HIPEC Does Not Add Benefit to Cytoreduction Surgery in CRC Peritoneal Metastasis

Muhammad Talha Waheed, MD, stated that a retrospective study found an OS benefit in CRC peritoneal metastasis with cytoreduction surgery without HIPEC vs with HIPEC.

CancerNetwork® interviewed Muhammed Talha Waheed, MD, a postdoctoral research fellow at City of Hope Comprehensive Cancer Center in Duarte, California, ahead of a presentation on a retrospective analysis of mitomycin C hyperthermic intraperitoneal chemotherapy (HIPEC) as a treatment for patients with colorectal cancer who have peritoneal metastasis he delivered at the 2025 Society of Surgical Oncology Annual Meeting (SSO).¹

The study found 1-year overall survival (OS) rates of 100% for cytoreduction surgery (CRS) alone and 84.3% for CRS with HIPEC (P = .006); the median OS was not reached in the CRS alone group—during the conversation, Waheed stated that it was 41.2 months—vs 31.5 months in the CRS with HIPEC group. The recurrence-free survival was 8.7 months (95% CI, 6.6-14.3) vs 8.7 months (95% CI, 6.0-31.1), respectively (P = .894).

The phase 3 PRODIGE-7 trial (NCT00769405), according to Waheed, was one of the first trials to question whether there was a benefit to adding HIPEC to CRS, and it also influenced this study.² Most centers after PRODIGE-7’s results were published either stopped offering HIPEC or started offering HIPEC with mitomycin C. This study analyzed and compared treatment results between those who received CRS alone (2021-2024) and those who received mitomycin C HIPEC (2009-2021).

While PRODIGE-7 identified that patients with a peritoneal carcinomatosis index (PCI) between 11 and 15 demonstrated variable benefit depending on whether they received CRS or HIPEC, this analysis did not find a correlation between any subgroups and clinical benefit.

Waheed concluded by highlighting the lack of clinical trials that exist in this space and emphasized the need for more randomized trials despite their length and costs. As he said, “This is a very difficult disease to treat, and our patients are relying on us.”

CancerNetwork: How did results from the PRODIGE-7 trial impact your decision to investigate mitomycin C HIPEC in CRC-PM?

Waheed: PRODIGE-7 was one of the first trials in the last 2 decades to ask the question: what is the added benefit of HIPEC when you combine it with cytoreductive surgery? This group compared patients undergoing CRS alone with patients who underwent CRS with HIPEC and oxaliplatin. To everyone’s surprise, this was a negative trial.

The 2 things that happened after PRODIGE-7 [were] either centers…continued to offer HIPEC or they switched to offering HIPEC with mitomycin C. Now we [did] not know the benefit of adding [mitomycin C] to HIPEC, and that prompted us to look at whether or not HIPEC with mitomycin C has any benefit. We, at City of Hope, stopped offering HIPEC altogether in 2021 after the results for PRODIGE-7 were published. We were able to look at patients who underwent HIPEC mitomycin C before that [and compare them with] patients who underwent CRS alone after that.

Are there still scenarios where you might still use MMC HIPEC?

When choosing a treatment option, there always has to be a discussion of risk vs benefit. When looking at the benefits specifically, our results report no added benefit of HIPEC. That really begs the question, what are you giving these patients and what is the benefit that you’re giving to these patients… At this point, we’re not able to comment on the risks because we were not able to compare the complications, but we’re in the process of abstracting that data. We will be able to compare the risks associated with either of the treatments, and we will report that in the paper.

Very interestingly, PRODIGE-7 did look at the complication rates between the 2 arms, which…is the cytoreductive surgery alone treatment arm, and compared that with patients who underwent cytoreductive surgery with HIPEC oxaliplatin. They reported, although non-significant, that 30-day severe complications were higher in patients undergoing HIPEC. [Complications] 31 to 60 days after surgery were significantly higher in patients undergoing HIPEC. That begs the question…when you’re not able to provide any benefit, and rather there’s a risk or chance of increased complications for these patients, is there utility to still offer HIPEC?

