Prophylactic Surgery Plus HIPEC With CO2 in Patients Affected by Colorectal Carcinoma. CHECK Study.

Study Overview
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Brief Summary
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This is a phase III randomized, multicenter study with two different arm: experimental: prophylactic surgery plus HIPEC CO2 performed with mitomycin comparator: standard surgery Adjuvant treatment after surgery is mandatory except for documented cases of non-eligibility. Patient will be randomized in a 1:1 ratio. Randomization will be done during surgery if the total resection of tumour will be reached and will use a stratification procedure based on center

Detailed Description
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This is a phase III randomized, multicenter study with two different arm: experimental: prophylactic surgery plus HIPEC CO2 performed with mitomycin comparator: standard surgery Adjuvant treatment after surgery is mandatory except for documented cases of non-eligibility. Patient will be randomized in a 1:1 ratio. Randomization will be done during surgery if the total resection of tumour will be reached and will use a stratification procedure based on center The HIPEC CO2 regimen will be as reported below: mitomycin: (total dose of 35 mg/mq, physiologic solution 0.9%) administrated 50% at time 0 from start of HIPEC CO2 treatment (17.5 mg/mq), 25% (8.8 mg/mq) after 30 minutes and the last dose 25% after 60 minutes. Recommended temperature for HIPEC treatment is 41-42 °C for 90 minutes. Adjuvant treatment consists of a 6 months chemotherapy after surgery. It is possible to choose between Oxaliplatin, Capecitabine (XELOX) or Oxaliplatin, Fluorouracil, Leucovorin (FOLFOX-4) Patients affected by CRC at high risk of developing peritoneal carcinomatosis will be randomized in the study.

Official Title
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Prophylactic Surgery Plus Hyperthermic Intraperitoneal Chemotherapy (HIPEC CO2) Versus Standard Surgery in Colorectal Carcinoma at High Risk Peritoneal Carcinomatosis. Short and Long-term Outcomes. CHECK STUDY

Conditions
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Colorectal Neoplasms

Intervention / Treatment
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* Procedure: HIPEC CO2 surgery
* Procedure: Standard surgery
* Drug: Mitomycin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with histologically documented colorectal adenocarcinoma eligible for R0, Presurgical or intraoperative stage T4a or T4b primary tumour (TNM 8 th) Urgent presentation: perforation without purulent generalized peritonitis or fecal peritonitis Peritumoral minimal peritoneal carcinomatosis: limited peritoneal disease in close proximity to the primary tumour, that may be removed en bloc Ovarian metastases (Krukenberg tumor) Age ≥ 18 and ≤75 years Written informed consent Exclusion Criteria: Distant metastatic disease (even if limited and completely resected) History of tumour diagnosed in the 3 years before entering the study, except for topical and healed pathologies that do not need further treatment (e.g. non-melanoma skin carcinomas, superficial bladder carcinomas or in situ carcinoma of the breast or cervix). Psychological, family or social conditions which may negatively affect the treatment and follow-up protocol. Poor general conditions (ECOG > 2). Impaired cardiac function (history of congestive heart failure or FE <40%). Clinically significant cardiovascular disease: cerebral vascular accident/stroke (<6 months prior to enrolment), myocardial infarction (<6 months prior to enrolment), unstable angina, congestive heart failure (New York Heart Association Classification Class > II or serious uncontrolled cardiac Arythmia requiring medication Impaired renal function (creatinine> 1.5 upper limit of normal or creatinine clearance <60 mL / min) Impaired hepatic function (AST, ALT >2.5 upper limit of normal, bilirubin> 1.5 upper limit of normal) Impaired hematopoietic function (leucocytes <4000 / mm3, neutrophils <1500 / mm3, platelets <100000 / mm3) Impaired pulmonary function (presence of COPD or other pulmonary restrictive conditions with FEV1 <50% or DLCO <40% of normal age value). Pregnancy History or presence of other diseases, metabolic dysfunction, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of HIPEC or chemotherapy or patient at high risk from treatment complications. Chronic inflammatory bowel disease Patients with acute bowel obstruction Refusal to join the study

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
Interventional Model Description: This is a phase III randomized, multicenter study with two different arm: experimental: prophylactic surgery plus HIPEC CO2 performed with mitomycin comparator: standard surgery
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental<br>ARM A: Prophylactic surgery plus HIPEC CO2 performed with mitomycin | Procedure: HIPEC CO2 surgery<br>* Prophylactic surgery plus HIPEC CO2 performed with mitomycin<br>Drug: Mitomycin<br>* Prophylactic surgery plus HIPEC CO2 performed with mitomycin<br>* Other names: HIPEC CO2 surgery with mitomycin;|
| Active Comparator: Comparator<br>ARM B: Standard surgey without HIPEC CO2 The arm B is with standard surgery without HIPEC CO2 | Procedure: Standard surgery<br>* Standard surgery without HIPEC CO2<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local recurrence free survival (LRFS) | The primary efficacy endpoint is LRFS defined as the time from randomization to the date of first local relapse, peritoneal carcinomatosis or death for any cause, whichever comes first. | This outcome measure will be assess approximately 3 years after the last patient enrolled | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Free Survival (DFS) | Disease Free Survival (DFS) DFS is defined as the time from randomization to the date of first local relapse, distant relapse, peritoneal carcinomatosis or death for any cause, whichever comes first. OS is defined as the time from randomization to death for any cause. | This outcome measure will be assess approximately 3 years after the last patient enrolled | 
| Overall Survival (OS) | death for any cause | This outcome measure will be assessed approximately 3 years after the last patient enrolled | 
| number of post-surgery complication | any type of complication | This outcome measure will be assessed approximately 3 years after the last patient enrolled | 
| morbidity | evaluated during and after surgery, graded according to the NCI-CTAE version 4.03 for AE related to chemotherapy and according to Clavien Dindo for surgery complications | This outcome measure will be assessed approximately 3 years after the last patient enrolled | 
| duration of surgery | timing of surgery | This outcome measure will be assessed approximately 3 years after the last patient enrolled | 
| number of patients performing the adjuvant chemotherapy. | patients performing the adjuvant chemotherapy | This outcome measure will be assessed approximately 3 years after the last patient enrolled | 
| length of hospitalization | length of hospitalization | This outcome measure will be assessed approximately 3 years after the last patient enrolled | 
| mortality at 30 and 90 days from surgery | mortality at 30 and 90 days from surgery | This outcome measure will be assessed approximately 3 years after the last patient enrolled | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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colorectal cancer, HIPEC CO2, prophylactic surgery, mitomycin