅助周期。

Intravenous bevacizumab was added to the first three neoadjuvant cycles of CAPOX (7·5 mg/kg) or the first four neoadjuvant cycles of FOLFOX or FOLFIRI (5 mg/kg).

静脉注射的贝伐单抗被添加到CAPOX的前三个新辅助治疗周期（7.5 mg/kg）或FOLFOX或FOLFIRI的前四个新辅助治疗周期（5 mg/kg）。

The primary outcome was overall survivalassessed in a prespecified modified intention-to-treatpopulation, excluding patients who withdrew consent before treatment or violated major eligibility criteria.

主要结果是总生存期，评估在一个预先设定的修改后的意向治疗人群中，排除了在治疗前撤回同意或违反主要资格标准的患者。

Major postoperative morbidity was defined as Clavien-Dindo grade 3-5 and assessed up to 90 days postoperatively.

主要的术后并发症定义为Clavien-Dindo分级3-5级，并在术后90天内进行评估。

Major systemic therapy-related toxicity was defined as Common Terminology Criteria for Adverse Events (CTCAE) grade 3-5 and assessed up to 30 days after its last administration.

主要的系统治疗相关毒性定义为不良事件通用术语标准（CTCAE）3-5级，并在最后一次给药后30天内进行评估。

The Dutch patient organisation for colorectal cancer was involved in the trial design.

荷兰结直肠癌患者组织参与了试验设计。

The trial is registered with Clinicaltrials.gov (NCT02758951) and is active but not recruiting.

该试验已在Clinicaltrials.gov注册（NCT02758951），目前处于活跃状态，但暂停招募。

Results

Between June 15, 2017, and April 29, 2024, 1922 patients were screened for eligibility.

2017年6月15日至2024年4月29日，共有1922名患者进行了资格筛查。

Of these, 358 patients were enrolled and randomly assigned to perioperative systemic therapy (n=180) or surgery alone (n=178). 351 patients were included in the modified intention-to-treatpopulation (173 patients randomly assigned to perioperative systemic therapy and 178 patients to surgery alone; 181 [52%] male and 170 [48%] female).

在这些患者中，358名患者被纳入研究并随机分配接受围手术期系统治疗（n=180）或仅手术治疗（n=178）。

After a median follow-up of 41 months (IQR 21-62), median overall survivalwas 44 months (95% CI 30-54) in the perioperative systemic therapy group versus 39 months (95% CI 31-46) in the surgery alone group (hazard ratio[HR] 0·85, 95% CI 0·62-1·15; p=0·28).

在中位随访41个月（四分位数间距21-62）后，围手术期系统治疗组的中位总生存期为44个月（95%置信区间30-54），而单纯手术组为39个月（95%置信区间31-46）（风险比[HR] 0·85，95%置信区间0·62-1·15；p=0·28）。

In 292 patients who underwent macroscopic complete or near complete CRS-HIPEC, major 90-day postoperative morbidity occurred in 49 (36%) of 138 patients in the perioperative systemic therapy group and in 40 (26%) of 154 patients in the surgery alone group.

在292名接受宏观完整或接近完整的CRS-HIPEC的患者中，围手术期系统治疗组的138名患者中有49名（36%）在术后90天内发生了主要并发症，而单纯手术组的154名患者中有40名（26%）发生了主要并发症。

The most common Clavien-Dindo grade 3-4 postoperative adverse events were intra-abdominal abscess (16 [12%] of 138 patients in the perioperative systemic therapy group vs 16 [10%] of 154 patients in the surgery alone group), anastomotic leakage (12 [9%] vs six [4%]), and fascia dehiscence (13 [9%] vs six [4%]). 90-day postoperative mortality occurred in two (1%) patients in the perioperative systemic therapy group (anastomotic leakage and cerebrovascular accident) and in one (1%) patient in the surgery alone group (anastomotic leakage).

最常见的Clavien-Dindo 3-4级术后不良事件包括腹腔脓肿（围手术期系统治疗组138名患者中有16名[12%]，仅手术组154名患者中有16名[10%]），吻合口漏（分别为12名[9%]和六名[4%]），以及筋膜裂开（分别为13名[9%]和六名[4%]）。围手术期系统治疗组中有两名（1%）患者在术后90天内死亡（一名因吻合口漏，一名因脑血管意外），仅手术组中有一名（1%）患者死亡（因吻合口漏）。

Major systemic therapy-related toxicity occurred in 92 (57%) of 161 patients who started perioperative systemic therapy.

在开始围手术期系统治疗的161名患者中，有92名（57%）患者出现了主要的系统治疗相关毒性反应。

The most common CTCAE grade 3-4 systemic therapy-related adverse events were hypertension (13 [8%] patients), diarrhoea (12 [7%] patients), neutropenia (11 [7%] patients), and thromboembolic events (ten [6%] patients).

最常见的CTCAE 3-4级全身治疗相关不良事件是高血压（13 [8%]患者）、腹泻（12 [7%]患者）、中性粒细胞减少症（11 [7%]患者）和血栓栓塞事件（十 [6%]患者）。

Systemic therapy-related death occurred in one (1%) patient (hyperglycaemia).

有一名（1%）患者因全身治疗相关死亡（高血糖）。

interpretation

Perioperative systemic therapy cannot be recommended in all patients with resectable colorectal peritoneal-only metastases.

对于所有可切除的结直肠癌仅限腹膜转移患者，不建议常规进行围手术期系统治疗。

funding

Dutch Cancer Society, F Hoffman-La Roche.

荷兰癌症协会，F 霍夫曼-拉罗奇公司。