Perioperative Systemic Therapy for Isolated Resectable Colorectal Peritoneal Metastases

Study Overview
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Brief Summary
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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).

Detailed Description
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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).

Official Title
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Perioperative Systemic Therapy and Cytoreductive Surgery With HIPEC Versus Upfront Cytoreductive Surgery With HIPEC Alone for Isolated Resectable Colorectal Peritoneal Metastases: a Multicentre, Open-label, Parallel-group, Phase II-III, Randomised Superiority Study

Conditions
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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

Intervention / Treatment
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* Other: Perioperative systemic therapy
* Combination Product: Perioperative CAPOX-bevacizumab
* Combination Product: Perioperative FOLFOX-bevacizumab
* Combination Product: Perioperative FOLFIRI-bevacizumab
* Procedure: CRS-HIPEC, experimental arm
* Procedure: CRS-HIPEC, control arm


Participation Criteria
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Eligibility Criteria
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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 abdominal computed tomography (CT) and a diagnostic laparoscopy/laparotomy; 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Perioperative systemic therapy and CRS-HIPEC<br>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<br>* 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.<br>Combination Product: Perioperative CAPOX-bevacizumab<br>* 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.<br>Combination Product: Perioperative FOLFOX-bevacizumab<br>* 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.<br>Combination Product: Perioperative FOLFIRI-bevacizumab<br>* 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.<br>Procedure: CRS-HIPEC, experimental arm<br>* CRS-HIPEC is performed according to the Dutch protocol in all study centres. The choice of HIPEC medication (oxaliplatin or mitomycin C) is left to the discretion of the treating physician, since neither one has a favourable safety or efficacy. CRS-HIPEC should be performed within six weeks after completion of neoadjuvant systemic therapy, and at least six weeks after the last administration of bevacizumab in order to minimise the risk of bevacizumab-related postoperative complications.<br>|
| Active Comparator: Upfront CRS-HIPEC alone<br>CRS-HIPEC is performed according to the Dutch protocol in all study centres. | Procedure: CRS-HIPEC, control arm<br>* CRS-HIPEC is performed according to the Dutch protocol in all study centres. The choice of HIPEC medication (oxaliplatin or mitomycin C) is left to the discretion of the treating physician, since neither one has a favourable safety or efficacy. CRS-HIPEC should be performed within six weeks after randomisation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase II (n=80): feasibility of perioperative systemic therapy (1) | Number of patients that start neoadjuvant systemic therapy | Approximately one month after randomisation | 
| Phase II (n=80): feasibility of perioperative systemic therapy (2) | Number of patients that complete neoadjuvant systemic therapy | Approximately four months after randomisation | 
| Phase II (n=80): feasibility of perioperative systemic therapy (3) | Number of patients with a dose reduction during neoadjuvant systemic therapy | Approximately four months after randomisation | 
| Phase II (n=80): feasibility of perioperative systemic therapy (4) | Number of patients that are scheduled for CRS-HIPEC | Approximately five months after randomisation | 
| Phase II (n=80): feasibility of perioperative systemic therapy (5) | Number of patients that undergo complete CRS-HIPEC | Approximately five months after randomisation | 
| Phase II (n=80): feasibility of perioperative systemic therapy (6) | Number of patients that start adjuvant systemic therapy | Approximately eight months after randomisation | 
| Phase II (n=80): feasibility of perioperative systemic therapy (7) | Number of patients that complete adjuvant systemic therapy | Approximately eleven months after randomisation | 
| Phase II (n=80): feasibility of perioperative systemic therapy (8) | Number of patients with a dose reduction during adjuvant systemic therapy | Approximately eleven months after randomisation | 
