Adjuvant HIPEC in High Risk Colon Cancer (COLOPEC)

• ClinicalTrials.gov Identifier: NCT02231086
• Recruitment Status: Completed
• First Posted: September 4, 2014
• Results First Posted: September 16, 2021
• Last Update Posted: September 16, 2021
• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Collaborators: ZonMw: The Netherlands Organisation for Health Research and Development; Dutch Health Care Insurance Board
• Information provided by (Responsible Party): P.J. Tanis, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Study Description

Brief Summary:

This study aims to determine the oncological effectiveness of adjuvant HIPEC, using intraperitoneal oxaliplatin with concomitant i.v. 5-FU/LV, following a curative resection of a T4 or intra-abdominally perforated Colon cancer in preventing the development of peritoneal carcinomatosis in addition to the standard adjuvant systemic treatment.

Hypothesis:

The hypothesis is that adjuvant HIPEC preceding routine adjuvant systemic therapy using i.p. oxaliplatin with concomitant i.v. 5-FU/LV following a curative resection of a T4 or intra-abdominally perforated colon cancer reduces the development of peritoneal carcinomatosis in comparison to standard adjuvant systemic treatment alone.

Condition or disease	Intervention/treatment	Phase
Colorectal Neoplasms; Peritoneal Neoplasms	Procedure: Adjuvant HIPEC (open/laparoscopic); Drug: Standard adjuvant systemic chemotherapy; Procedure: Diagnostic laparoscopy	Phase 3

Detailed Description:

Background:

The peritoneum is the second most common site of recurrence in patients with colon cancer. Early detection of peritoneal carcinomatosis (PC) by imaging is difficult and adjuvant systemic treatment does not seem to affect peritoneal dissemination in contrast to haematogenous dissemination in the liver or lungs. Of all patients eventually presenting with clinically apparent PC, only a quarter have potentially curable disease. The curative option is cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CR/HIPEC), but the effectiveness depends highly on the extent of disease and is associated with a considerable complication rate. These clinical problems underline the need for effective adjuvant intraperitoneal therapy in high risk colon cancer patients in order to prevent the development of PC with treatment at a subclinical stage.

Study design:

This will be a multicentre study in which 176 eligible patients will be randomized to adjuvant HIPEC followed by adjuvant systemic chemotherapy in the experimental arm, or the standard adjuvant systemic chemotherapy alone in the control arm. Adjuvant HIPEC will be performed preferably simultaneously or within 10 days after resection of the primary tumour, either by laparoscopy or open approach, similar to the technique used for resection of the primary tumour. If adjuvant HIPEC cannot be performed within 10 days (i.e. complicated postoperative course), the procedure will be delayed until 5 to 8 weeks postoperatively. Subsequently, patients will receive routine adjuvant chemotherapy (CAPOX) within 3 weeks from HIPEC. Diagnostic laparoscopy will be performed routinely after 18 months postoperatively in both arms of the study in patients without evidence of disease based on routine follow-up using CT imaging and CEA. If peritoneal carcinomatosis is found during staging laparoscopy, CR/ HIPEC will be performed in patients with a maximum of 5 involved regions and without evidence of systemic disease.

Study population:

Patients who underwent intentionally curative resection for a T4N0-2M0 or intra-abdominally perforated colon cancer.

Intervention:

Adjuvant HIPEC procedure: access to the abdominal cavity by laparoscopy or laparotomy under general anaesthesia, adhesiolysis if necessary, complete staging of the intra-abdominal cavity, positioning of in- and outflow catheters, perfusion with a minimum of 2l isotonic dialysis fluid at a flow rate of 1-2l/min and an inflow temperature of 42-43˚C. Before the beginning of HIPEC, 5-fluorouracil 400 mg/m2 and leucovorin 20 mg/m2 will be administered intravenously to potentiate oxaliplatin activity. Oxaliplatin (460 mg/m2) is added to the perfusate after attaining at least 42 degrees inflow temperature with a total of 30 minutes perfusion time.

