Chemo-immunotherapy before and after surgery for peritoneal metastases of large bowel cancer

Rationale: CRS-HIPEC is a curative intent treatment for patients with isolated resectable colorectal 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, 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 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 .



Intervention: at the discretion of the treating medical oncologist, perioperative systemic therapy consists of either four 3-weekly neoadjuvant and adjuvant cycles of CAPOX, six 2-weekly neoadjuvant and adjuvant cycles of FOLFOX, or six 2-weekly neoadjuvant cycles of 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 endpoint 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, grade ≥3 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.

Patient with isolated resectable colorectal peritoneal metastases (PM) have a 3-year overall survival of 50% after upfront cytoreductive surgery with HIPEC (CRS-HIPEC) alone, and a 3-year overall survival of 65% after perioperative systemic therapy and CRS-HIPEC.

See primary and secondary outcomes

At the discretion of the treating medical oncologist, perioperative systemic therapy consists of either:


• Four three-weekly neoadjuvant and adjuvant cycles of CAPOX (130 mg/m2body-surface area [BSA] of oxaliplatin, intravenously [IV] on day 1; 1000 mg/m2BSA 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, or;

• Six two-weekly neoadjuvant and adjuvant cycles of FOLFOX (85 mg/m2BSA of oxaliplatin, IV on day 1; 400 mg/m2BSA of leucovorin, IV on day 1; 400/2400 mg/m2BSA 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, or;

• Six two-weekly neoadjuvant cycles of FOLFIRI (180 mg/m2BSA of irinotecan, IV on day 1; 400 mg/m2BSA of leucovorin, IV on day 1; 400/2400 mg/m2BSA of bolus/continuous 5-fluorouracil, IV on day 1-2) and either four three-weekly (1000 mg/m2BSA of capecitabine, orally twice daily on days 1-14) or six two-weekly (400 mg/m2BSA of leucovorin, IV on day 1; 400/2400 mg/m2BSA 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.

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, co-interventions, and escape medication 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.