The current data does support the use of HIPEC in patients with appendix cancer with peritoneal metastasis, so we continue to offer that for those patients. HIPEC, with some other agents, continues to be offered for patients with ovarian cancer at our center and nationwide. That is where I think this application—[CRS with HIPEC]—still is relevant.

What do these results mean for colorectal cancer peritoneal metastasis standards of care?

Based on the available data that we have right now, the current consensus guidelines recommend CRS plus or minus HIPEC along with systemic chemotherapy for resectable disease. Our study, at this point, is retrospective and it is not able to change the current standard of care at the national level, but it does put the use of HIPEC or regular use of HIPEC mitomycin C for [patients with colorectal cancer who have] peritoneal metastasis into question. The most important takeaway from our study must be that we see a benefit in OS for patients undergoing only CRS; that is also something that we saw in 37 patients. Those patients had a median OS of 41.2 months, which is substantial and huge. This was not something that we were getting a couple of years back.

That begs the question of whether or not it is because of modern systemic chemotherapy. Is it [because of] better tolerance to salvage therapies for these patients who have recurrences in the future? Or is there more availability of experimental clinical trials for these patients? There is something that is going on that is increasing the benefit—increasing the OS—for patients undergoing CRS alone. There has been some hesitation from most of the centers to [stop using] HIPEC altogether for [patients with] colorectal cancer who have peritoneal metastasis, but we at City of Hope switched to CRS alone in 2021 after the PRODIGE-7 results were published. Looking at our data right now, 4 years later, we remain confident in our decision to switch to CRS alone. The only caution there is [with] complete cytoreduction getting these patients to CC-0 or CC-1 resection [because it] is the most important prognostic factor. Our results are from a high-volume expert center, so getting these patients to an expert, high-volume center is the key, and these results should only be extrapolated to those centers.

Moreover, there is a very famous trial that is growing—the phase IV GECOP-MMC trial (NCT05250648)—which will compare patients undergoing HIPEC mitomycin C combined with CRS with patients undergoing CRS alone. That would also be able to guide us further.

Were there any specific patients that had enhanced benefits or enhanced risks?

PRODIGE-7 did a stratified subgroup analysis where they found that patients who had a peritoneal carcinomatosis index or PCI score of 11 to 15 had a variable benefit if they underwent CRS with HIPEC. That is used to justify the continued use of HIPEC for patients with colorectal cancer with peritoneal metastasis. We had to do a similar analysis for our paper, and…unfortunately, we did not find any benefit for any of the subgroups for our paper and for our study. To answer your question, not really. For the enhanced risk, at this point, I’m not able to comment on the complication rates between these 2 treatments, but that is something in the plans, and we will report that in the paper.

What are some of the next steps for the future of this research?

Simply put, we need more randomized trials. We need more level 1 evidence. This is a very difficult disease to treat, and our patients are relying on us. The trials in this field are so [few] that you can count them on your fingers, and the biggest roadblocks to conducting these trials have been the time and costs associated with these trials. That is because OS is the most common end point that is used to conduct these trials, and it takes too long to do is to do these trials. Very fortunately, our group was able to have a very big collaboration across 20 centers [and] across 4 countries to look at different surrogate end points for OS that could potentially be used to accelerate the time that is needed to conduct these trials. We presented this data at SSO last year, and we’re very enthusiastic to publish these results in a few months, hopefully. That would probably be able to guide how we conduct clinical trials in the future.

References

1. Waheed MT, Paz IB, Lwin T, et al. Impact of systematic discontinuation of mitomycin C (MMC) HIPEC for colorectal peritoneal metastasis (CRCPM) on oncologic outcomes at an NCI cancer center. Presented at SSO 2025; March 27-29, 2025; Tampa, FL.
2. Quénet F, Elias D, Roca L, et al. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal metastases (PRODIGE 7): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(2):256-266. doi:10.1016/S1470-2045(20)30599-4