Past, present and future of adjuvant HIPEC in patients at high risk for colorectal peritoneal metastases

Peritoneal metastases (PM) from colorectal cancer (CRC) still represent a huge health-care problem. Recent population-based studies report an overall 3.5–4.2% incidence of CRC-PM after potentially curative primary surgery [1,2]. These rates can reach up to about 25% in locally advanced CRC penetrating visceral peritoneum (pT4a), or directly infiltrating surrounding organs (pT4b) [[1], [2], [3]]. Accordingly, the peritoneum is one of the most common site of metastatic spread for CRC, following the liver and lung, even though incidences may be likely underestimated because PM are more difficult to detect than liver or lung metastases. A strategy involving local-regionally delivered chemotherapy to prevent the outgrowth of occult peritoneal seeding into macroscopic metastases is supported by a strong rationale: first, cytoreductve surgery (CRS) combined with hyperthermic intraperitoneal chemotheray (HIPEC) improve CRC-PM survival, but most patients are not suitable for this demanding treatment due to extensive peritoneal involvement, systemic metastases, and/or poor clinical conditions. Second, CRS/HIPEC is maximally effective and safe when small-volume disease is treated. Third, in the palliative setting, modern systemic chemotherapy (s-CT) and targeted agents appear to be less effective for peritoneal metastatic CRC than non-peritoneal metastatic CRC. Finally, the absence of symptoms, as well as current limitations of imaging, hamper early diagnosis and treatment [3]. On these bases, the use of HIPEC for the prevention or early treatment of CRC-PM has been tested at different time-points, either simultaneously with primary surgery [[3], [4], [5]], at the time of second-look surgery after adjuvant s-CT [6], or as a staged procedure at 5–8 weeks postoperatively [7]. Since we were amongst the first groups to investigate the role of adjuvant HIPEC, we were surprised to read that in the COLOPEC randomized trial such a treatment approach failed to demonstrate improved peritoneal-free survival in pT4a/b or perforated CRC [7]. The Dutch investigators randomly assigned patients to oxaliplatin-based HIPEC given either at primary resection in 9% of patient, or 5–8 weeks later in the remaining 91%, and followed by adjuvant s-CT. Patients assigned to the control arm received standard adjuvant s-CT only. All patients showing no recurrent disease at 18 months underwent diagnostic laparoscopy. There was no difference in 18-month peritoneal-free survival between groups: 80.9% (95% confidence interval [CI] 73.3–88.5) for the experimental arm vs. 76.2% (95%CI 68–84.4) for the control arms (log-rank two-sided P = 0.28) [7]. Analogously, the randomized French trial Prophylochip failed to demonstrate a survival benefit associated with a strategy of systematic second-look surgery plus HIPEC in high risk patients, as compared with standard surveillance. The French trial was done in a different clinical setting than the COLOPEC trial, as high risk to develop CRC-PM was defined as history of ovarian or low-volume peritoneal metastases resected with the primary, or perforated primary tumor [6]. Investigators in Rome and Milan have completed two pilot studies to test oxaliplatin-based HIPEC, and mitomycin plus cisplatin-based HIPEC, respectively. In both studies, HIPEC was given at the same time as primary resection [3,4]. Limiting the analysis to patients with pT4a/b or perforated CRC (the same population as in COLOPEC trial), PM occurred in one of seven patients treated in Rome, with a median follow-up of 48 months [4]. After an up-dated follow-up of more than 10 years (median 128.0 months), PM has occurred so far in one of 14 patients treated in Milan, and another patient has died of liver metastases (Baratti D, unpublished data). The study by Tentes et al. is the third relevant literature series of simultaneous adjuvant HIPEC. The authors report no PM occurring in 15 patients treated with either ox