Addition of HIPEC to Cytoreductive Surgery in CRC Peritoneal Carcinomatosis Warrants Further Investigation

Although the survival benefit of cytoreductive surgery in colorectal cancer (CRC) peritoneal carcinomatosis has been well documented, the independent prognostic value of adding hyperthermic intraperitoneal chemotherapy (HIPEC) has been muddied by mixed interpretations of the phase 3 PRODIGE 7 (NCT00769405) and PROPHYLOCHIP-PRODIGE 15 (NCT01226394) studies, and further exploration is needed, according to Prakash Pandalai, MD.

In the PRODIGE 7 study, investigators examined the survival benefit of HIPEC in patients with CRC peritoneal carcinomatosis and found that morbidity rates did not differ significantly at 30 days between those who received HIPEC and those who did not.

After a median follow-up of 63.8 months, the median overall survival (OS) was 41.7 months in the HIPEC arm compared with 41.2 months in the non-HIPEC arm (HR, 1.00; 95% CI, 0.73-1.37; P = .995). Additionally, the median recurrence-free survival was 13.1 months versus 11.1 months, respectively (HR, 0.90; 95% CI, 0.69-1.90).

“The outcomes in terms of safety were outstanding. Patients had very low morbidity and mortality,” said Pandalai. Certainly, it shows that in a good, high-volume cancer center, you can do these pretty big operations with minimal risk and excellent outcomes safety-wise. Patients have an outstanding benefit with regard to OS. However, the question of the contribution of HIPEC is still unfortunately open to debate and further study.”

In an interview with OncLive® during a 2020 Institutional Perspectives in Cancer webinar on gastrointestinal malignancies, Pandalai, an assistant professor of surgery and a surgical oncologist at the University of Kentucky Markey Cancer Center, discussed the role of HIPEC in CRC peritoneal carcinomatosis and data from the PRODIGE 7 and PROPHYLOCHIP-PRODIGE 15 trials.

OncLive®: Could you speak to the rationale of adding HIPEC to cytoreductive surgery (CRS) in patients with CRC peritoneal carcinomatosis?

Pandalai: This is a devastating disease process that affects far too many patients with CRC. In particular, peritoneal carcinomatosis is when the primary tumor either perforates or spreads outside of the colon and sheds its tumor cells into the abdominal cavity, often sticking to different layers of the cavity, such as the peritoneum. It can also stick to organs such as the small intestine and the omentum. This is often what causes a lot of the morbidity that these patients experience in terms of symptoms of abdominal pain and bowel blockages. Unfortunately, we know that systemic chemotherapy is often not that effective at penetrating the peritoneal cavity. The fact is that CRS with HIPEC came about as a way to potentially overcome this limitation.

What outcomes have we seen with this approach in this population?

Historically, when patients with peritoneal carcinomatosis are treated with chemotherapy alone, we know that the outcome is typically a median OS of less than 12 months. When you add aggressive CRS and HIPEC, the results are much better. Single institutional series, as well as multi- institutional series, have demonstrated a median OS of 40 months to 45 months, which is more than 3.5 years; this is quite profound for these patients.

PRODIGE 7 was a wonderful trial that came out of France and was published in 2018. This trial was meant to answer the question regarding the value of [adding] HIPEC [to the mix]. We talk about CRS and HIPEC as a combination operation, but it’s really 2 separate procedures. The first procedure is the CRS, where we physically remove the gross physical tumor that we can see. Often, this results in a multivisceral resection or removing a small piece of the intestine, colon, appendix, or whatever organ we see tumor deposits in.

Once that is complete, we hope that we will not see any additional cancer cells, but we know they’re hiding somewhere in the abdominal cavity. We then place catheters into the abdominal cavity and profuse it for a period of time with chemotherapy that’s infused in a heated solution. With CRS and HIPEC, [some] question the value of each component.

PRODIGE 7 was the first randomized clinical trial to evaluate this particular question. To do this, patients [underwent] CRS, and immediately following surgery, one group would receive HIPEC and the other would not. [Investigators] directly assessed the impact of HIPEC on OS.

What was learned from this effort?

The results of this study were a little bit mixed. If you look at the primary end point, which was OS, no difference [was observed] between the groups in terms of the HIPEC contribution. The investigators who designed this trial were very aggressive and were looking for an 18-month OS benefit, which is quite long. In terms of OS for both groups, the median OS was equivalent at [more than] 41 months, which is phenomenal if you look at that compared with systemic therapy alone. We have to be very cautious. Some will look at this trial and interpret [these results] to mean that there is no additional value to HIPEC, whereas others will say, “Wow, this promotes an amazing response to good CRS plus or minus HIPEC.” These are really the gaps in knowledge [that we face].

When we look at the choice of chemotherapy, this group received oxaliplatin. We do know that worldwide, the most common drug used in HIPEC is actually mitomycin C, not oxaliplatin. Certainly, there could be some controversy with regard to the choice of agent they used [in the trial]. However, the groups themselves were very well matched, and all of them underwent excellent CRS. What cannot be criticized is the quality of surgery that had been performed.

Then, the PROPHYLOCHIP-PRODIGE 15 study examined the benefit of second-look surgery with prophylactic HIPEC in those at increased risk of developing colorectal peritoneal metastases. Did these data provide any further clarity regarding HIPEC?

We want to identify patients who may be at risk for developing peritoneal carcinomatosis. The PRODIGE 15 study sought to answer the question of whether patients who we know are at risk for peritoneal carcinomatosis benefit from a second-look operation with a prophylactic HIPEC approach. Investigators looked at several patients who were at high risk for developing this condition—namely, those who have bigger tumors that are advanced and/ or perforated; we call those T3 and T4 tumors. [These are] patients who have evidence of limited peritoneal carcinomatosis at the time of their index operation; you might see a few tumor deposits around the area of the tumor, but those are removed. This can also include patients who have ovarian droplet metastasis.

Essentially, patients [received] standard of care. They had surgery for their primary tumor, they had their ovarian metastasis or limited peritoneal carcinomatosis resected, and then they received 6 months of adjuvant chemotherapy, just like they would in normal practice. Following this, these patients were randomized to undergo CRS and HIPEC as a second-look option versus a standard surveillance program.

The primary end point of this trial was disease-free survival [DFS] at 3 years. [Results] showed that those patients who had second-look operations had evidence of peritoneal carcinomatosis that was not picked up through standard routine surveillance; that was present in approximately 50% of those who underwent second-look surgery. All patients had successful HIPEC performance, with the exception of 3 who did not because they had widespread disease that was not actually amenable to complete CRS. However, the vast majority were able to undergo CRS with HIPEC safely.

The group that did not undergo surgery and was randomized to observation had an equivalent 3-year DFS. Interestingly, 17 of those patients were identified to have radiographic peritoneal carcinomatosis during their follow-up, and they all crossed over into the surgical arm. Although the results of the trial were equivalent— no additional 3-year DFS benefit was in the group that underwent second-look surgery and HIPEC—this is probably not entirely accurate, because a good portion of the control arm was identified as having disease progression and they underwent surgery. That muddied the water a little bit in terms of interpreting the results of this particular trial.

Reference

Quenet F, Elias D, Roca L, et al. A UNICANCER phase III trial of hyperthermic intra-peritoneal chemotherapy (HIPEC) for colorectal peritoneal carcinomatosis (PC): PRODIGE 7. J Clin Oncol. 2018;36(suppl 18):LBA3503. doi:10.1200/JCO.2018.36.18_suppl.LBA3503