Outcomes:

Primary endpoint is peritoneal recurrence-free survival at 18 months. Secondary endpoints are number of participants with adverse events as a measure of safety and tolerability, incidence of PC at end of follow-up with or without concomitant liver/lung metastases, percentage of false negative CT at 18 months (second look laparoscopy/laparotomy as gold standard), disease-free survival, overall survival, quality of life and costs.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 204 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: Adjuvant Hyperthermic Intraperitoneal Chemotherapy in Patients With Colon Cancer at High Risk of Peritoneal Carcinomatosis
• Actual Study Start Date: March 2015
• Actual Primary Completion Date: September 2018
• Actual Study Completion Date: June 1, 2019

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Standard adjuvant systemic chemotherapy; Standard adjuvant systemic chemotherapy according to the Dutch colon cancer guideline, using a capecitabine and oxaliplatin (CAPOX) or 5-FU and oxaliplatin (FOLFOX) schedule. Presence or absence of peritoneal recurrence will be evaluated by laparoscopy in case of negative routine examination (CEA and CT thorax/abdomen) at 18 months postoperatively.	Drug: Standard adjuvant systemic chemotherapy; Colon cancer patients with a high risk of developing PC, but do not have (yet) proven macroscopic peritoneal metastasis, are standardly treated with adjuvant systemic chemotherapy. Standard adjuvant systemic chemotherapy consists in the Netherlands of a capecitabine and oxaliplatin (CAPOX) or 5-FU and oxaliplatin (FOLFOX) for a total of 6 months.; Other Names: adjuvant capecitabine and oxaliplatin (CAPOX); adjuvant 5-FU and oxaliplatin (FOLFOX); Procedure: Diagnostic laparoscopy; Presence or absence of peritoneal recurrence will be evaluated by laparoscopy in case of negative routine examination (CEA and CT thorax/abdomen) at 18 months postoperatively in both study arms.; Other Name: Diagnostic laparoscopic surgery
Experimental: Adjuvant HIPEC (open/laparoscopic); Adjuvant HIPEC will be performed simultaneously with primary tumor resection, or as a staged procedure (<10 days or 5-8 weeks postoperatively). The chemotherapy during oxaliplatin-HIPEC consists of an intravenous phase with leucovorin 20 mg/m2 (maximum 40 mg) and 5-fluorouracil 400 mg/m2 (maximum 800 mg) and an intraperitoneal phase with oxaliplatin 460 mg/m2 (maximal 920 mg). Standard adjuvant systemic chemotherapy according to the national guideline will be given within 3 weeks from HIPEC. Presence or absence of peritoneal recurrence will be evaluated by laparoscopy in case of negative routine examination (CEA and CT thorax/abdomen) at 18 months postoperatively.	Procedure: Adjuvant HIPEC (open/laparoscopic); Adjuvant HIPEC procedure: access to the abdominal cavity by laparoscopy or laparotomy under general anaesthesia, adhesiolysis if necessary, complete staging of the intra-abdominal cavity, positioning of in- and outflow catheters, perfusion with a minimum of 2l isotonic dialysis fluid at a flow rate of 1-2l/min and an inflow temperature of 42-43˚C. Before the beginning of HIPEC, 5-fluorouracil 400 mg/m2 and leucovorin 20 mg/m2 will be administered intravenously to potentiate oxaliplatin activity. Oxaliplatin (460 mg/m2) is added to the perfusate after attaining at least 42 degrees inflow temperature with a total of 30 minutes perfusion time.; Other Names: I.V. leucovorin 20 mg/m2 (maximum 40 mg); I.V. 5-fluorouracil 400 mg/m2 (maximum 800 mg); Intraperitoneal oxaliplatin 460 mg/m2 (maximum 920 mg); Drug: Standard adjuvant systemic chemotherapy; Colon cancer patients with a high risk of developing PC, but do not have (yet) proven macroscopic peritoneal metastasis, are standardly treated with adjuvant systemic chemotherapy. Standard adjuvant systemic chemotherapy consists in the Netherlands of a capecitabine and oxaliplatin (CAPOX) or 5-FU and oxaliplatin (FOLFOX) for a total of 6 months.; Other Names: adjuvant capecitabine and oxaliplatin (CAPOX); adjuvant 5-FU and oxaliplatin (FOLFOX); Procedure: Diagnostic laparoscopy; Presence or absence of peritoneal recurrence will be evaluated by laparoscopy in case of negative routine examination (CEA and CT thorax/abdomen) at 18 months postoperatively in both study arms.; Other Name: Diagnostic laparoscopic surgery

