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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).
Full description
Rationale: cytoreductive surgery with HIPEC (CRS-HIPEC) is a curative intent treatment for patients with isolated resectable colorectal peritoneal metastases (PM). Upfront CRS-HIPEC alone is the standard treatment in the Netherlands. The addition of neoadjuvant and adjuvant systemic therapy, together commonly referred to as perioperative systemic therapy, to CRS-HIPEC could have benefits and drawbacks. Potential benefits are eradication of systemic micrometastases, preoperative intraperitoneal tumour downstaging, elimination of post-surgical residual cancer cells, and improved patient selection for CRS-HIPEC. Potential drawbacks are preoperative disease progression and secondary unresectability, systemic therapy related toxicity, increased postoperative morbidity, decreased quality of life, and higher costs. Currently, there is a complete lack of randomised studies that prospectively compare the oncological efficacy of perioperative systemic therapy and CRS-HIPEC with upfront CRS-HIPEC alone. Notwithstanding this lack of evidence, perioperative systemic therapy is widely administered to patients with isolated resectable colorectal PM. However, administration and timing of perioperative systemic therapy vary substantially between countries, hospitals, and guidelines. More importantly, it remains unknown whether perioperative systemic therapy has an intention-to-treat benefit in this setting. Therefore, this study randomises patients with isolated resectable colorectal PM to receive either perioperative systemic therapy (experimental arm) or upfront CRS-HIPEC alone (control arm).
Study design: multicentre, open-label, parallel-group, phase II-III, randomised superiority study.
Setting: nine Dutch tertiary referral centres qualified for the surgical treatment of colorectal PM.
Objectives: objectives of the phase II study (80 patients) are to explore the feasibility of accrual, the feasibility, safety, and tolerance of perioperative systemic therapy, and the radiological and histological response of colorectal PM to neoadjuvant systemic therapy. The primary objective of the phase III study (an additional 278 patients) is to compare survival outcomes between both arms. Secondary objectives are to compare surgical characteristics, major postoperative morbidity, health-related quality of life, and costs between both arms. Other objectives are to assess major systemic therapy related toxicity and the objective radiological and histological response of colorectal PM to neoadjuvant systemic therapy.
Study population: adults who have a good performance status, histological or cytological proof of PM of a colorectal adenocarcinoma, resectable disease, no systemic colorectal metastases within three months prior to enrolment, no systemic therapy for colorectal cancer within six months prior to enrolment, no previous CRS-HIPEC, no contraindications for the planned systemic treatment or CRS-HIPEC, and no relevant concurrent malignancies.
Randomisation and stratification: eligible patients are randomised in a 1:1 ratio by using central randomisation software with stratified minimisation by a peritoneal cancer index of 0-10 or 11-20, metachronous or synchronous onset of PM, previous systemic therapy for colorectal cancer, and HIPEC with oxaliplatin or mitomycin C.
Intervention: at the discretion of the treating medical oncologist, 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.
Outcomes: outcomes of the phase II study are to explore the feasibility of accrual, the feasibility, safety, and tolerance of perioperative systemic therapy, and the radiological/histological response of colorectal PM to neoadjuvant systemic therapy. The primary outcome of the phase III study is 3-year overall survival, which is hypothesised to be 50% in the control arm and 65% in the experimental arm, thereby requiring 358 patients (179 in each arm). Secondary endpoints are surgical characteristics, major postoperative morbidity, progression-free survival, disease-free survival, health-related quality of life, costs, major systemic therapy related toxicity, and objective radiological and histological response rates of colorectal PM to neoadjuvant systemic therapy.
Burden, risks, and benefits associated with participation: it is hypothesised that perioperative systemic therapy and CRS-HIPEC (experimental arm) significantly improve the overall survival of patients with isolated resectable colorectal PM compared to the current standard treatment in the Netherlands: upfront CRS-HIPEC alone (control arm). This potential overall survival benefit should be weighed against the burden and risks of the experimental arm. The most important are: additional hospital visits for the perioperative systemic therapy, preoperative disease progression and secondary unresectability, increased postoperative morbidity, systemic therapy related toxicity, and an intensified and prolonged initial treatment that could decrease health-related quality of life. The investigators feel that the potential overall survival benefit of the experimental arm outweighs the burden and risks (that are closely monitored in the phase II study).
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Inclusion and exclusion criteria
Eligible patients are adults who have:
Importantly, enrolment is allowed for patients with radiologically non-measurable disease. 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.:
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358 participants in 2 patient groups
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Central trial contact
Checca Bakkers, MD; Koen P Rovers, MD
Data sourced from clinicaltrials.gov
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