Efficacy of HIPEC in Patients With Colorectal Cancer at High Risk of Peritoneal Carcinomatosis

Study Overview
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Brief Summary
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The purpose of this study is to determine the efficacy of adjuvant HIPEC with Mitomycin C after colectomy in the treatment of colorectal cancer patients at high risk of peritoneal carcinomatosis.

Detailed Description
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The effectiveness of cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) have been addressed for the treatment of peritoneal carcinomatosis in selected patients. However, prophylactic HIPEC in colorectal cancer patients at high risk of metachronous peritoneal metastases remained controversial. In this study, patients with colorectal cancer cT4N0-2M0(AJCC/UICC staging system 8th edition) and planed to undergo intentionally colectomy (laparotomy, laparoscopy，or robotic ) are randomized into HIPEC group and control group. In HIPEC group, closed HIPEC is performed with Mitomycin C(30mg/m2) at 43 °C for 90 minutes, simultaneously or within 2 days after colectomy and followed by systemic chemotherapy. For the patients in the control group, systemic chemotherapy were administered after colectomy. The primary endpoint is peritoneal recurrence-free survival (pRFS) rate. Secondary end points include overall survival (OS) rate, disease free survival (DFS) rate, liver metastatic rate, toxic effects, quality of life scores. All efficacy analyses are conducted in the intention-to-treat population, per-protocol population and pT4 subgroups due to pathologic tumor invasion can not be acquired before HIPEC. Safety analysis include only patients who receive their randomly assigned treatment.

Official Title
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A Multicenter Prospective Randomized Controlled Clinical Trial of Hyperthermic Intraperitoneal Chemotherapy After Colectomy in Patients With Colorectal Cancer at High Risk of Peritoneal Carcinomatosis

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Procedure: Radical colectomy
* Procedure: HIPEC
* Drug: Systemic chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age between 18 and 70 years Nonpregnant or breast-feeding women ECOG status 0-1 Colorectal adenocarcinoma or mucinous adenocarcinoma; Intraoperative confirmed cT4N0-2M0 Colorectal cancer (visual determination - according to AJCC 8th edition) without previous anti-cancer treatment and R0 resection could be achieved Laboratory tests within 2 weeks before Randomization：Neutrophil ≥ 2.0 /mm3, , platelets ≥ 100,000/mm3, hemoglobin≥90g/l, Alanine transaminase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 ×ULN), total bilirubin(TBIL)≤ 1.5 × ULN, serum creatinine ≤ 1.5 ×ULN Written informed consent Exclusion Criteria: Rectal cancer below peritoneal reflection Concurrent with or have other cancer within the past 5 years ( except for skin basal cell carcinoma, or cervical carcinoma in situ, who have received radical treatment) Severe abdominal infection or extensive fibrosis of peritoneal cavity that lead to impossible separation Surgical procedures conversion(from robotic or laparoscopic surgery to laparotomy) or emergency surgery due to perforation or obstruction Existence of distance metastasis during surgery (M1) or can not achieve R0 resection Contraindiction of mitomycin c(chickenpox or shingles) Poorly controlled respiratory or cardiac disease, severe hepatic or renal dysfunction,drug abuse or uncontrolled mental disease

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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 |
| --- | --- |
| Active Comparator: Matched control<br>Patients undergo radical resection of primary colorectal cancer and receive standard adjuvant systemic chemotherapy | Procedure: Radical colectomy<br>* Patients undergo radical resection of the primary colorectal cancer(open or laparoscopic/robotic)<br>Drug: Systemic chemotherapy<br>* Systemic chemotherapy regimens: CapeOx and mFOLFOX6 are preferred for stage Ⅲ patients. CapeOx:oxaliplatin 130 mg/m2 IV d1 + capecitabine 1000mg/m2 po bid d1-14. Repeat every three weeks for eight cycles. mFOLFOX6:oxaliplatin 85 mg/m2 IV d1 + leucovorin calcium 400 mg/m2 IV d1 + 5-FU 400 mg/m2 IV bolus d1 + 5-FU 2400 mg/m2 continuous IV over 46-48 hours d1-2. Repeat every two weeks for twelve cycles. For stageⅡpatiens, regimens recommend by NCCN guide line(2019 v1) are acceptable.<br>|
| Experimental: HIPEC<br>Patients undergo radical resection of colorectal cancer and HIPEC simultaneously or within 2 days after primary tumor resection. Followed by standard adjuvant systemic chemotherapy | Procedure: Radical colectomy<br>* Patients undergo radical resection of the primary colorectal cancer(open or laparoscopic/robotic)<br>Procedure: HIPEC<br>* HIPEC(simultaneously or within 2days after resection) with mitomycin c (30 mg/m2) at 43°C for 90 minutes.<br>Drug: Systemic chemotherapy<br>* Systemic chemotherapy regimens: CapeOx and mFOLFOX6 are preferred for stage Ⅲ patients. CapeOx:oxaliplatin 130 mg/m2 IV d1 + capecitabine 1000mg/m2 po bid d1-14. Repeat every three weeks for eight cycles. mFOLFOX6:oxaliplatin 85 mg/m2 IV d1 + leucovorin calcium 400 mg/m2 IV d1 + 5-FU 400 mg/m2 IV bolus d1 + 5-FU 2400 mg/m2 continuous IV over 46-48 hours d1-2. Repeat every two weeks for twelve cycles. For stageⅡpatiens, regimens recommend by NCCN guide line(2019 v1) are acceptable.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peritoneal recurrence free survival | Peritoneal recurrence free survival is calculated from the date of randomization to the date of record peritoneal recurrence(with or without other metastasis), ovarian metastasis, malignant ascites, or death from any cause, whichever occurred first. | 3-year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease free survival | Disease free survival is calculated from randomization to to the date of a first relapse, the diagnosis of a secondary colorectal cancer after the initial diagnosis, or death from any cause, whichever occurred first. | 3-year | 
| Overall survival | Overall survival is calculated from randomization to death from any cause. | 5-year | 
| Liver metastatic rate | Liver metastatic rate is calculated from randomization to to the date of liver metastasis with or without other organ metastasis. | 3-year | 
| Number of participants with adverse events | Incidence of acute and late toxicity | Up to 1 month after the last chemotherapy cycle | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Colorectal cancer, Colectomy, Hyperthermic intraperitoneal chemotherapy, Peritoneal carcinomatosis