Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal metastases (PRODIGE 7): a multicentre, randomised, open-label, phase 3 trial

Summary

Background

The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to cytoreductive surgery has been associated with encouraging survival results in some patients with colorectal peritoneal metastases who were eligible for complete macroscopic resection. We aimed to assess the specific benefit of adding HIPEC to cytoreductive surgery compared with receiving cytoreductive surgery alone.

Methods

We did a randomised, open-label, phase 3 trial at 17 cancer centres in France. Eligible patients were aged 18–70 years and had histologically proven colorectal cancer with peritoneal metastases, WHO performance status of 0 or 1, a Peritoneal Cancer Index of 25 or less, and were eligible to receive systemic chemotherapy for 6 months (ie, they had adequate organ function and life expectancy of at least 12 weeks). Patients in whom complete macroscopic resection or surgical resection with less than 1 mm residual tumour tissue was completed were randomly assigned (1:1) to cytoreductive surgery with or without oxaliplatin-based HIPEC. Randomisation was done centrally using minimisation, and stratified by centre, completeness of cytoreduction, number of previous systemic chemotherapy lines, and timing of protocol-mandated systemic chemotherapy. Oxaliplatin HIPEC was administered by the closed (360 mg/m²) or open (460 mg/m²) abdomen techniques, and systemic chemotherapy (400 mg/m² fluorouracil and 20 mg/m² folinic acid) was delivered intravenously 20 min before HIPEC. All individuals received systemic chemotherapy (of investigators' choosing) with or without targeted therapy before or after surgery, or both. The primary endpoint was overall survival, which was analysed in the intention-to-treat population. Safety was assessed in all patients who received surgery. This trial is registed with ClinicalTrials.gov, NCT00769405, and is now completed.

Findings

Between Feb 11, 2008, and Jan 6, 2014, 265 patients were included and randomly assigned, 133 to the cytoreductive surgery plus HIPEC group and 132 to the cytoreductive surgery alone group. After median follow-up of 63·8 months (IQR 53·0–77·1), median overall survival was 41·7 months (95% CI 36·2–53·8) in the cytoreductive surgery plus HIPEC group and 41·2 months (35·1–49·7) in the cytoreductive surgery group (hazard ratio 1·00 [95·37% CI 0·63–1·58]; stratified log-rank p=0·99). At 30 days, two (2%) treatment-related deaths had occurred in each group.. Grade 3 or worse adverse events at 30 days were similar in frequency between groups (56 [42%] of 133 patients in the cytoreductive surgery plus HIPEC group vs 42 [32%] of 132 patients in the cytoreductive surgery group; p=0·083); however, at 60 days, grade 3 or worse adverse events were more common in the cytoreductive surgery plus HIPEC group (34 [26%] of 131 vs 20 [15%] of 130; p=0·035).

Interpretation

Considering the absence of an overall survival benefit after adding HIPEC to cytoreductive surgery and more frequent postoperative late complications with this combination, our data suggest that cytoreductive surgery alone should be the cornerstone of therapeutic strategies with curative intent for colorectal peritoneal metastases.

Funding

Institut National du Cancer, Programme Hospitalier de Recherche Clinique du Cancer, Ligue Contre le Cancer.

Introduction

Peritoneal metastases, a clinical form of disease progression in colorectal cancer, are synchronous in approximately 7% of cases of colorectal cancer and the first and only localisation of metastases in more than 4% of cases. In population-based studies, the 5-year cumulative risk of metachronous peritoneal metastases in colorectal cancer is 6%.¹ Peritoneal metastases are associated with reduced overall survival, and, in 30–40% of cases, they are associated with significantly worse prognosis compared with non-peritoneal metastases (16·3 months [95% CI 13·5–18·8] for peritoneal metastases vs 19·1 months [18·3–19·8] for liver-only metastases and 24·6 months [22·7–26·4] for lung-only metastases).2, 3

Research in context

Evidence before this study

We searched PubMed with the medical subject heading terms “cytoreduction surgical procedures”, “peritoneum, “neoplasm metastasis”, “colorectal neoplasms”, “colorectal cancer”, and “hyperthermia, induced” to identify articles published in English between Jan 1, 2000, and Dec 31, 2019. We identified only one randomised clinical trial (cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy [HIPEC] versus systemic chemotherapy), which was done in 2003. Peritoneal metastases secondary to colorectal cancer are associated with poorer prognosis than extraperitoneal metastases from colorectal cancer. In patients eligible for complete surgical resection, the combination of cytoreductive surgery and HIPEC has been used for more than a decade. Retrospective studies show median overall survival of 35–40 months for patients amenable to macroscopically complete resection of peritoneal metastases. However, we did not identify any studies in which the specific effect of HIPEC on survival was assessed.

Added value of this study

To our knowledge, ours is the first study to address the specific role of HIPEC when used in combination with cytoreductive surgery to treat peritoneal metastases secondary to colorectal cancer. The addition of oxaliplatin-based HIPEC to cytoreductive surgery did not significantly affect overall survival or relapse-free survival compared with cytoreductive surgery alone, but was associated with a higher number of postoperative complications at 60 days. The curative management of peritoneal metastases secondary to colorectal cancer with cytoreductive surgery alone (in association with systemic chemotherapy) at specialised cancer centres was unexpectedly efficacious in terms of long-term recurrence-free survival.

Implications of all the available evidence

High-dose oxaliplatin-based HIPEC given over a short duration should no longer be used, and macroscopically complete cytoreductive surgery should be considered the mainstay of treatment of peritoneal metastases. Eligibility for surgical resection should be the main consideration in patients with colorectal cancer and peritoneal metastases. Such changes to clinical practice would spare patients with colorectal cancer from undergoing unnecessary intraperitoneal chemotherapy.

In patients with isolated peritoneal metastases, administration of systemic chemotherapeutic regimens—the only treatment available for patients with unresectable disease—slightly increases median overall survival to 16·3 months (95% CI 13·5–18·8).³ In patients with potentially resectable disease, surgical management of peritoneal metastases of colorectal origin has evolved profoundly in the past 15 years. Worldwide, hyperthermic intraperitoneal chemotherapy (HIPEC) has been added to cytoreductive surgery. HIPEC delivers high local concentrations of antineoplastic drugs, the cytotoxic effects of which are enhanced by hyperthermia. In several retrospective studies,4, 5, 6, 7 median overall survival with cytoreductive surgery plus HIPEC was encouraging in patients amenable to macroscopically complete resection (as long as 40 months in some patients). In a Dutch phase 3 controlled trial,⁸ cytoreductive surgery plus HIPEC was superior to systemic chemotherapy in terms of overall survival in patients in whom surgery was done only to relieve symptoms caused by bowel obstruction. In specialised centres, cytoreductive surgery plus HIPEC can cure (ie, no evidence of disease at 5 years) around 16% of patients in whom resection is macroscopically complete.⁹

In clinical practice, surgical resection and HIPEC have always been used in combination. The specific benefits associated with adding HIPEC to cytoreductive surgery have not been assessed in prospective trials. In this trial, we aimed to evaluate the specific role of HIPEC when added to cytoreductive surgery in patients with peritoneal metastases of colorectal origin.