Perioperative Systemic Therapy for Isolated Resectable Colorectal Peritoneal Metastases

NCT02758951 | Active Not Recruiting Phase 2 DMC

• 4 other identifiers: NL57644.100.162016-001865-99ISRCTN15977568NTR6301
• Study Type: interventional
• Target: 358
• Locations: 2 countries
• Sites: 9

Brief Summary

This is a multicentre, open-label, parallel-group, phase II-III, superiority study that randomises patients with isolated resectable colorectal peritoneal metastases in a 1:1 ratio to receive either perioperative systemic therapy and cytoreductive surgery with HIPEC (experimental arm) or upfront cytoreductive surgery with HIPEC alone (control arm).

Conditions

Colorectal Neoplasm; Colorectal Cancer; Colorectal Carcinoma; Colorectal Adenocarcinoma; Peritoneal Neoplasms; Peritoneal Carcinomatosis; Peritoneal Cancer; Peritoneal Metastases; Peritoneal Neoplasm Malignant Secondary Carcinomatosis; Peritoneal Neoplasm Malignant Secondary; Colorectal Neoplasms Malignant

Keywords

Colorectal Neoplasms; Peritoneal Neoplasms; Cytoreduction Surgical Procedures; Hyperthermia, Induced; Neoadjuvant Therapy; Adjuvant Chemotherapy; Bevacizumab; Randomized Controlled Trial; Mortality; Progression-Free Survival

Outcome Measures

Primary Outcomes (1)

• Overall survival

  Time between enrolment and death due to any cause

  From enrolment up to five years thereafter

Secondary Outcomes (14)

• Progression-free survival

  From enrolment up to five years thereafter

• Disease-free survival

  From enrolment up to five years thereafter

• Macroscopic complete CRS-HIPEC

  From enrolment up to approximately six weeks (control arm) or five months (experimental arm) thereafter

• Surgical characteristics: peritoneal cancer index

  During CRS-HIPEC, one to five months after enrolment

• Surgical characteristics: bowel anastomoses

  During CRS-HIPEC, , one to five months after enrolment

Other Outcomes (3)

• Major systemic therapy-related toxicity (experimental arm)

  From the first administration of systemic therapy up to 30 days after the last administration

• Radiological response to neoadjuvante treatment (experimental arm)

  After radiological restaging during neoadjuvant treatment, approximately three months after randomisation

• Pathological response to neoadjuvant treatment (experimental arm)

  After (intended) CRS-HIPEC, approximately five months after randomisation

Study Arms (2)

Perioperative systemic therapy and CRS-HIPEC

EXPERIMENTAL

At the discretion of the treating physician, perioperative systemic therapy consists of either four 3-weekly neoadjuvant and adjuvant cycles of capecitabine with oxaliplatin (CAPOX), six 2-weekly neoadjuvant and adjuvant cycles of 5-fluorouracil/leucovorin with oxaliplatin (FOLFOX), or six 2-weekly neoadjuvant cycles of 5-fluorouracil/leucovorin with irinotecan (FOLFIRI) followed by either four 3-weekly (capecitabine) or six 2-weekly (5-fluorouracil/leucovorin) adjuvant cycles of fluoropyrimidine monotherapy. Bevacizumab is added to the first three (CAPOX) or four (FOLFOX/FOLFIRI) neoadjuvant cycles. CRS-HIPEC is performed according to the Dutch protocol in all study centres.

Other: Perioperative systemic therapy; Combination Product: Perioperative CAPOX-bevacizumab; Combination Product: Perioperative FOLFOX-bevacizumab; Combination Product: Perioperative FOLFIRI-bevacizumab; Procedure: CRS-HIPEC, experimental arm

Upfront CRS-HIPEC alone

ACTIVE COMPARATOR

CRS-HIPEC is performed according to the Dutch protocol in all study centres.

Procedure: CRS-HIPEC, control arm

Interventions

Perioperative systemic therapy OTHER

Neoadjuvant systemic therapy should start within four weeks after randomisation. Adjuvant systemic therapy should start within twelve weeks after CRS-HIPEC. In case of unacceptable toxicity or contraindications to oxaliplatin or irinotecan in the neoadjuvant setting, CAPOX or FOLFOX may be switched to FOLFIRI and vice versa. In case of unacceptable toxicity or contraindications to oxaliplatin in the adjuvant setting, CAPOX of FOLFOX may be switched to fluoropyrimidine monotherapy. Dose reduction, prohibited concomitant care, permitted concomitant care, and strategies to improve adherence are not specified a priori, but left to the discretion of the treating medical oncologist. Perioperative systemic therapy can be prematurely discontinued due to radiological or clinical disease progression, unacceptable toxicity, physicians decision, or at patients request.

