Adjuvant HIPEC in High Risk Colon Cancer

NCT02231086 | Completed Phase 3 Results DMC

• 2 other identifiers: NL49960.018.142014-002794-11
• Study Type: interventional
• Target: 204
• Locations: 1 country
• Sites: 9

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.

Conditions

Colorectal Neoplasms; Peritoneal Neoplasms

Keywords

Chemotherapy, Adjuvant; Laparoscopy; Peritoneal Lavage; HIPEC

Outcome Measures

Primary Outcomes (1)

• Peritoneal Recurrence Free Survival at 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.

  18 months

Secondary Outcomes (7)

• Treatment Related Toxicity of Adjuvant HIPEC

  30 days after adjuvant HIPEC

• Hospital Stay for Simultaneous and Staged HIPEC, Either Open or Laparoscopic

  10 weeks

• False-negative Rate of CT-scan for Peritoneal Metastases

  5 years

• Patterns of Dissemination (Peritoneal Plus or Minus Distant Metastases)

  5 years

• Disease-free Survival

  5 years

Study Arms (2)

Standard adjuvant systemic chemotherapy

ACTIVE COMPARATOR

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; Procedure: Diagnostic laparoscopy

Adjuvant HIPEC (open/laparoscopic)

EXPERIMENTAL

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); Drug: Standard adjuvant systemic chemotherapy; Procedure: Diagnostic laparoscopy

Interventions

Adjuvant HIPEC (open/laparoscopic) PROCEDURE

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.

Also known as: 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)

Adjuvant HIPEC (open/laparoscopic)

Standard adjuvant systemic chemotherapy DRUG

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.

Also known as: adjuvant capecitabine and oxaliplatin (CAPOX), adjuvant 5-FU and oxaliplatin (FOLFOX)

Adjuvant HIPEC (open/laparoscopic); Standard adjuvant systemic chemotherapy

Diagnostic laparoscopy PROCEDURE

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.

Also known as: Diagnostic laparoscopic surgery

Adjuvant HIPEC (open/laparoscopic); Standard adjuvant systemic chemotherapy

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA): lead
• ZonMw: The Netherlands Organisation for Health Research and Development: collaborator
• Dutch Health Care Insurance Board: collaborator

Study Sites (9)

Academic Medical Center

Amsterdam, 1105 AZ, Netherlands

Location

Antoni van Leeuwenhoek hospital

Amsterdam, Netherlands

Location

Free University Medical Center

Amsterdam, Netherlands

Location

Catharina hospital

Eindhoven, Netherlands

Location

University Medical Centre Groningen

Groningen, Netherlands

Location

Antonius hospital

Nieuwegein, Netherlands

Location

Radboud University Medical Center

Nijmegen, Netherlands

Location

Erasmus Medical Center

Rotterdam, Netherlands

Location

University Medical Center Utrecht

Utrecht, Netherlands

Location

Related Publications (5)

• Zwanenburg ES, Wisselink DD, Klaver CEL, Bilt JDWV, den Berg JGV, Kodach LL, Nagtegaal ID, Tanis PJ, Snaebjornsson P; COLOPEC collaborators. Underdiagnosis of positive resection margins and synchronous peritoneal metastases in locally advanced colon cancer: histopathological reassessment of primary resection in the COLOPEC trial. Virchows Arch. 2025 Oct;487(4):787-797. doi: 10.1007/s00428-025-04065-x. Epub 2025 May 16.

  PMID: 40374989 DERIVED

• Zwanenburg ES, El Klaver C, Wisselink DD, Punt CJA, Snaebjornsson P, Crezee J, Aalbers AGJ, Brandt-Kerkhof ARM, Bremers AJA, Burger PJWA, Fabry HFJ, Ferenschild FTJ, Festen S, van Grevenstein WMU, Hemmer PHJ, de Hingh IHJT, Kok NFM, Kusters M, Musters GD, Schoonderwoerd L, Tuynman JB, van de Ven AWH, van Westreenen HL, Wiezer MJ, Zimmerman DDE, van Zweeden A, Dijkgraaf MGW, Tanis PJ; COLOPEC Collaborators Group; COLOOPEC Collaborators Group. Adjuvant Hyperthermic Intraperitoneal Chemotherapy in Patients With Locally Advanced Colon Cancer (COLOPEC): 5-Year Results of a Randomized Multicenter Trial. J Clin Oncol. 2024 Jan 10;42(2):140-145. doi: 10.1200/JCO.22.02644. Epub 2023 Nov 3.

  PMID: 37922442 DERIVED

• 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.

  PMID: 36123540 DERIVED

• 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.

  PMID: 31371228 DERIVED

• 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.

  PMID: 26003804 DERIVED

MeSH Terms

Conditions

Colorectal Neoplasms; Peritoneal Neoplasms

Interventions

Oxaliplatin; Folfox protocol; Laparoscopy

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Abdominal Neoplasms; Peritoneal Diseases

Intervention Hierarchy (Ancestors)

Coordination Complexes; Organic Chemicals; Endoscopy; Diagnostic Techniques, Surgical; Diagnostic Techniques and Procedures; Diagnosis; Minimally Invasive Surgical Procedures; Surgical Procedures, Operative

Results Point of Contact

• Title: Prof. dr. P.J. Tanis
• Organization: Amsterdam UMC

p.j.tanis@amsterdamumc.nl

+31-20-4444444

Study Officials

• Pieter J. Tanis, M.D., Ph.D.

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

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: M.D. Ph.D

Study Record Dates

• First Submitted: August 22, 2014
• First Posted: September 4, 2014
• Study Start: March 1, 2015
• Primary Completion: September 1, 2018
• Study Completion: June 1, 2019
• Last Updated: September 16, 2021
• Results First Posted: September 16, 2021

Record last verified: 2021-08

Locations

NL (9)