| Phase II (n=80): safety of perioperative systemic therapy (1) | Number of patients with systemic related toxicity, defined as grade 2 or higher according to CTCAE v4.0 | Up to one month after the last administration of systemic therapy (approximately one year after randomisation) | 
| Phase II (n=80): safety of perioperative systemic therapy (2) | Number of patients with postoperative morbidity, defined as grade 2 or higher according to Clavien-Dindo | Up to three months after CRS-HIPEC (approximately eight months after randomisation) | 
| Phase II (n=80): tolerance of perioperative systemic therapy (1) | EuroQol Five-Dimension Five-Level Questionnaire (EQ-5D-5L) during the initial treatment | Up to six months after CRS-HIPEC (approximately eleven months after randomisation) | 
| Phase II (n=80): tolerance of perioperative systemic therapy (2) | European Organisation for Research and Treatment of Cancer Qualify of Life Questionnaire C30 during the initial treatment | Up to six months after CRS-HIPEC (approximately eleven months after randomisation) | 
| Phase II (n=80): tolerance of perioperative systemic therapy (3) | European Organisation for Research and Treatment of Cancer Qualify of Life Questionnaire CR29 during the initial treatment | Up to six months after CRS-HIPEC (approximately eleven months after randomisation) | 
| Phase II (n=80): radiological response of colorectal PM to neoadjuvant systemic therapy | Number of patients with an objective radiological response. Central review of thoracoabdominal CT during neoadjuvant systemic therapy. Classification not defined a priori. | Approximately three months after randomisation | 
| Phase II (n=80): histological response of colorectal PM to neoadjuvant systemic therapy | Number of patients with an objective histological response. Central review of specimens resected during CRS-HIPEC. Classification not defined a priori. | Approximately five months after randomisation | 
| Phase III (n=358): overall survival | Time between randomisation and death | Up to five years after randomisation | 
| Phase III (n=358): progression-free survival | Time between randomisation and disease progression before CRS-HIPEC, CRS-HIPEC in case of unresectable disease, radiological proof of recurrence, or death | Up to five years after randomisation | 
| Phase III (n=358): disease-free survival | Time between CRS-HIPEC and radiological proof of recurrence or death in operated patients | Up to five years after randomisation | 
| Phase III (n=358): health-related quality of life (1) | EuroQol Five-Dimension Five-Level Questionnaire (EQ-5D-5L) | Up to five years after randomisation | 
| Phase III (n=358): health-related quality of life (2) | European Organisation for Research and Treatment of Cancer Qualify of Life Questionnaire C30 | Up to five years after randomisation | 
| Phase III (n=358): health-related quality of life (3) | European Organisation for Research and Treatment of Cancer Qualify of Life Questionnaire CR29 | Up to five years after randomisation | 
| Phase III (n=358): costs (1) | Institute for Medical Technology Assessment Productivity Cost Questionnaire | Up to five years after randomisation | 
| Phase III (n=358): costs (2) | Institute for Medical Technology Assessment Medical Consumption Questionnaire | Up to five years after randomisation | 
| Phase III (n=358): major postoperative morbidity | Number of patients with postoperative morbidity, defined as grade 2 or higher according to Clavien-Dindo | Up to three months after CRS-HIPEC (approximately eight months after randomisation) | 
| Phase III (n=358): major systemic therapy related toxicity | Number of patients with systemic related toxicity, defined as grade 2 or higher according to CTCAE v4.0 | Up to one month after the last administration of systemic therapy (approximately one year after randomisation) | 
| Phase III (n=358): radiological response of colorectal PM to neoadjuvant systemic therapy | Number of patients with an objective radiological response. Central review of thoracoabdominal CT during neoadjuvant systemic therapy. Classification determined after exploration of the radiological response in the phase II study | Approximately three months after randomisation | 
| Phase III (n=358): histological response of colorectal PM to neoadjuvant systemic therapy | Number of patients with an objective histological response. Central review of specimens resected during CRS-HIPEC. Classification determined after exploration of the histological response in the phase II study. | Approximately five months after randomisation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bevacizumab, Colorectal Neoplasms, Peritoneal Neoplasms, Cytoreduction Surgical Procedures, Hyperthermia, Induced, Neoadjuvant Therapy, Adjuvant Chemotherapy, Randomized Controlled Trial, Mortality, Progression-Free Survival