HIPEC with oxaliplatin for colorectal peritoneal metastasis: The end of the road?
Introduction
Colorectal cancer (CRC) is one of the commonest causes of cancer related death in developed countries. Peritoneal carcinomatosis is present in 25–30% of patients with recurrent or metastatic colorectal cancer; in approximately 3% isolated peritoneal disease without systemic spread is observed [1]. These patients are amenable for locoregional therapy consisting of surgical cytoreduction followed by intraoperative hyperthermic intraperitoneal chemoperfusion (HIPEC). The combined approach results in a median survival of more than 30 months [2,3]. Historically, several chemotherapeutic drugs including the platinum compounds, mitomycin C, fluorouracil, and irinotecan have been used in HIPEC, either as a single agent or as a combination regimen. Since its introduction by Elias et al., in 2002, many centers have adopted oxaliplatin (OX), the standard of care in the adjuvant and palliative chemotherapy treatment of CRC, as the drug of choice in HIPEC treatment [4]. The available evidence from retrospective and non-randomized studies in CRC suggests that the survival benefit from CRS and HIPEC is independent from the type of intraperitoneal (IP) drug regimen used [5].
The recently presented Prodige 7 trial, which compared cytoreductive surgery (CRS) alone with CRS combined with HIPEC using OX, failed to demonstrate an overall survival advantage in the HIPEC arm, while the 60 day complication rate was significantly higher [6]. Here, I suggest possible explanations for this lack of benefit and propose an approach to further evaluate the use of intraperitoneal drug delivery in CRC.
Section snippets
What did the prodige 7 trial show?
Patients with histology proven peritoneal metastases (PM) from CRC, with a peritoneal cancer index (PCI) < 25 and who underwent optimal surgery (residual tumor ≤1 mm), where randomized to either no HIPEC or HIPEC with OX. The primary endpoint was overall survival (OS). Over a six-year period (2008–2014), 265 patients were randomized. The HIPEC arm patients developed more abdominal and extra-abdominal complications. Overall survival was unexpectedly high in both groups, but did not differ
Limitations of the study design
The most important explanation of the lack of benefit is, without doubt, the overestimation of the effect size in the design of the trial. Several studies have shown that HIPEC is ineffective when gross residual disease is present, and complete CRS is the major determinant of the efficacy of the combined treatment. The Prodige 7 investigators hypothesized a huge treatment effect of HIPEC alone: the estimated improvement in median OS was 18 months (from 30 to 48 months). To put this number in
Conclusions and implications for further research
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Given its limited power to detect a clinically meaningful benefit, the results of the Prodige 7 trial cannot exclude a potential benefit in locoregional disease control in the first 18 months after surgery. Even without any difference in OS, a decrease in peritoneal recurrence would be a sufficient ground for the continued use of HIPEC in CRC. This is comparable with the use of chemoradiation in locally advanced rectal cancer, which lowers local recurrence rate and is accepted as the standard
Acknowledgment
W Ceelen is a senior clinical researcher from the Fund for Scientific Research – Flanders (FWO).
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