The quest of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC): searching for evidence

Randomized controlled trials (RCTs), when appropriately designed, conducted and reported, are the gold standard in evaluating medical interventions. In the present issue of “Pleura and Peritoneum”, Clarisse Eveno and Marc Pocard from University Paris 7 – two recognized experts in the field – present a timely update on RCT evaluating the combination of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for the therapy of peritoneal metastasis [1]. This report takes into account latest information on ongoing trials presented at the 10th PSOGI congress in Washington in November 2016, a meeting attended by more than 600 international participants on invitation of Dr Paul Sugarbaker.

This systematic review of published, ongoing and planned RCTs evaluating CRS and HIPEC in various diseases and indications delivers several important messages:

1. The number of published randomized trials in CRS and HIPEC is so far modest with only nine such trials published to date.

2. All nine trials showed a survival advantage for the test group (CRS and HIPEC).

3. The methodological robustness of these trials is questionable, at least for three of them. Only a single trial was properly designed [2], but its results have been challenged since the therapy administered in the control group (systemic chemotherapy with 5-fluorouracil-leucovorin) does not match today’s standard of care anymore. Seven of these trials were not registered in a public trial database, a condition for ICH-GCP studies. A statistical hypothesis with corresponding sample size calculation was not provided in any of these trials. Two trials were clearly underpowered [3, 4]. One of these trials has not provided any data on mortality and morbidity [5]. None of the reports has followed the CONSORT guidelines for reporting parallel group randomized trials [6].

4. While 29 additional RCTs are ongoing, five of them have already completed patient recruitment. We are eagerly waiting for their results: additional evidence on CRS and HIPEC will be available in colorectal and ovarian cancers within the next 2–3 years. In particular, the multicentric French PRODIGE 7 trial (NCT00769405) will deliver decisive answers about the relative role of CRS vs. HIPEC in the outcome of patients with peritoneal metastasis of colorectal origin treated with this combination therapy.

5. There is a clear trend in recent RCT protocols on CRS and HIPEC into the direction of prevention of peritoneal metastasis in high-risk patients with colorectal, ovarian and gastric cancers.

How should we interpret these messages? Surgical interventions are complex, with multiple components that require consideration in trial reporting [7]. Interventions combining surgery with drug application – such as CRS and HIPEC – are even more complex. Thus, RCT evaluating CRS and HIPEC will continue to face considerable methodological and practical challenges. These include

1. the choice of the intraperitoneal drug;

2. the standardization of the parameters, in particular the technique of intraperitoneal drug application, the target dose applied and the temperature;

3. the choice of the adequate comparator as a control (CRS alone or combination chemotherapy?);

4. the precise definition of the therapy in the control arm in the recurrence situation, in particular in ovarian cancer where the options are multiple (physician’s best choice);

5. the precise definition of surgery in the experimental arm, in particular the extent and quality of surgery and an objective report on the completeness of cytoreduction;

6. the determination of progression-free survival considering the poor accuracy of CT scan for early detection of intraperitoneal recurrence and low-volumetric peritoneal disease;

7. the challenging risk–benefit analysis since a small proportion of patients will be cured by CRS, HIPEC and systemic chemotherapy, and the majority will eventually die of disease;

8. the inclusion and the proper evaluation of patient-reported outcomes in the palliative setting, when patients are lost due to progression of disease;

9. the difficulty of blinding patients and physicians;

10. the reluctance of patients for giving their consent for a study when the choice between radically different therapy options is determined by chance;

11. the long time period needed for such RCTs and the consequences of this delay for the validity of the results (the chemotherapy selected for the control arm might no longer be considered standard at the time point of publication).

The shift from therapeutic CRS and HIPEC protocols (in the presence of peritoneal metastasis) toward prophylactic CRS and HIPEC (for prevention of such metastases) raises questions about a potential loss of interest in the HIPEC community for the therapeutic indications. No trial has been recently opened for recruitment in the recurrence situation. In gastric cancer, only a single trial worldwide is currently recruiting in the therapeutic indication and including only highly selected patients. This shift is challenging indeed the role of CRS since, in the prophylactic situation, no extensive resection of organs and peritoneal stripping is necessary.

The courageous investigators of RCTs in CRS and HIPEC should be blessed for their efforts and should be forgiven for having been imperfect. The challenges described above explain why the degree of evidence of CRS and HIPERC is not where it should be – 30 years after the introduction of this therapy into clinical practice by Dr Paul Sugarbaker. However, absence of more data from high-quality RCT is regrettable since a number of retrospective cohorts, case–control studies and prospective registries strongly suggest an efficacy of CRS and HIPEC in select patients in good general condition, with limited extent of peritoneal disease and biologically less aggressive disease. In the absence of robust data, logic is replaced by belief and this might encourage corporate witch-hunt between cancer surgeons and medical oncologists [8].

For those who fear for the future of CRS and HIPEC, the hope is that investigators of ongoing RCT will provide lucid descriptions of the critical information needed. Complete, clear and transparent information on the methodology and finding of the ongoing RCT will enhance acceptance of results by the oncological community and a better implementation of CRS and HIPEC into clinical practice.