Department of Surgical Oncology, Institut du Cancer de Montpellier, University of Montpellier, Montpellier, France.
Department of Surgery, Gustave Roussy, Villejuif, France.
Lancet Oncol. 2021 Feb;22(2):256-266. doi: 10.1016/S1470-2045(20)30599-4. Epub 2021 Jan 18.
The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to cytoreductive surgery has been associated with encouraging survival results in some patients with colorectal peritoneal metastases who were eligible for complete macroscopic resection. We aimed to assess the specific benefit of adding HIPEC to cytoreductive surgery compared with receiving cytoreductive surgery alone.
We did a randomised, open-label, phase 3 trial at 17 cancer centres in France. Eligible patients were aged 18-70 years and had histologically proven colorectal cancer with peritoneal metastases, WHO performance status of 0 or 1, a Peritoneal Cancer Index of 25 or less, and were eligible to receive systemic chemotherapy for 6 months (ie, they had adequate organ function and life expectancy of at least 12 weeks). Patients in whom complete macroscopic resection or surgical resection with less than 1 mm residual tumour tissue was completed were randomly assigned (1:1) to cytoreductive surgery with or without oxaliplatin-based HIPEC. Randomisation was done centrally using minimisation, and stratified by centre, completeness of cytoreduction, number of previous systemic chemotherapy lines, and timing of protocol-mandated systemic chemotherapy. Oxaliplatin HIPEC was administered by the closed (360 mg/m) or open (460 mg/m) abdomen techniques, and systemic chemotherapy (400 mg/m fluorouracil and 20 mg/m folinic acid) was delivered intravenously 20 min before HIPEC. All individuals received systemic chemotherapy (of investigators' choosing) with or without targeted therapy before or after surgery, or both. The primary endpoint was overall survival, which was analysed in the intention-to-treat population. Safety was assessed in all patients who received surgery. This trial is registed with ClinicalTrials.gov, NCT00769405, and is now completed.
Between Feb 11, 2008, and Jan 6, 2014, 265 patients were included and randomly assigned, 133 to the cytoreductive surgery plus HIPEC group and 132 to the cytoreductive surgery alone group. After median follow-up of 63·8 months (IQR 53·0-77·1), median overall survival was 41·7 months (95% CI 36·2-53·8) in the cytoreductive surgery plus HIPEC group and 41·2 months (35·1-49·7) in the cytoreductive surgery group (hazard ratio 1·00 [95·37% CI 0·63-1·58]; stratified log-rank p=0·99). At 30 days, two (2%) treatment-related deaths had occurred in each group.. Grade 3 or worse adverse events at 30 days were similar in frequency between groups (56 [42%] of 133 patients in the cytoreductive surgery plus HIPEC group vs 42 [32%] of 132 patients in the cytoreductive surgery group; p=0·083); however, at 60 days, grade 3 or worse adverse events were more common in the cytoreductive surgery plus HIPEC group (34 [26%] of 131 vs 20 [15%] of 130; p=0·035).
Considering the absence of an overall survival benefit after adding HIPEC to cytoreductive surgery and more frequent postoperative late complications with this combination, our data suggest that cytoreductive surgery alone should be the cornerstone of therapeutic strategies with curative intent for colorectal peritoneal metastases.
Institut National du Cancer, Programme Hospitalier de Recherche Clinique du Cancer, Ligue Contre le Cancer.
对于有资格接受完全宏观切除术的结直肠腹膜转移患者，在细胞减灭术的基础上添加腹腔内热灌注化疗（HIPEC）与令人鼓舞的生存结果相关。我们旨在评估与单独接受细胞减灭术相比，添加 HIPEC 对细胞减灭术的具体益处。
我们在法国的 17 家癌症中心进行了一项随机、开放标签、3 期试验。合格的患者年龄在 18-70 岁之间，组织学证实患有结直肠癌症合并腹膜转移，世界卫生组织表现状态为 0 或 1，腹膜癌指数为 25 或更低，并且有资格接受 6 个月的全身化疗（即他们有足够的器官功能和至少 12 周的预期寿命）。完成完全宏观切除术或残留肿瘤组织小于 1 毫米的手术切除的患者被随机分配（1:1）接受细胞减灭术加或不加奥沙利铂为基础的 HIPEC。中央随机化采用最小化，按中心、细胞减灭术的完成程度、以前全身化疗线的数量和方案规定的全身化疗的时间进行分层。奥沙利铂 HIPEC 通过封闭（360 mg/m）或开放（460 mg/m）腹部技术进行，全身化疗（400 mg/m 氟尿嘧啶和 20 mg/m 亚叶酸）在 HIPEC 前 20 分钟静脉内给予。所有患者在手术前后或两者都接受了研究者选择的全身化疗（加或不加靶向治疗）。主要终点是总生存期，在意向治疗人群中进行分析。对接受手术的所有患者进行安全性评估。这项试验在 ClinicalTrials.gov 注册，NCT00769405，现已完成。
在 2008 年 2 月 11 日至 2014 年 1 月 6 日期间，纳入了 265 名患者，并随机分配，133 名患者接受细胞减灭术加 HIPEC 组，132 名患者接受细胞减灭术组。在中位数为 63.8 个月（IQR 53.0-77.1）的中位随访后，细胞减灭术加 HIPEC 组的中位总生存期为 41.7 个月（95%CI 36.2-53.8），细胞减灭术组为 41.2 个月（35.1-49.7）（危险比 1.00 [95.37%CI 0.63-1.58]；分层对数秩检验 p=0.99）。在 30 天时，两组各有 2 例（2%）与治疗相关的死亡。30 天内的 3 级或更高级别的不良事件在两组中的频率相似（细胞减灭术加 HIPEC 组 133 例患者中有 56 例[42%]，细胞减灭术组 132 例患者中有 42 例[32%]；p=0.083）；然而，在 60 天时，细胞减灭术加 HIPEC 组的 3 级或更高级别的不良事件更为常见（细胞减灭术加 HIPEC 组 131 例中有 34 例[26%]，细胞减灭术组 130 例中有 20 例[15%]；p=0.035）。
考虑到在细胞减灭术的基础上添加 HIPEC 后没有总生存获益，并且这种联合治疗后术后晚期并发症更频繁，我们的数据表明，单独的细胞减灭术应该是有治愈意图的结直肠腹膜转移治疗策略的基石。
法国国家癌症研究所，癌症临床研究计划，法国癌症联盟。
