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

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

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

Study Overview

• Status: Recruiting
• Conditions: Colorectal Neoplasms
• Intervention / Treatment: Procedure: Standard surgery; Procedure: HIPEC CO2 surgery; Drug: Mitomycin

Detailed 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 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.

• Study Type: Interventional
• Enrollment (Estimated): 330
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Fabio Pacelli, MD; Phone Number: 7255 0039063015; Email: fabio.pacelli@policlinicogemelli.it
• Study Contact Backup: Name: Chiara Gerardi; Phone Number: 4659 0039023901; Email: chiara.gerardi@marionegri.it

Study Locations

• Italy
  • Bari, Italy
    • Recruiting
    • IRCCS Istituto Tumori Giovanni Paolo II
    • Contact: Michele Simone
  • Caltanissetta, Italy
    • Recruiting
    • ASP PO Sant'Elia
    • Contact: Giovanni Ciaccio
  • Cuneo, Italy
    • Active, not recruiting
    • AO Santa Croce e Carle
  • Feltre, Italy
    • Active, not recruiting
    • ULLS1 1 Dolomiti - Ospedale di Feltre
  • Mestre, Italy
    • Recruiting
    • Ospedale Dell Angelo
    • Contact: Maurizio Rizzo
  • Milano, Italy
    • Recruiting
    • Asst Grande Ospedale Metropolitano Niguarda
    • Contact: Giovanni Ferrari, MD
  • Milano, Italy
    • Recruiting
    • Policlinico di Milano
    • Contact: Luigi Boni
  • Napoli, Italy
    • Active, not recruiting
    • Ospedale Evangelico Betania
  • Napoli, Italy
    • Recruiting
    • Azienda Ospedaliera Universitaria Federico II
    • Contact: Francesco Corcione
  • Napoli, Italy
    • Recruiting
    • A.O.R.N. A. Cardarelli
    • Contact: Carmine Antropoli
  • Palermo, Italy
    • Recruiting
    • AOU Policlinico Paolo Giaccone
    • Contact: Antonino Agrusa
  • Roma, Italy
    • Active, not recruiting
    • Azienda Ospedaliera S. Camillo Forlanini
  • Roma, Italy
    • Recruiting
    • Fondazione Policlinico Universitario A. Gemelli
    • Contact: Roberto Persiani
  • Roma, Italy
    • Recruiting
    • Policlinico Universitario Agostino Gemelli Irccs Universita' Cattolica Del Sacro Cuore
    • Contact: Fabio Pacelli, MD
  • San Donato Milanese, Italy
    • Recruiting
    • IRCCS Policlinico San Donato
    • Contact: Luigi Bonavina
  • San Giovanni Rotondo, Italy
    • Recruiting
    • IRCCS Casa Sollievo della Sofferenza
    • Contact: Francesca Bazzocchi

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients with histologically documented colorectal adenocarcinoma eligible for R0,

   1. Presurgical or intraoperative stage T4a or T4b primary tumour (TNM 8 th)
   2. Urgent presentation: perforation without purulent generalized peritonitis or fecal peritonitis
   3. Peritumoral minimal peritoneal carcinomatosis: limited peritoneal disease in close proximity to the primary tumour, that may be removed en bloc
   4. Ovarian metastases (Krukenberg tumor)
2. Age ≥ 18 and ≤75 years
3. Written informed consent

Exclusion Criteria:

1. Distant metastatic disease (even if limited and completely resected)
2. 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).
3. Psychological, family or social conditions which may negatively affect the treatment and follow-up protocol.
4. Poor general conditions (ECOG > 2).
5. 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
6. Impaired renal function (creatinine> 1.5 upper limit of normal or creatinine clearance <60 mL / min)
7. Impaired hepatic function (AST, ALT >2.5 upper limit of normal, bilirubin> 1.5 upper limit of normal)
8. Impaired hematopoietic function (leucocytes <4000 / mm3, neutrophils <1500 / mm3, platelets <100000 / mm3)
9. Impaired pulmonary function (presence of COPD or other pulmonary restrictive conditions with FEV1 <50% or DLCO <40% of normal age value).
10. Pregnancy
11. 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.
12. Chronic inflammatory bowel disease
13. Patients with acute bowel obstruction
14. Refusal to join the study

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Mario Negri Institute for Pharmacological Research
• Investigators: Principal Investigator: Fabio Pacelli, MD, fabio.pacelli@policlinicogemelli.it

Publications and helpful links

General Publications

• Pacelli F, Gerardi C, Rulli E, Abatini C, Rotolo S, Garattini S, Melotti G, Torri V, Galli F, Rulli E, Di Giorgio A; CHECK Investigators. Prophylactic surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC CO2) versus standard surgery in colorectal carcinoma at high risk of peritoneal carcinomatosis: short-term and long-term outcomes from the CHECK study - protocol for a randomised, multicentre, phase 3 trial. BMJ Open. 2022 Aug 1;12(8):e051324. doi: 10.1136/bmjopen-2021-051324.

Study record dates

Study Major Dates

• Study Start (Actual): June 19, 2020
• Primary Completion (Estimated): June 1, 2025
• Study Completion (Estimated): June 1, 2025

Study Registration Dates

• First Submitted: April 2, 2019
• First Submitted That Met QC Criteria: April 11, 2019
• First Posted (Actual): April 16, 2019

Study Record Updates

• Last Update Posted (Actual): October 27, 2023
• Last Update Submitted That Met QC Criteria: October 25, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: colorectal cancer; prophylactic surgery; mitomycin; HIPEC CO2
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Alkylating Agents; Antibiotics, Antineoplastic; Mitomycins; Mitomycin
• Other Study ID Numbers: IRFMN-CRC- 7813; 2019-001437-14 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No