1. Bennett, Christina

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CHICAGO-No survival benefit was found when hyperthermic intraperitoneal chemotherapy (HIPEC) was added to cytoreductive surgery for patients with advanced colorectal cancer that had metastasized to the peritoneum. In addition, long-term complication rate was higher when HIPEC was used during surgery. Phase III trial findings were presented at the 2018 ASCO Annual Meeting (Abstract LBA3503).


About 20 percent of patients with metastatic colorectal cancer develop peritoneal carcinomatosis, and those patients have significantly worse survival compared to patients with metastatic colorectal cancer that has not spread to the peritoneum (Lancet Oncol 2016;17:1709-1719). Retrospective studies have suggested that adding HIPEC to surgery may improve survival, so a randomized phase III trial in France was conducted to answer the question.


"It's the largest randomized study comparing surgery plus HIPEC versus surgery alone," said Manish Shah, MD, Director of the Gastrointestinal Oncology Program at Weill Cornell Medicine and NewYork-Presbyterian. He explained that the standard of care for this patient population is cytoreductive surgery and systemic chemotherapy, but HIPEC is done during surgery for select patients.


"HIPEC has been done for many years on a case-by-case basis without randomized data because these kinds of studies are hard to do," he said, "so the fact that the patients participated [and] the investigators persisted and were able to perform a randomized study in this population is really compelling and noteworthy."


Trial Details

The PRODIGE 7 trial (NCT00769405) was conducted at multiple centers throughout France and enrolled participants with colorectal cancer that had metastasized to the peritoneum, but no other locations in the body. All participants were required to receive systemic chemotherapy for 6 months preoperatively, postoperatively, or both. Participants could not be older than 70. The primary endpoint was overall survival (OS). Secondary endpoints were recurrence-free survival (RFS), toxicity, morbidity, and prognostic factors of survival.


Treatment randomization was done at the time of cytoreductive surgery to ensure complete resection or residual tumor status of 1 mm or less was achieved. Between 2008 and 2014, a total of 265 participants were randomly assigned to receive either HIPEC with oxaliplatin during surgery or surgery alone.


"It was a challenging study because they were only able to enroll roughly 260 patients over a long period of time," said Shah.


Baseline characteristics were similar between the two arms. Lead study author Francois Quenet, MD, Head of the hepato-biliary and peritoneal surface malignancy unit at the Regional Cancer Institute in Montpellier, France, noted, "The complete microscopy cytoreduction rate was pretty good in both arms, almost 90 percent."


No Benefit, More Complications

The mortality rates were similar between both groups. At 30 days post-surgery, two patients died in each arm. Later at 60 days post-surgery, three more deaths occurred; two in the surgery plus HIPEC arm and one in the surgery alone arm, yielding a total mortality rate of 2.6 percent.


No statistically significant differences were found between arms for morbidity at 30 days post-surgery; however, at 60 days, the rate of grade 3 or higher complications was greater for the surgery plus HIPEC arm than for the surgery alone arm (24.1% vs. 13.6%), and the difference was statistically significant (P=0.030). Those in the HIPEC plus surgery arm had higher rates of intra-abdominal complications (6% vs. 3%) and extra-abdominal complications (20.3% vs. 21.1%), but the differences did not reach statistical significance. Also, the surgery plus HIPEC arm had a 5-day longer hospital stay length than did the surgery alone arm, and the difference was statistically significant (P<0.0001).


At a median follow-up of 64 months, no difference was found in median OS between the two treatment arms. The surgery alone arm had a median OS of 41.2 months and the surgery plus HIPEC arm had a median OS of 41.7 months. The 1-year and 5-year survival rates also had no statistically significant differences between arms.


Median RFS was 13.1 months in the surgery plus HIPEC arm compared to 11.1 months in the surgery alone arm and did not reach statistical significance. At 1-year follow-up, there was a 17 percent difference for median RFS between the two arms, but by 5 years the rates were the same between arms.


"Overall, what they've found is that there was no significant difference in outcome whether you received HIPEC or not," said Shah.


Potential Prognostic Factor

A subgroup analysis was performed to determine whether factors such as sex, prior chemotherapy, and nutrition were prognostic for OS.


One factor analyzed was peritoneal cancer index, which is a measure of the extent of peritoneal disease. Participants were divided into three groups based on volume of peritoneal disease: low (<11), intermediate (11-15), and high (>15). The subgroup analysis showed that, in the HIPEC plus surgery arm, participants with intermediate volume of peritoneal disease had a statistically higher median OS rate than those in the surgery alone arm, suggesting intermediate volume may be a prognostic factor for benefit with HIPEC (41.6 months vs. 32.7 months; HR=0.437; P=0.0209).


However, Shah cautioned against over interpretation: "People who had the intermediate volume maybe had some benefit, but that's a subgroup analysis."


Quenet echoed a similar view, "We must be very cautious with those results, because it was an unplanned analysis, and the sample is very small."


Take-Home Message

Randomized trials have shown that adding HIPEC to surgery can improve outcomes, such as was the case for ovarian cancer, but the PRODIGE 7 trial does not provide evidence for a new standard of care (N Engl J Med 2018;378:230-240).


"I think it's a very important study, and particularly an excellent example about how less is more," commented ASCO Expert Andrew Epstein, MD. He said it's important that "we could have a study like this to be able to show the lack of role for HIPEC in addition to surgery."


"The take-home message for me is that in general HIPEC is probably not indicated in patients with colorectal cancers with peritoneal disease," noted Shah. He said the best approach remains systemic chemotherapy; however, on a case-by-case basis, HIPEC could offer some advantages, but more studies are needed to really "fine-tune" that.


Christina Bennett is a contributing writer.