Perioperative systemic therapy and CRS-HIPEC

Perioperative CAPOX-bevacizumab COMBINATION_PRODUCT

Four three-weekly neoadjuvant and adjuvant cycles of CAPOX (130 mg/m2 body-surface area \[BSA\] of oxaliplatin, intravenously \[IV\] on day 1; 1000 mg/m2 BSA of capecitabine, orally twice daily on days 1-14), with bevacizumab (7.5 mg/kg body weight, IV on day 1) added to the first three neoadjuvant cycles.

Perioperative systemic therapy and CRS-HIPEC

Perioperative FOLFOX-bevacizumab COMBINATION_PRODUCT

Six two-weekly neoadjuvant and adjuvant cycles of FOLFOX (85 mg/m2 body-surface area \[BSA\] of oxaliplatin, intravenously \[IV\] on day 1; 400 mg/m2 BSA of leucovorin, IV on day 1; 400/2400 mg/m2 BSA of bolus/continuous 5-fluorouracil, IV on day 1-2), with bevacizumab (5 mg/kg body weight, IV on day 1) added to the first four neoadjuvant cycles.

Perioperative systemic therapy and CRS-HIPEC

Perioperative FOLFIRI-bevacizumab COMBINATION_PRODUCT

Six two-weekly neoadjuvant cycles of FOLFIRI (180 mg/m2 body-surface area \[BSA\] of irinotecan, intravenously \[IV\] on day 1; 400 mg/m2 BSA of leucovorin, IV on day 1; 400/2400 mg/m2 BSA of bolus/continuous 5-fluorouracil, IV on day 1-2) and either four three-weekly (capecitabine (1000 mg/m2 BSA, orally twice daily on days 1-14) or six two-weekly (400 mg/m2 BSA of leucovorin, IV on day 1; 400/2400 mg/m2 BSA of bolus/continuous 5-fluorouracil, IV on day 1-2) adjuvant cycles of fluoropyrimidine monotherapy, with bevacizumab (5 mg/kg body weight, IV on day 1) added to the first four neoadjuvant cycles.

Perioperative systemic therapy and CRS-HIPEC

CRS-HIPEC, experimental arm PROCEDURE

CRS-HIPEC is performed according to the Dutch protocol in all study centres. Until publication of the PRODIGE7 trial, the choice of HIPEC medication (oxaliplatin or mitomycin C) has been left to the discretion of the treating physician, since neither one had a favourable safety or efficacy until then. After publication of the PRODIGE7 trial in 2021, oxaliplatin-based HIPEC was omitted in all centres (and therefore automatically omitted in the present study), and all centres switched to mitomycin C-based HIPEC. CRS-HIPEC should be performed within six weeks after completion of neoadjuvant systemic therapy in case of sufficient clinical condition, and at least six weeks after the last administration of bevacizumab in order to minimise the risk of bevacizumab-related postoperative complications.

Perioperative systemic therapy and CRS-HIPEC

CRS-HIPEC, control arm PROCEDURE

CRS-HIPEC is performed according to the Dutch protocol in all study centres. Until publication of the PRODIGE7 trial, the choice of HIPEC medication (oxaliplatin or mitomycin C) has been left to the discretion of the treating physician, since neither one had a favourable safety or efficacy until then. After publication of the PRODIGE7 trial in 2021, oxaliplatin-based HIPEC was omitted in all centres (and therefore automatically omitted in the present study), and all centres switched to mitomycin C-based HIPEC. CRS-HIPEC should be performed within six weeks after randomisation.

