Perioperative systemic therapy and cytoreductive surgery with HIPEC versus upfront cytoreductive surgery with HIPEC alone for isolated resectable colorectal peritoneal metastases: protocol of a multicentre, open-label, parralel-group, phase II-III, randomised, superiority study (CAIRO6)
Perioperative systemic therapy and cytoreductive surgery with HIPEC versus upfront cytoreductive surgery with HIPEC alone for isolated resectable colorectal peritoneal metastases: protocol of a multicentre, open-label, parralel-group, phase II-III, randomised, superiority study (CAIRO6)
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DOI：
10.1186/s12885-019-5545-0
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发表时间：
2019-04-25
期刊：
影响因子：
3.8
通讯作者：
de Hingh, Ignace H. J. T.
中科院分区：
文献类型：
--
作者：
Rovers, Koen P.;Bakkers, Checca;de Hingh, Ignace H. J. T.
在荷兰，HIPEC（CRS-HIPEC）的前期细胞减灭术是孤立的可切除的结直肠腹膜转移瘤（PM）的标准治疗方法。本研究探讨是否增加围手术期全身治疗CRS-HIPEC改善肿瘤outcomes.MethodsThis开放标签，平行组，第二，第三阶段，随机，优越性研究是在9个荷兰三级转诊中心。合格患者为体能状态良好、经组织学或细胞学证实可切除的结直肠腺癌PM、无全身结直肠转移、入组前6个月内未接受结直肠癌全身治疗且既往无CRS-HIPEC的成人。通过使用中心随机化软件将合格患者随机化（1：1）至围手术期全身治疗和CRS-HIPEC（实验组）或仅预先CRS-HIPEC（对照组），其中最小化按腹膜癌指数0-10或11-20、异时或同步PM、结直肠癌的既往全身治疗和使用奥沙利铂或丝裂霉素C的HIPEC分层。根据治疗医生的判断，围手术期全身治疗包括卡培他滨与奥沙利铂（CAPOX）的四个3周新辅助和辅助周期，5-氟尿嘧啶/亚叶酸与奥沙利铂（FOLFOX）的六个2周新辅助和辅助周期，或6个2周一次的5-氟尿嘧啶/亚叶酸联合伊立替康（FOLFIRI）新辅助治疗周期，随后4个3周一次（卡培他滨）或6个2周（5-氟尿嘧啶/亚叶酸）辅助周期的氟尿嘧啶单药治疗。贝伐珠单抗添加到前三个（CAPOX）或四个（FOLFOX/FOLFIRI）新辅助治疗周期。第一批80例患者入组II期研究，以探索累积的可行性以及围手术期全身治疗的可行性、安全性和耐受性。如果符合预定义的可行性和安全性标准，则该研究将继续作为III期研究，3年总生存期作为主要终点。总共需要358例患者来检测假设的3年总生存率增加15%（对照组50%;实验组65%）。次要终点是手术特征、主要术后发病率、无进展生存期、无病生存期、健康相关生活质量、费用、主要全身治疗相关毒性，这是第一个前瞻性比较围手术期全身治疗和CRS-HIPEC与前期CRS-HIPEC的肿瘤学结局的随机研究。HIPEC单独治疗孤立性可切除结直肠PM。试验注册Clinicaltrials.gov/NCT02758951、NTR/NTR 6301、ISRCTN/ISRCTN 15977568、EudraCT/2016-001865-99。
BackgroundUpfront cytoreductive surgery with HIPEC (CRS-HIPEC) is the standard treatment for isolated resectable colorectal peritoneal metastases (PM) in the Netherlands. This study investigates whether addition of perioperative systemic therapy to CRS-HIPEC improves oncological outcomes.MethodsThis open-label, parallel-group, phase II-III, randomised, superiority study is performed in nine Dutch tertiary referral centres. Eligible patients are adults who have a good performance status, histologically or cytologically proven resectable PM of a colorectal adenocarcinoma, no systemic colorectal metastases, no systemic therapy for colorectal cancer within six months prior to enrolment, and no previous CRS-HIPEC. Eligible patients are randomised (1:1) to perioperative systemic therapy and CRS-HIPEC (experimental arm) or upfront CRS-HIPEC alone (control arm) by using central randomisation software with minimisation stratified by a peritoneal cancer index of 0-10 or 11-20, metachronous or synchronous PM, previous systemic therapy for colorectal cancer, and HIPEC with oxaliplatin or mitomycin C. At the treating physician's discretion, perioperative systemic therapy consists of either four 3-weekly neoadjuvant and adjuvant cycles of capecitabine with oxaliplatin (CAPOX), six 2-weekly neoadjuvant and adjuvant cycles of 5-fluorouracil/leucovorin with oxaliplatin (FOLFOX), or six 2-weekly neoadjuvant cycles of 5-fluorouracil/leucovorin with irinotecan (FOLFIRI) followed by four 3-weekly (capecitabine) or six 2-weekly (5-fluorouracil/leucovorin) adjuvant cycles of fluoropyrimidine monotherapy. Bevacizumab is added to the first three (CAPOX) or four (FOLFOX/FOLFIRI) neoadjuvant cycles. The first 80 patients are enrolled in a phase II study to explore the feasibility of accrual and the feasibility, safety, and tolerance of perioperative systemic therapy. If predefined criteria of feasibility and safety are met, the study continues as a phase III study with 3-year overall survival as primary endpoint. A total of 358 patients is needed to detect the hypothesised 15% increase in 3-year overall survival (control arm 50%; experimental arm 65%). Secondary endpoints are surgical characteristics, major postoperative morbidity, progression-free survival, disease-free survival, health-related quality of life, costs, major systemic therapy related toxicity, and objective radiological and histopathological response rates.DiscussionThis is the first randomised study that prospectively compares oncological outcomes of perioperative systemic therapy and CRS-HIPEC with upfront CRS-HIPEC alone for isolated resectable colorectal PM.Trial registrationClinicaltrials.gov/NCT02758951, NTR/NTR6301, ISRCTN/ISRCTN15977568, EudraCT/2016-001865-99.