Preoperative Systemic Therapy for Colorectal Cancer Peritoneal Metastases

Study Overview
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Brief Summary
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This is an open-label, parallel-group, phase 2 randomized trial which randomizes patients with isolated resectable colorectal cancer peritoneal metastases to receive preoperative systematic therapy followed by CRS+HIPEC and postoperative chemotherapy or upfront CRS+HIPEC followed by postoperative chemotherapy.

Official Title
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Preoperative Systemic Therapy With FOLFOXIRI Plus Bevacizumab Followed by Cytoreductive Surgery Versus Upfront Cytoreductive Surgery for Resectable Colorectal Peritoneal Metastases: A Randomized Phase 2 Trial

Conditions
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Colorectal Neoplasms, Colorectal Cancer, Colorectal Cancer Metastatic, Peritoneal Metastases, Peritoneal Cancer, Peritoneal Neoplasms, Chemotherapy Effect, Cytoreductive Surgery, Hyperthermic Intraperitoneal Chemotherapy

Intervention / Treatment
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* Drug: Preoperative systematic therapy
* Procedure: CRS+HIPEC
* Drug: Postoperative chemotherapy
* Drug: Postoperative chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; Historically and radiologically confirmed colorectal cancer peritoneal metastasis except for appendical origin; Tolerable to scheduled chemotherapy; No evidence of extraperitoneal metastases at enrollment; Resectable disease determined by radiological and laparoscopy/laparotomy; No systematic therapy within 6 months before enrollment; Tolerable to cytoreductive surgery. Exclusion Criteria: Without adequate organ function (e.g. :neutrophil countt≤1.5×10^9/L, or platelets≤75×10^12/L，or hemoglobin<90g/L, or aminotransferase、aspartate aminotransferaseAST<2.5ULN, or total bilirubin<1.5ULN, or creatinine<1.5ULN; Emergency surgery; Recent thromboembolic event or cerebrovascular disease (12 months before enrollment); Pregnancy or lactation Comorbid with severe physical or mental disease.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Chemotherapy group<br>6 cycles of mFOLFOXIRI±Bev is followed by cytoreductive surgery. Postoperative 6 cycles of mFOLFOX is scheduled. | Drug: Preoperative systematic therapy<br>* 6 cycles of mFOLFOXIRI±Bev is administrated before CRS+HIPEC. Irinotecan165mg/m2 IV day 1, oxaliplatin 85mg/m2 IV day 1, leucovorin 400mg/m2 IV day , bevacizumab mg/kg IV day 1, 5-fluorouracil 400mg/m2, continuous infusion over 46-48h. Dose reduction is permitted. Bev will not be administrated in at the last two cycles for minimizing surgery complications.<br>Procedure: CRS+HIPEC<br>* CRS+HIPEC aims to achieve CC0/CC1 resection. Oxaliplatin or mitomycin C is determined by the treating physician.<br>Drug: Postoperative chemotherapy<br>* 6 cycles of mFOLFOX+Bev is administrated after CRS+HIPEC. Oxaliplatin 85mg/m2 IV day 1, leucovorin 400mg/m2 IV day , bevacizumab mg/kg IV day 1, 5-fluorouracil 400mg/m2 IV bolus day 1,5-fluorouracil 400mg/m2, continuous infusion over 46-48h. Dose reduction is permitted.<br>|
| Active Comparator: Upfront surgery group<br>Upfront surgery group is followed by 12 cycles of mFOLFOX+Bev | Procedure: CRS+HIPEC<br>* CRS+HIPEC aims to achieve CC0/CC1 resection. Oxaliplatin or mitomycin C is determined by the treating physician.<br>Drug: Postoperative chemotherapy<br>* 12 cycles of mFOLFOX+Bev is administrated after CRS+HIPEC. Oxaliplatin 85mg/m2 IV day 1, leucovorin 400mg/m2 IV day , bevacizumab mg/kg IV day 1, 5-fluorouracil 400mg/m2 IV bolus day 1,5-fluorouracil 400mg/m2, continuous infusion over 46-48h. Dose reduction is permitted.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival | From randomization to progression by RECIST1.1, or appearance of measurable lesion after non-measureable lesion, or intraoperative unresectable disease, or recurrence after surgery, or death from any reason. | Up to five years after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response to preoperative systematic therapy | Assessed by tumor regression grade | About 4 months after randomization | 
| Major adverse events of systematic therapy | Grade ≥3 adverse events by CTCAE 5.0 | Up to 8 months after randomization | 
| Overall survival | From randomization to death of any cause | Up to five years after randomization | 
| Intraoperative peritoneal cancer index | Peritoneal cancer index (PCI) is a tool which sum scores in thirteen abdominal regions according to tumor size. | About 4 months after randomization | 
| Complete cytoreductive surgery | R0/R1 resection or CC0/CC1 resection | About 4 months after randomization | 
| Hospitalization time | Safety of cytoreductive surgery | About 4 months after randomization |