Upfront CRS-HIPEC alone

Eligibility Criteria

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

Eligible patients are adults who have: * a World Health Organisation (WHO) performance status of ≤1; * histological or cytological proof of PM of a non-appendiceal colorectal adenocarcinoma with ≤50% of the tumour cells being signet ring cells; * resectable disease determined by a diagnostic laparoscopy/laparotomy in combination with abdominal computed tomography and/or magnetic resonance imaging (MRI); only in patients in whom diagnostic laparoscopy or laparotomy is considered not feasible or valuable (e.g. due to known adhesions impeding adequate PCI scoring), it is also allowed to determine resectability by CT or MRI only (provided that the colorectal PM are histologically or cytologically proven); * no evidence of systemic colorectal metastases within three months prior to enrolment; * no systemic therapy for colorectal cancer within six months prior to enrolment; * no contraindications for CRS-HIPEC; * no previous CRS-HIPEC; * no concurrent malignancies that interfere with the planned study treatment or the prognosis of resected colorectal PM. Importantly, enrolment is allowed for patients with radiologically non-measurable disease. Enrolment is also allowed for patients who are referred to a study centre after a macroscopically complete resection of colorectal PM in a referring centre, since it is assumed that microscopic (and often macroscopic) colorectal PM are still present. The diagnostic laparoscopy/laparotomy may be performed in a referring centre, provided that the peritoneal cancer index (PCI) is appropriately scored and documented before enrolment. Patients are excluded in case of any comorbidity or condition that prevents safe administration of the planned perioperative systemic therapy, determined by the treating medical oncologist, e.g.: * Inadequate bone marrow, renal, or liver functions (e.g. haemoglobin \<6.0 mmol/L, neutrophils \<1.5 x 109/L, platelets \<100 x 109/L, serum creatinine \>1.5 x ULN, creatinine clearance \<30 ml/min, bilirubin \>2 x ULN, serum liver transaminases \>5 x ULN); * Previous intolerance of fluoropyrimidines or both oxaliplatin and irinotecan; * Dehydropyrimidine dehydrogenase deficiency; * Serious active infections; * Severe diarrhoea; * Stomatitis or ulceration in the mouth or gastrointestinal tract; * Recent major cardiovascular events; * Unstable or uncompensated respiratory or cardiac disease; * Bleeding diathesis or coagulopathy; * Pregnancy or lactation. The aforementioned laboratory values and tests are to be determined at the discretion of the physician, e.g. only if the patient is suspect for abnormal conditions tests will be conducted.

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• Koen Rovers: lead
• Dutch Cancer Society: collaborator
• Comprehensive Cancer Centre The Netherlands: collaborator
• Hoffmann-La Roche: collaborator

Study Sites (9)

Ziekenhuis Oost-Limburg

Genk, Flanders, 3600, Belgium

Location

Amsterdam University Medical Centre, Location VUMC

Amsterdam, Netherlands

Location

Netherlands Cancer Institute

Amsterdam, Netherlands

Location

Catharina Hospital

Eindhoven, Netherlands

Location

University Medical Centre Groningen

Groningen, Netherlands

Location

St. Antonius Hospital

Nieuwegein, Netherlands

Location

Radboud University Medical Centre

Nijmegen, Netherlands

Location

Erasmus University Medical Centre

Rotterdam, Netherlands

Location

University Medical Centre Utrecht

Utrecht, Netherlands

Location

Related Publications (3)

• Rovers KP, Bakkers C, Nienhuijs SW, Burger JWA, Creemers GM, Thijs AMJ, Brandt-Kerkhof ARM, Madsen EVE, van Meerten E, Tuynman JB, Kusters M, Versteeg KS, Aalbers AGJ, Kok NFM, Buffart TE, Wiezer MJ, Boerma D, Los M, de Reuver PR, Bremers AJA, Verheul HMW, Kruijff S, de Groot DJA, Witkamp AJ, van Grevenstein WMU, Koopman M, Nederend J, Lahaye MJ, Kranenburg O, Fijneman RJA, van 't Erve I, Snaebjornsson P, Hemmer PHJ, Dijkgraaf MGW, Punt CJA, Tanis PJ, de Hingh IHJT; Dutch Peritoneal Oncology Group and the Dutch Colorectal Cancer Group. Perioperative Systemic Therapy vs Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy Alone for Resectable Colorectal Peritoneal Metastases: A Phase 2 Randomized Clinical Trial. JAMA Surg. 2021 Aug 1;156(8):710-720. doi: 10.1001/jamasurg.2021.1642.

