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)

Tracking Information

• First Submitted Date: August 22, 2014
• First Posted Date: September 4, 2014
• Results First Submitted Date: July 23, 2021
• Results First Posted Date: September 16, 2021
• Last Update Posted Date: September 16, 2021
• Actual Study Start Date: March 2015
• Actual Primary Completion Date: September 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 18, 2021)

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.

Original Primary Outcome Measures (submitted: August 30, 2014)

Peritoneal recurrence free survival [ Time Frame: 18 months ]

Peritoneal recurrence-free survival at 18 months determined by CT and if negative by laparoscopy.

Current Secondary Outcome Measures (submitted: August 18, 2021)

• 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.
• 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.
• 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.
• Patterns of Dissemination (Peritoneal Plus or Minus Distant Metastases) [ Time Frame: 5 years ]
  Patterns of dissemination (peritoneal plus or minus distant metastases).
• Disease-free Survival [ Time Frame: 5 years ]
  Disease-free survival.
• Overall Survival [ Time Frame: 5 years ]
  Overall survival.
• Quality of Life Questionnaire Survey 5- Year Follow-up [ Time Frame: 5 years ]
  Quality of life questionnaire survey 5- year follow-up.

Original Secondary Outcome Measures (submitted: August 30, 2014)

• Treatment related toxicity of adjuvant HIPEC, including 30-day complication rate, re-intervention rate, and re-admission rate [ Time Frame: 5 years ]
• Hospital stay for simultaneous and staged HIPEC, either open or laparoscopic [ Time Frame: 10 weeks ]
• Peritoneal metastasis on CT-scan [ Time Frame: 5 years ]
  The presence or absence of peritoneal metastasis on CT-scan will be compared to the findings during diagnostic laparoscopy, MRI-imaging or cytology.
• Patterns of dissemination (peritoneal plus or minus distant metastases) [ Time Frame: 5 years ]
• Disease-free survival [ Time Frame: 5 years ]
• Overall survival [ Time Frame: 5 years ]
• Quality of life [ Time Frame: 5 years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Adjuvant HIPEC in High Risk Colon Cancer
• Official Title: Adjuvant Hyperthermic Intraperitoneal Chemotherapy in Patients With Colon Cancer at High Risk of Peritoneal Carcinomatosis

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.

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 Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Prevention

Condition

• Colorectal Neoplasms
• Peritoneal Neoplasms

Intervention

• 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

Study Arms

• 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.
  Interventions:

  • Drug: Standard adjuvant systemic chemotherapy
  • Procedure: Diagnostic laparoscopy
• 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.
  Interventions:

  • Procedure: Adjuvant HIPEC (open/laparoscopic)
  • Drug: Standard adjuvant systemic chemotherapy
  • Procedure: Diagnostic laparoscopy

Publications *

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 9, 2018): 204
• Original Estimated Enrollment (submitted: August 30, 2014): 176
• Actual Study Completion Date: June 1, 2019
• Actual Primary Completion Date: September 2018 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Netherlands

Administrative Information

• NCT Number: NCT02231086
• Other Study ID Numbers: NL49960.018.14; 2014-002794-11 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: P.J. Tanis, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Original Responsible Party: Same as current
• Current Study Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Original Study Sponsor: Same as current

Collaborators

• 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)

• PRS Account: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Verification Date: August 2021