What is heated chemotherapy? Does HIPEC work in colon and rectal cancer?

Colorectal (colon and rectal) cancer surgery involving washing the peritoneal cavity (the space between the abdominal lining) with heated chemotherapy was found not to improve disease-free or overall survival, while increasing complication rates.

Heated intraperitoneal chemotherapy is an appealing and increasingly popular cancer treatment. However, its scope of effectiveness is not as broad as is believed or widely promoted, and it is incorrect to say it works for every cancer involving the abdominal lining.

Peritoneal carcinomatosis is a condition caused by widespread tumor metastasis (spread) to the abdominal lining, and may cause ileus (intestinal obstruction) . Ileus occurs in approximately 20% of patients with colorectal cancer that has spread to the peritoneum.

If surgery is chosen for colon cancer that has spread to the abdominal lining, standard treatment is surgical removal of as much of all the tumors spread throughout the lining as possible. In some centers, Hyperthermic IntraPEritoneal Chemotherapy (HIPEC), heated to as much as 43ºC, is delivered into the peritoneal cavity during surgery while the patient remains under anesthesia.

Interest in heated chemotherapy

Heated intraperitoneal chemotherapy has been tried for years in many cancers involving the abdominal lining, but evidence showing that its benefits outweigh its harms is limited. So far, convincing evidence of meaningful benefit from adding HIPEC to peritoneal surgery exists for only a few cancer types. Two examples are:

• For newly diagnosed gastric cancer with peritoneal metastases, heated chemotherapy combined with surgery prolonged survival and improved disease outcomes compared with surgery alone, without causing additional side effects.
• In newly diagnosed stage 3C ovarian cancer, HIPEC resulted in longer recurrence-free and overall survival than surgery alone (for details of these two studies and our commentary, see here).

In other words, although some centers use HIPEC as if it were standard treatment for many cancers involving the abdominal lining—including colon and rectal cancers—there are insufficient data to establish its added benefit. This makes the present study particularly important.

Many patients and relatives have heard about HIPEC in some way and go from hospital to hospital asking, "Do you perform HIPEC?" Unfortunately, we see this very demanding treatment being recommended to patients despite insufficient evidence of benefit.

Is HIPEC effective in colon and rectal cancer?

In this article, we will share the results of 2 recent, comprehensive studies on the use of HIPEC in treating colorectal cancers.

The PRODIGE 7 study

HIPEC was adopted by many cancer centers approximately 15 years ago and became a standard of care in some countries. However, in the first randomized clinical trial examining this approach in colorectal cancer, no significant difference in overall or recurrence-free survival was found between patients having surgery with HIPEC and those having surgery alone. François Quenet, head of the hepatobiliary and peritoneal surface malignancy unit at Institut Régional du Cancer de Montpellier in France, presented this study at ASCO 2018.

This clinical trial does not describe a new and successful treatment, as we are accustomed to seeing in oncology; instead, it examines in a detailed, rigorous manner a method whose effectiveness is uncertain. In this respect, it is one of a small number of valuable examples.

Furthermore, the complication rate (procedure-related side effects) within 60 days after surgery was twice as high with surgery plus HIPEC as with surgery alone.

Study details

Quenet, who presented the study, emphasized that median survival in untreated patients with peritoneal carcinomatosis is less than 6 months; with modern systemic chemotherapies, it rises only to a median of 16 months.

Some earlier studies suggested that adding HIPEC to surgery could improve survival by as much as 40%, reaching 40 months.

• To determine HIPEC’s contribution to these outcomes, the PRODIGE 7 clinical trial assessed patients from 17 centers across France: stage 4 colorectal cancer with peritoneal carcinomatosis was present in 265 patients.
• Between 2008 and 2014, all patients underwent complete surgical resection (removal) of their tumors with negative (clear) surgical margins. Patients were randomly assigned to two groups, stratified by their center, completeness of surgical resection (R0/1, R2 resection), and the neoadjuvant systemic chemotherapy they received. During surgery, 133 patients received HIPEC with the chemotherapy drug oxaliplatin , while 132 patients did not receive HIPEC.
• Both groups received neoadjuvant systemic chemotherapy for 6 months.
• The median age was 60, and the two treatment groups were well balanced in their baseline characteristics.
• The 30-day postoperative mortality (death after surgery) rate was 1.5% in both groups.
• However, grade 3 to 5, meaning serious, complications (side effects) were significantly more frequent in the HIPEC group (24.1% versus 13.6%).
• One interesting point was that the most common complications were pulmonary (lung) infections, meaning outside the abdomen.

The researcher presenting the study suggested this was because "HIPEC extends the time during which patients are at risk," he proposed.

No difference in survival!

• After a median follow-up of 63.8 months, median overall survival was 41.7 months and 41.2 months in the HIPEC and non-HIPEC groups respectively, with no significant difference.
• Recurrence-free survival was also similar between the groups, at a median of 13.1 months and 11.1 months, with no significant difference (p = .486).
• However, 1-year recurrence-free survival was higher in the HIPEC group (59% versus 46%). This did not translate into overall survival.
• In addition, a subgroup analysis found that overall survival with HIPEC increased substantially in those with an intermediate peritoneal cancer index (PCI) value (11 to 15 points).

Previously, patients with a higher peritoneal cancer index were thought to benefit more from HIPEC. The finding of benefit in patients with lower scores in this study is another surprising result.

Because surgery for peritoneal carcinomatosis is "meticulous and lengthy," the experience of the surgeons in the study was another subject of discussion. Quenet explained that 75% of trial patients were treated in three highly experienced, high-volume centers with a 90% complete resection rate.

The PROPHYLOCHIP–PRODIGE 15 study

The Lancet Oncology published the results in August 2020 of this multicenter French phase III study involving 150 colorectal cancer patients. Goéré and colleagues showed that, in patients with colorectal cancer at high risk of developing peritoneal metastases, second-look surgery plus HIPEC, compared with standard surveillance, did not improve disease-free survival.

Patients were enrolled between 2010-2015. At diagnosis, in addition to their colorectal tumors, they had regional peritoneal or ovarian metastases, or their tumors had perforated. After complete tumor removal at initial surgery and 6 months of adjuvant chemotherapy, 150 patients with no signs of recurrence were divided into two arms: 75 underwent standard surveillance and 75 underwent second-look surgery plus HIPEC.

At the end of the study, the findings were:

• Median follow-up was 50,8 months.
• Of the 75 patients in the second-look surgery group, 71 underwent second-look surgery; 67 of them received HIPEC and 59 received oxaliplatin HIPEC.
• The 3-year disease-free survival rate was 53% in the surveillance group and 44% in the second-look surgery group (no statistically significant difference).
• No significant difference was observed in 5-year disease-free survival or 3-year peritoneal recurrence-free survival.
• There was no difference in 3-year overall survival (80% versus 79%) or 5-year overall survival (72% versus 68%).

Conclusion

Patients with tumors spread throughout the abdominal lining are at high risk and have poor disease outcomes. Data from the early 2000s, arising from poorly designed earlier studies, suggest HIPEC improves survival. However, current studies show that adding heated chemotherapy to standard surgery benefits only certain cancers, with initial surgery at diagnosis plus HIPEC providing benefit; according to this study, colon and rectal cancers are not among them. The researchers also emphasized that, because of the demanding nature of cytoreductive surgery , meaning complete removal of all tumors in the abdominal lining, centers need to perform at least 100 procedures (operations) to achieve the best results.

- Related topic: Innovations in colon and rectal cancer treatments