Perioperative Systemic Therapy for Isolated Resectable Colorectal Peritoneal Metastases
- Conditions
- Colorectal Neoplasms MalignantPeritoneal CarcinomatosisPeritoneal Neoplasm Malignant Secondary CarcinomatosisColorectal NeoplasmColorectal CarcinomaPeritoneal MetastasesPeritoneal NeoplasmsPeritoneal CancerColorectal CancerColorectal Adenocarcinoma
- Interventions
- Other: Perioperative systemic therapyProcedure: CRS-HIPEC, control armCombination Product: Perioperative CAPOX-bevacizumabCombination Product: Perioperative FOLFOX-bevacizumabCombination Product: Perioperative FOLFIRI-bevacizumabProcedure: CRS-HIPEC, experimental arm
- Registration Number
- NCT02758951
- Lead Sponsor
- Koen Rovers
- 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).
- Detailed 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: 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 for CRS-HIPEC, 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: a multicentre, open-label, parallel-group, phase II-III, superiority study that randomises eligible patients in a 1:1 ratio.
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 pathological response of colorectal PM to neoadjuvant systemic therapy. The primary objective of the phase III study (358 patients) is to compare overall survival between both arms. Secondary objectives are to assess progression-free and disease-free survival, surgical characteristics, major postoperative morbidity, patient-reported outcomes, and costs in both arms. Other objectives are to assess major systemic therapy related toxicity and the objective radiological and pathological 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.
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.
Endpoints: primary endpoints of the phase II study are to explore the feasibility and safety of perioperative systemic therapy by comparing proportions of patients undergoing complete CRS-HIPEC and proportions of patients with major postoperative morbidity between both arms. The primary comparative endpoint of the phase III study is overall survival. Major secondary endpoints assessed in both arms are proportions of major postoperative morbidity, progression-free survival, disease-free survival, patient-reported outcomes (PROs), and costs. Major secondary endpoints assessed in the experimental arm are the proportion of patients with major systemic therapy related toxicity and the proportions of patients with objective radiological and pathological responses of colorectal PM to neoadjuvant systemic therapy.
Statistical analysis: the study is powered to detect an increase in 3-year overall survival from 50% in the control arm to 65% in the experimental arm (corresponding hazard ratio 0.62), which is considered to be a clinically relevant difference by the investigators. A total number of 358 patients (179 in each arm) is needed to detect this hypothesized difference with 5% drop-out, 80% power, and a two-sided log-rank test of p\<0.05. In August 2024, when several patients in the experimental arm were still receiving trial treatment, a regular follow-up update revealed that 156 events for the primary outcome (i.e. deaths) had occurred. The study then had 85% power to detect the hypothesized hazard ratio of 0.62 for overall survival in the analysis of superiority of the experimental arm relative to the control arm at a two-sided alpha of 0.05. After discussing these data with the Data Monitoring Committee and the medical ethics committee, it was decided to schedule data cut-off for a first analysis of the primary outcome at the time the last patient in the experimental arm (enrolled April 2024) finishes trial treatment, which is expected 1 November 2024 at an estimated number of +/- 172 events (+/- 88% power).
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 358
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Perioperative systemic therapy and CRS-HIPEC Perioperative FOLFIRI-bevacizumab 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. Perioperative systemic therapy and CRS-HIPEC Perioperative systemic therapy 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. Perioperative systemic therapy and CRS-HIPEC CRS-HIPEC, experimental arm 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. Upfront CRS-HIPEC alone CRS-HIPEC, control arm CRS-HIPEC is performed according to the Dutch protocol in all study centres. Perioperative systemic therapy and CRS-HIPEC Perioperative CAPOX-bevacizumab 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. Perioperative systemic therapy and CRS-HIPEC Perioperative FOLFOX-bevacizumab 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.
- Primary Outcome Measures
Name Time Method Overall survival From enrolment up to five years thereafter Time between enrolment and death due to any cause
- Secondary Outcome Measures
Name Time Method Progression-free survival From enrolment up to five years thereafter Time between enrolment and physician-determined disease progression before CRS-HIPEC, CRS-HIPEC in case of unresectable disease or incomplete CRS, physician-determined recurrence after CRS-HIPEC, or death due to any cause;
Disease-free survival From enrolment up to five years thereafter Time between macroscopic complete CRS-HIPEC and physician-determined recurrence or death due to any cause
Macroscopic complete CRS-HIPEC From enrolment up to approximately six weeks (control arm) or five months (experimental arm) thereafter The proportion of patients undergoing macroscopic complete CRS-HIPEC
Surgical characteristics: peritoneal cancer index During CRS-HIPEC, one to five months after enrolment The peritoneal cancer index during explorative laparotomy
Surgical characteristics: bowel anastomoses During CRS-HIPEC, , one to five months after enrolment The proportion of patients with a bowel anastomosis during CRS-HIPEC
Surgical characteristics: ostomy formations During CRS-HIPEC, one to five months after enrolment The proportion of patients with an ostomy formation during CRS-HIPEC
Surgical characteristics: operating time During CRS-HIPEC, one to five months after enrolment The operating time of CRS-HIPEC
Major postoperative morbidity From (intended) CRS-HIPEC up to three months postoperatively The proportions of patients with Clavien-Dindo grade 3 or higher, grade 4 or higher, and grade 5 postoperative morbidity
Postoperative hospital stay During the postoperative course of CRS-HIPEC, up to 90 days postoperatively The number of days between (intended) CRS-HIPEC and initial discharge
Postoperative readmissions From CRS-HIPEC to 90 days postoperatively The proportion of patients with a readmission within 90 days after (intended) CRS-HIPEC
Patient-reported outcomes: EQ-5D-5L From enrolment up to five years thereafter Extracted from EQ-5D-5L questionnaire at different points in time
Patient-reported outcomes: QLQ-C30 From enrolment up to five years thereafter Extracted from EORTC QLQ-C30 questionnaires at different points in time
Patient-reported outcomes: QLQ-CR29 From enrolment up to five years thereafter Extracted from EORTC QLQ-CR29 questionnaire at different points in time
Costs From enrolment up to five years thereafter Extracted from questionnaire (iMTA PCQ, iMTA MCQ) at different points in time
Trial Locations
- Locations (9)
Amsterdam University Medical Centre, Location VUMC
🇳🇱Amsterdam, Netherlands
Ziekenhuis Oost-Limburg
🇧🇪Genk, Vlaanderen, Belgium
University Medical Centre Groningen
🇳🇱Groningen, Netherlands
Catharina Hospital
🇳🇱Eindhoven, Netherlands
St. Antonius Hospital
🇳🇱Nieuwegein, Netherlands
University Medical Centre Utrecht
🇳🇱Utrecht, Netherlands
Netherlands Cancer Institute
🇳🇱Amsterdam, Netherlands
Radboud University Medical Centre
🇳🇱Nijmegen, Netherlands
Erasmus University Medical Centre
🇳🇱Rotterdam, Netherlands