Perioperative Systemic Therapy for Isolated Resectable Colorectal Peritoneal Metastases

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

Interventions

OTHER

Perioperative systemic therapy

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.

COMBINATION_PRODUCT

Perioperative CAPOX-bevacizumab

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.

COMBINATION_PRODUCT

Perioperative FOLFOX-bevacizumab

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.

COMBINATION_PRODUCT

Perioperative FOLFIRI-bevacizumab

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.

PROCEDURE

CRS-HIPEC, experimental arm

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.

PROCEDURE

CRS-HIPEC, control arm

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.

Sponsors & Collaborators

• Dutch Cancer Society

  collaborator OTHER

• Comprehensive Cancer Centre The Netherlands

  collaborator OTHER

• Hoffmann-La Roche

  collaborator INDUSTRY

• Koen Rovers

  lead OTHER

Principal Investigators

• Ignace H de Hingh, MD, PhD · Catharina Hospital, Eindhoven, Netherlands

• Pieter J Tanis, MD, PhD · Department of Surgery, Amsterdam University Medical Centre, Location AMC, Amsterdam, Netherlands

• Cornelis J Punt, MD, PhD · Department of Medical Oncology, Amsterdam University Medical Centre, Location AMC, Amsterdam, Netherlands

• Alexandra R Brandt-Kerkhof, MD · Department of Surgery, Erasmuc University Medical Centre, Rotterdam, Netherlands

• Jurriaan B Tuynman, MD, PhD · Department of Surgery, Amsterdam University Medical Centre, Location VUMC, Amsterdam, Netherlands

• Arend G Aalbers, MD · Department of Surgery, Netherlands Cancer Institute, Amsterdam, Netherlands

• Marinus J Wiezer, MD, PhD · Department of Surgery, St. Antonius Hospital, Nieuwegein, Netherlands

• Patrick H Hemmer, MD · Department of Surgery, University Medical Centre Groningen, Groningen, Netherlands

• Sandra A Radema, MD, PhD · Department of Medical Oncology, Radboud University Medical Centre, Nijmegen, Netherlands

• Wilhemina M van Grevenstein, MD, PhD · Department of Surgery, University Medical Centre Utrecht, Utrecht, Netherlands

• Eino B van Duyn, MD, PhD · Department of Surgery, Medisch Spectrum Twente, Enschede, Netherlands

• Ignace H de Hingh, MD, PhD · Department of Surgery, Catharina Hospital, Eindhoven, Netherlands

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2017-06-01

Primary Completion

2024-10-31

Completion

2029-06-01

Countries

• Belgium
• Netherlands

Study Locations