Outcome Measures

Primary Outcome Measures :

1. Peritoneal Recurrence Free Survival at 18 Months [ Time Frame: 18 months ]
   Peritoneal recurrence-free survival at 18 months determined by CT and CEA. If CEA was normal and CT did not show any signs of peritoneal metastase at 18 months, a diagnostic laparoscopy was performed in those patients who consented to this intervention. Complete peritoneal staging was performed during laparoscopy, and biopsies were taken from suspicious lesions. If no peritoneal lesions were seen or biopsies were negative, this indicated that the patient was free from peritoneal recurrence.

Secondary Outcome Measures :

1. Treatment Related Toxicity of Adjuvant HIPEC [ Time Frame: 30 days after adjuvant HIPEC ]
   Toxicity directly related to adjuvant HIPEC included 30-day complication rate, re-intervention rate, and re-admission rate.
2. Hospital Stay for Simultaneous and Staged HIPEC, Either Open or Laparoscopic [ Time Frame: 10 weeks ]
   Hospital stay for simultaneous and staged HIPEC, either open or laparoscopic.
3. False-negative Rate of CT-scan for Peritoneal Metastases [ Time Frame: 5 years ]
   The presence or absence of peritoneal metastasis on CT-scan will be compared to the findings during diagnostic laparoscopy, histological biopsy or fine needle aspiration cytology.
4. Patterns of Dissemination (Peritoneal Plus or Minus Distant Metastases) [ Time Frame: 5 years ]
   Patterns of dissemination (peritoneal plus or minus distant metastases).
5. Disease-free Survival [ Time Frame: 5 years ]
   Disease-free survival.
6. Overall Survival [ Time Frame: 5 years ]
   Overall survival.
7. Quality of Life Questionnaire Survey 5- Year Follow-up [ Time Frame: 5 years ]
   Quality of life questionnaire survey 5- year follow-up.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• age between 18 and 75 years
• Intention to start routine adjuvant systemic therapy
• adequate clinical condition to undergo simultaneous HIPEC or re- laparoscopy or re-laparotomy with HIPEC within either 10 days or between week 5-8 from --primary resection
• written informed consent
• white blood cell count of at least 3000/mm3, platelet count of at least 100.000/mm3
• no bleeding diathesis or coagulopathy
• normal creatinine or creatinine clearance of at least 50 ml/min

Exclusion Criteria:

• postoperative complications that interfere with adjuvant HIPEC within 8 weeks (i.e. persisting intra-abdominal abscess, significant fascial dehiscence, enteric fistula)
• no intention to start routine adjuvant systemic therapy
• liver and/or lung metastases
• pregnant or lactating women
• unstable or uncompensated respiratory or cardiac disease
• serious active infections
• other concurrent chemotherapy
• hypersensitivity to fluorouracil, folinic acid or another substance of leucovorin or oxaliplatin
• stomatitis, ulceration in the mouth or gastrointestinal tract.
• severe diarrhea
• severe hepatic and / or renal dysfunction.
• plasma bilirubin concentrations greater than 85 μmol/l.
• pernicious anemia or other anaemias due to vitamin B12 deficiency.
• peripheral sensory neuropathy with functional impairment.

