No Survival Benefit With Heated Chemo in CRC Surgery

Liam Davenport

June 05, 2018

CHICAGO — Flooding the peritoneal cavity with heated chemotherapy during surgical resection of a form of metastatic colorectal cancer (CRC) does not improve survival over surgery alone and may increase complication rates, a French trial demonstrates.

Peritoneal carcinomatosis is a metastatic tumor that spreads to the peritoneum and occurs in approximately 20% of patients with CRC.

Usual treatment is surgical resection, which can be lengthy owing to the large numbers of tumor nodules across the peritoneal surfaces.

Some centers also use hyperthermic intraperitoneal chemotherapy (HIPEC), in which chemotherapy heated to 43ºC is delivered to the peritoneal cavity while the patient is still under anesthesia.

Introduced about 15 years ago, this approach has been adopted in many centers and has become the standard of care in some countries.

However, the first randomized trial to study this approach found no significant difference in overall survival or relapse-free survival between patients who had surgery with HIPEC and those who had surgery alone.

It also found that the rate of complications at 60 days after the procedure was twice as high with HIPEC as with surgery alone.

Dr François Quenet

François Quenet, MD, head of the hepato-biliary and peritoneal surface malignancy unit, Institut Régional du Cancer de Montpellier, France, presented the study here at the American Society of Clinical Oncology (ASCO) 2018.

Commenting on the new results, ASCO expert Andrew Epstein, MD, said that the study is "very important" and "a particularly excellent example about how less is more, which is something we've seen in other studies at this meeting."

Dr Andrew Epstein

Epstein told Medscape Medical News that the use of HIPEC in the United States is "variable" — it  is accepted and "even the standard of care in some places" but not in others. However, he commented that its use is "ill-defined" and there have been no data "to demonstrate what the additional benefit of HIPEC is, and that's why this [study] is critical."

He said that he and his colleagues see patients and families "who've heard about it in some way, shape, or form and therefore ask about HIPEC, and these are critical data to be able discuss, and need to be discussed with patients."

ASCO Chief Medical Officer Richard L. Schilsky, MD, agreed, saying that the lack of consistency in the use of HIPEC "underscores the success of Dr Quenet and colleagues in completing this study."

He said, "There is not equipoise on this in the surgical community. There are surgeons in the US who are fervent believers in HIPEC and there are others who are true skeptics."

Schilsky added: "If patients travel around and get different surgical opinions, they're going to hear the entire spectrum of opinion from many different surgeons, so you need to be able to do a randomized study."

"In that sort of sceptical environment, it is quite remarkable that that could be achieved."

Study Details

Presenting the study, Quenet noted that without treatment, the median survival of patients with peritoneal carcinomatosis is less than 6 months; this rises to 16 months with modern systemic chemotherapy alone.

Some previous studies have suggested that median survival can increase to 40 months with surgery plus HIPEC, at a cure rate of 16%.

To determine the contribution of HIPEC to those outcomes, the Partenariat de Recherche en Oncologie Digestive (PRODIGE 7) study enrolled 265 patients with stage IV CRC with isolated peritoneal carcinomatosis from 17 centers across France.

Between 2008 and 2014, all patients underwent complete surgical resection with a margin of 1 mm or less and were randomly assigned during the procedure to HIPEC with oxaliplatin (n = 133) or no HIPEC (n = 132).

Both groups, which were stratified by centers and degree of macroscopic resection, also received perioperative neoadjuvant systemic chemotherapy for 6 months.

The median age of the patients was 60 years, and the two treatment groups were well balanced in terms of their baseline characteristics.

The 30-day postoperative mortality rate was the same in both groups, at 1.5%. The 30-day morbidity rates also did not differ.

However, the rate of grade 3 to 5 complications at 60 days was significantly higher in the HIPEC group than in patients who did not have HIPEC, at 24.1% vs 13.6% (P = .030).

Quenet told Medscape Medical News that the complications were primarily extraabdominal, with the most common being pulmonary infections.

He postulated that the reason is "probably because HIPEC prolongs the time during which the patients are at risk."

No Difference in Survival

After a median follow-up of 63.8 months, the median overall survival rate did not significantly differ between the HIPEC and non-HIPEC groups, at 41.7 months vs 41.2 months (P = .995).

There was also no difference in the relapse-free survival rates between the two groups, at a median of 13.1 months and 11.1 months, respectively (P = .486).

It is notable, however, that 1-year relapse-free survival rates were higher with HIPEC than without, at 59.0% vs 46.1%.

In addition, a subgroup analysis indicated that patients with a medium amount of peritoneal carcinomatosis, defined as a score of 11 to 15 on the Peritoneal Cancer Index (PCI), had a benefit from HIPEC, with the procedure significantly increasing overall survival.

Quenet believes that, patients with a higher PCI had too much disease for HIPEC to have a benefit, while patients with a lower score did not have enough disease for it to make a difference.

He said that the "surgery was aimed at working on the macroscopic disease, and the HIPEC was designed to have an effect on the microscopic one, and probably it has a benefit only in this particular portion of patients [with mid-level disease]."

Schilsky commented that surgery for peritoneal carcinomatosis is both "meticulous and lengthy," and he asked Quenet during the postpresentation discussion about the level of surgical experience of the surgeons in the study.

Quenet explained that 75% of the patients in the trial were treated at just three very experienced high-volume centers, which achieved a resection rate of 90%.

Schilsky therefore said that "one important message is that, although each patient who has peritoneal carcinomatosis should be considered for surgery, where they have the surgery and the experience of the surgeon is likely to important."

Quenet agreed that it was "absolutely crucial."

Study discussant Larissa K.F. Temple, MD, professor of surgery and oncology at the University of Rochester Medical Center, New York, said after the presentation of the data that HIPEC, which has been used in several abdominal tumors, has a long history stretching back 30 years.

She pointed out that the literature shows that individuals with peritoneal disease are at high risk and have poor outcomes, and data from the early 2000s showed that HIPEC substantially increased survival.

While there were caveats to interpreting those findings due to selection biases, she said those and other more recent data with similar results have led to greater understanding of peritoneal carcinomatosis, including identifying the best candidates for surgery.

She also emphasized the challenging nature of cytoreductive surgery and the need to maximize resection in order to achieve outcomes, with studies indicating that centers need to perform at least 100 procedures to get the best outcomes.

Another issue in interpreting the results of studies with HIPEC is that practice varies widely and, despite standardized protocols in the United States and France, there is no one established method of performing it.

Temple said that the finding that the HIPEC and non-HIPEC groups in the current study achieved similar outcomes therefore "is very important."

As a consequence, "the use of HIPEC now comes into question," leading to one to ask: "Does this tudy change our practice?"

Temple thinks that "it's way too early to know that...but like every RCT [randomized controlled trial] there will be comments and criticisms" over the details of how the study was conducted.

"Nonetheless, it begins to look at whether we need to reduce the use of HIPEC, and there are questions remaining," she said, especially over its use in high-risk patients and its potential prophylactic use.

Temple nevertheless concluded that she believes "the technique has been shown to impact survival in very selected groups of patients" and that its role is "evolving."

This study received funding from R&D UNICANCER. Quenet received honoraria from Ethicon, Novartis, and Sanofi/Aventis; had a consulting or advisory role with Ethicon, Gamida Cell, and Sanofi/Aventis; and received travel, accommodations, and expenses from Ethicon, Novartis, and Sanofi. No other financial relationships have been disclosed. Temple has disclosed no relevant financial relationships.

American Society of Clinical Oncology (ASCO) 2018. Presented June 5, 2018. Abstract LBA3503

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