  PMID: 34009291 RESULT

• Rovers KP, Bakkers C, Simkens GAAM, Burger JWA, Nienhuijs SW, Creemers GM, Thijs AMJ, Brandt-Kerkhof ARM, Madsen EVE, Ayez N, de Boer NL, van Meerten E, Tuynman JB, Kusters M, Sluiter NR, Verheul HMW, van der Vliet HJ, Wiezer MJ, Boerma D, Wassenaar ECE, Los M, Hunting CB, Aalbers AGJ, Kok NFM, Kuhlmann KFD, Boot H, Chalabi M, Kruijff S, Been LB, van Ginkel RJ, de Groot DJA, Fehrmann RSN, de Wilt JHW, Bremers AJA, de Reuver PR, Radema SA, Herbschleb KH, van Grevenstein WMU, Witkamp AJ, Koopman M, Haj Mohammad N, van Duyn EB, Mastboom WJB, Mekenkamp LJM, Nederend J, Lahaye MJ, Snaebjornsson P, Verhoef C, van Laarhoven HWM, Zwinderman AH, Bouma JM, Kranenburg O, van 't Erve I, Fijneman RJA, Dijkgraaf MGW, Hemmer PHJ, Punt CJA, Tanis PJ, de Hingh IHJT; Dutch Peritoneal Oncology Group (DPOG); Dutch Colorectal Cancer Group (DCCG). Perioperative systemic therapy and cytoreductive surgery with HIPEC versus upfront cytoreductive surgery with HIPEC alone for isolated resectable colorectal peritoneal metastases: protocol of a multicentre, open-label, parallel-group, phase II-III, randomised, superiority study (CAIRO6). BMC Cancer. 2019 Apr 25;19(1):390. doi: 10.1186/s12885-019-5545-0.

  PMID: 31023318 RESULT

• Peng S, Chen D, Cai J, Yuan Z, Huang B, Li Y, Wang H, Luo Q, Kuang Y, Liang W, Liu Z, Wang Q, Cui Y, Wang H, Liu X. Enhancing cancer-associated fibroblast fatty acid catabolism within a metabolically challenging tumor microenvironment drives colon cancer peritoneal metastasis. Mol Oncol. 2021 May;15(5):1391-1411. doi: 10.1002/1878-0261.12917. Epub 2021 Feb 16.

  PMID: 33528867 DERIVED

Related Links

• Related Info

MeSH Terms

Conditions

Colorectal Neoplasms; Colonic Neoplasms; Peritoneal Neoplasms; Hyperthermia

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; Body Temperature Changes; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Heat Stress Disorders; Wounds and Injuries

Study Officials

• Ignace H de Hingh, MD, PhD

  Catharina Hospital, Eindhoven, Netherlands

  STUDY CHAIR

• Pieter J Tanis, MD, PhD

  Department of Surgery, Amsterdam University Medical Centre, Location AMC, Amsterdam, Netherlands

  STUDY DIRECTOR

• Cornelis J Punt, MD, PhD

  Department of Medical Oncology, Amsterdam University Medical Centre, Location AMC, Amsterdam, Netherlands

  STUDY DIRECTOR

• Alexandra R Brandt-Kerkhof, MD

  Department of Surgery, Erasmuc University Medical Centre, Rotterdam, Netherlands

  PRINCIPAL INVESTIGATOR

• Jurriaan B Tuynman, MD, PhD

  Department of Surgery, Amsterdam University Medical Centre, Location VUMC, Amsterdam, Netherlands

  PRINCIPAL INVESTIGATOR

• Arend G Aalbers, MD

  Department of Surgery, Netherlands Cancer Institute, Amsterdam, Netherlands

  PRINCIPAL INVESTIGATOR

• Marinus J Wiezer, MD, PhD

  Department of Surgery, St. Antonius Hospital, Nieuwegein, Netherlands

  PRINCIPAL INVESTIGATOR

• Patrick H Hemmer, MD

  Department of Surgery, University Medical Centre Groningen, Groningen, Netherlands

  PRINCIPAL INVESTIGATOR

• Sandra A Radema, MD, PhD

  Department of Medical Oncology, Radboud University Medical Centre, Nijmegen, Netherlands

  PRINCIPAL INVESTIGATOR

• Wilhemina M van Grevenstein, MD, PhD

  Department of Surgery, University Medical Centre Utrecht, Utrecht, Netherlands

  PRINCIPAL INVESTIGATOR

• Eino B van Duyn, MD, PhD

  Department of Surgery, Medisch Spectrum Twente, Enschede, Netherlands

  PRINCIPAL INVESTIGATOR

• Ignace H de Hingh, MD, PhD

  Department of Surgery, Catharina Hospital, Eindhoven, Netherlands

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Coordinating Investigator

Study Record Dates

• First Submitted: April 26, 2016
• First Posted: May 3, 2016
• Study Start: June 1, 2017
• Primary Completion: October 31, 2024
• Study Completion (Estimated): June 1, 2029
• Last Updated: March 24, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, ANALYTIC CODE
• Time Frame: The full protocol and Dutch informed consent forms are publicly accessible (https://dccg.nl/trial/cairo-6). Participant-level datasets and statistical codes will become available upon reasonable request after the results of the study have been published.
• Access Criteria: Reasonable request.

Locations

BE (1); NL (8)