Contacts and Locations

Locations

Netherlands

Academic Medical Center

Amsterdam, Netherlands, 1105 AZ

Antoni van Leeuwenhoek hospital

Amsterdam, Netherlands

Free University Medical Center

Amsterdam, Netherlands

Catharina hospital

Eindhoven, Netherlands

University Medical Centre Groningen

Groningen, Netherlands

Antonius hospital

Nieuwegein, Netherlands

Radboud University Medical Center

Nijmegen, Netherlands

Erasmus Medical Center

Rotterdam, Netherlands

University Medical Center Utrecht

Utrecht, Netherlands

Sponsors and Collaborators

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

ZonMw: The Netherlands Organisation for Health Research and Development

Dutch Health Care Insurance Board

Investigators

• Principal Investigator: Pieter J. Tanis, M.D., Ph.D.; Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

  Study Documents (Full-Text)

Documents provided by P.J. Tanis, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA):

Study Protocol and Statistical Analysis Plan  [PDF] December 5, 2018

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Zwanenburg ES, Wisselink DD, Klaver CEL, van der Bilt JDW, Tanis PJ, Snaebjornsson P; COLOPEC trial collaborators. The measured distance between tumor cells and the peritoneal surface predicts the risk of peritoneal metastases and offers an objective means to differentiate between pT3 and pT4a colon cancer. Mod Pathol. 2022 Dec;35(12):1991-2001. doi: 10.1038/s41379-022-01154-z. Epub 2022 Sep 19.

Klaver CEL, Wisselink DD, Punt CJA, Snaebjornsson P, Crezee J, Aalbers AGJ, Brandt A, Bremers AJA, Burger JWA, Fabry HFJ, Ferenschild F, Festen S, van Grevenstein WMU, Hemmer PHJ, de Hingh IHJT, Kok NFM, Musters GD, Schoonderwoerd L, Tuynman JB, van de Ven AWH, van Westreenen HL, Wiezer MJ, Zimmerman DDE, van Zweeden AA, Dijkgraaf MGW, Tanis PJ; COLOPEC collaborators group. Adjuvant hyperthermic intraperitoneal chemotherapy in patients with locally advanced colon cancer (COLOPEC): a multicentre, open-label, randomised trial. Lancet Gastroenterol Hepatol. 2019 Oct;4(10):761-770. doi: 10.1016/S2468-1253(19)30239-0. Epub 2019 Jul 29.

Klaver CE, Musters GD, Bemelman WA, Punt CJ, Verwaal VJ, Dijkgraaf MG, Aalbers AG, van der Bilt JD, Boerma D, Bremers AJ, Burger JW, Buskens CJ, Evers P, van Ginkel RJ, van Grevenstein WM, Hemmer PH, de Hingh IH, Lammers LA, van Leeuwen BL, Meijerink WJ, Nienhuijs SW, Pon J, Radema SA, van Ramshorst B, Snaebjornsson P, Tuynman JB, Te Velde EA, Wiezer MJ, de Wilt JH, Tanis PJ. Adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with colon cancer at high risk of peritoneal carcinomatosis; the COLOPEC randomized multicentre trial. BMC Cancer. 2015 May 24;15:428. doi: 10.1186/s12885-015-1430-7.

• Responsible Party: P.J. Tanis, M.D. Ph.D, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• ClinicalTrials.gov Identifier: NCT02231086
• Other Study ID Numbers: NL49960.018.14; 2014-002794-11 ( EudraCT Number )
• First Posted: September 4, 2014
• Results First Posted: September 16, 2021
• Last Update Posted: September 16, 2021
• Last Verified: August 2021

Keywords provided by P.J. Tanis, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA):

Chemotherapy, Adjuvant; Laparoscopy; Peritoneal Lavage; HIPEC

Additional relevant MeSH terms:

Neoplasms; Colorectal Neoplasms; Peritoneal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Abdominal Neoplasms; Peritoneal Diseases; Leucovorin; Capecitabine; Fluorouracil; Oxaliplatin; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antidotes; Protective Agents; Vitamin B Complex; Vitamins; Micronutrients