Elsevier

The Lancet Oncology

Volume 21, Issue 9, September 2020, Pages 1147-1154
The Lancet Oncology

Articles
Second-look surgery plus hyperthermic intraperitoneal chemotherapy versus surveillance in patients at high risk of developing colorectal peritoneal metastases (PROPHYLOCHIP–PRODIGE 15): a randomised, phase 3 study

https://doi.org/10.1016/S1470-2045(20)30322-3Get rights and content

Summary

Background

Diagnosis and treatment of colorectal peritoneal metastases at an early stage, before the onset of signs, could improve patient survival. We aimed to compare the survival benefit of systematic second-look surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC), with surveillance, in patients at high risk of developing colorectal peritoneal metastases.

Methods

We did an open-label, randomised, phase 3 study in 23 hospitals in France. Eligible patients were aged 18–70 years and had a primary colorectal cancer with synchronous and localised colorectal peritoneal metastases removed during tumour resection, resected ovarian metastases, or a perforated tumour. Patients were randomly assigned (1:1) to surveillance or second-look surgery plus oxaliplatin-HIPEC (oxaliplatin 460 mg/m2, or oxaliplatin 300 mg/m2 plus irinotecan 200 mg/m2, plus intravenous fluorouracil 400 mg/m2), or mitomycin-HIPEC (mitomycin 35 mg/m2) alone in case of neuropathy, after 6 months of adjuvant systemic chemotherapy with no signs of disease recurrence. Randomisation was done via a web-based system, with stratification by treatment centre, nodal status, and risk factors for colorectal peritoneal metastases. Second-look surgery consisted of a complete exploration of the abdominal cavity via xyphopubic incision, and resection of all peritoneal implants if resectable. Surveillance after resection of colorectal cancer was done according to the French Guidelines. The primary outcome was 3-year disease-free survival, defined as the time from randomisation to peritoneal or distant disease recurrence, or death from any cause, whichever occurred first, analysed by intention to treat. Surgical complications were assessed in the second-look surgery group only. This study was registered at ClinicalTrials.gov, NCT01226394.

Findings

Between June 11, 2010, and March 31, 2015, 150 patients were recruited and randomly assigned to a treatment group (75 per group). After a median follow-up of 50·8 months (IQR 47·0–54·8), 3-year disease-free survival was 53% (95% CI 41–64) in the surveillance group versus 44% (33–56) in the second-look surgery group (hazard ratio 0·97, 95% CI 0·61–1·56). No treatment-related deaths were reported. 29 (41%) of 71 patients in the second-look surgery group had grade 3–4 complications. The most common grade 3–4 complications were intra-abdominal adverse events (haemorrhage, digestive leakage) in 12 (23%) of 71 patients and haematological adverse events in 13 (18%) of 71 patients.

Interpretation

Systematic second-look surgery plus oxaliplatin-HIPEC did not improve disease-free survival compared with standard surveillance. Currently, essential surveillance of patients at high risk of developing colorectal peritoneal metastases appears to be adequate and effective in terms of survival outcomes.

Funding

French National Cancer Institute.

Introduction

Over the past two decades, the prognosis of patients with peritoneal metastases from colorectal cancer has been improved by aggressive treatment, including complete surgical resection and hyperthermic intraperitoneal chemotherapy (HIPEC). This combined treatment has improved 5-year survival outcomes in these patients by up to 40–45%,1, 2, 3, 4, 5 and has been curative (disease-free interval of at least 5 years) in 16% of patients in one retrospective study.6 After complete resection and HIPEC, the prognosis depends primarily on two factors, the completeness of resection and the extent of the peritoneal disease as evaluated with the peritoneal cancer index.7, 8 Thus, the earlier the disease is treated, the better the prognosis. Unfortunately, colorectal peritoneal metastases are typically asymptomatic at early disease stages, and all non-invasive imaging strategies tested to date have had disappointing detection rates in nodules smaller than 5 mm in diameter.9 To overcome this difficulty in detection, a strategy based on a complete surgical exploration of the abdomen in patients at high risk for colorectal peritoneal metastases has been described and evaluated in prospective non-randomised studies.10, 11, 12, 13, 14 Results of these studies suggested that systematic second-look surgery was efficient for diagnosing colorectal peritoneal metastases that were not visible on imaging (in more than half of the patients), and that any such patients with a low peritoneal cancer index should be treated at an early stage, thereby improving survival.

Research in context

Evidence before this study

We searched PubMed from Jan 1, 1980, to Jan 1, 2012, for studies with the terms “second-look surgery”, “peritoneal carcinomatosis” or “peritoneal metastases”, and “colorectal cancer” or “peritoneal malignancy”. We found no randomised trials published during this time.

Only two prospective studies have been reported investigating systematic second-look surgery in patients at high risk of developing colorectal peritoneal metastases, and one retrospective study in patients after initial resection of peritoneal carcinomatosis from appendiceal malignancy. For patients at high risk of colorectal peritoneal metastases, the previous studies showed that peritoneal metastases are diagnosed during second-look surgery in 55% of patients, and that prolonged survival can be obtained with this strategy.

An updated search done on Jan 1, 2018, found no further relevant randomised trials.

Added value of this study

To our knowledge, this is the first reported phase 3 study to evaluate systematic second-look surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC) in patients at high risk of colorectal peritoneal metastases.

Implications of all the available evidence

This randomised phase 3 study (PROPHYLOCHIP) does not support a disease-free survival or overall survival benefit from systematic second-look surgery plus oxaliplatin-HIPEC in patients at high risk of colorectal peritoneal metastases. However, an important point raised by this study is that this at-risk population should be recognised, and that all medical staff should be aware of this risk and systematically look for signs of colorectal peritoneal metastases during routine surveillance.

The aim of this study was to analyse the effect on disease-free survival of surveillance according to standard guidelines, versus systematic second-look surgery plus HIPEC, in patients at high risk of developing colorectal peritoneal metastases.

Section snippets

Study design and participants

We did an open-label, randomised, phase 3 trial at 23 hospitals in France (appendix p 1). Eligible patients were those who met the criteria for high risk of developing colorectal peritoneal metastases, meaning patients with a histologically proven primary colorectal cancer and one of the following: synchronous and localised colorectal peritoneal metastases removed during tumour resection, resected ovarian metastases, or a perforated tumour. To be included in the trial, patients also had to have

Results

Between June 11, 2010, and March 31, 2015, 150 patients were randomly assigned to the control group (standard surveillance, n=75) or the experimental group (second-look surgery plus HIPEC, n=75; figure 1) and were included in the intention-to-treat population. 71 (95%) of the 75 patients allocated to the experimental group had a surgical exploration of the abdomen, with a median delay of 38 days (IQR 25–60) after randomisation. In the remaining four patients, surgery was not performed because

Discussion

The results of this open-label, randomised, phase 3 study that enrolled patients at high risk of developing colorectal peritoneal metastases after a clinical, biological, and radiological assessment, did not show a significant difference in disease-free survival or overall survival between standard surveillance and systematic second-look surgery plus HIPEC. We aimed to compare these two strategies, but the study was not designed to evaluate the potential benefit of prophylactic HIPEC, since

Data sharing

External researchers can make written requests to the corresponding author (DG) for sharing of data before publication or presentation. Requests will be assessed on a case-by-case basis in consultation with lead and co-investigators. A brief analysis plan and data request will be required and reviewed by the investigators for approval of data sharing. When requests are approved, data will be sent electronically in password protected files. All data sharing will abide by rules and policies

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