No survival benefit of adding hyperthermic intraperitoneal chemotherapy to surgery in patients with colorectal peritoneal carcinomatosis

A randomized phase III trial showed that patients with advanced colorectal cancer and peritoneal carcinomatosis may not need hyperthermic intraperitoneal chemotherapy (HIPEC). In the study at hand, there was no difference in survival between patients with metastases in the abdomen who received HIPEC during surgery and those who received surgery alone. Moreover, long-term side effects were seen more common in patients who did receive chemotherapy.

Peritoneal carcinomatosis refers to a metastatic tumour on the lining of the abdominal cavity (i.e. the peritoneum) and occurs in about 20% of people with metastatic colorectal cancer. In many countries, the addition of HIPEC to complete surgical removal of the disease is either an accepted option, or even standard of care. The latter is based on promising results obtained during the last decade using cytoreductive surgery (CRS) plus HIPEC for selected patients with colorectal peritoneal carcinomatosis who are amenable to complete macroscopic resection. With this approach, up to 16% of patients with peritoneal carcinomatosis may be cured. PRODIGE 7 is the first randomized trial to evaluate the specific role of HIPEC, after CRS, for the treatment of peritoneal carcinomatosis of colorectal origin.

The French trial enrolled 265 stage IV colorectal cancer patients with peritoneal carcinomatosis and no metastases elsewhere in the body. The patients were randomly assigned to receive surgery plus HIPEC (chemotherapy oxaliplatin heated to 43°C in an attempt to increase chemotherapy efficacy) or surgery alone. Most (96%) of the patients also received systemic chemotherapy, before surgery, after surgery or both. The type of systemic therapy was per physician choice. The primary endpoint of the trial was overall survival (OS), with relapse-free survival (RFS) and toxicity as key secondary objectives.

The median age of patients in the study was 60 years and all baseline patient and disease characteristics were well balanced between the two treatment arms. After a median follow-up of 64 months, the median OS was 41.2 months in the non-HIPEC group, which was almost identical to the 41.7 months median OS seen in the group of patients who did receive HIPEC (HR[95%CI]: 1.00[0.73-1.37]; p=0.995). At 1 year, 86.9% of the HIPEC patients were still alive as compared to 88.3% in the non-HIPEC arm. At 5 years, these rates were 39.4% and 36.7%, respectively. Also the RFS did not differ significantly between both treatment arms at a median of 13.1 months in HIPEC treated patients and 11.1 in the non-HIPEC cohort (HR[95%CI]:  0.90[0.69-1.90]; p=0.486). The 1 and 5 year RFS rates in the HIPEC arm were 59.0% and 14.8% as compared to 46.1% and 13.1% in the non-HIPEC patients. The overall mortality rate at 30 days after surgery was 1.5% in both groups, and there was no difference in the rate of side effects during the first 30 days. At 60 days, however, the rate of complications in the HIPEC group was almost double the incidence seen in the non-HIPEC group (24.1% vs. 13.6%).

More research is needed to determine if there are patients who would still benefit from receiving HIPEC with surgery. A subgroup analysis from this study suggests that HIPEC might be beneficial for patients with a mid-range peritoneal cancer index (PCI 11-15), but the patient numbers were too small to be conclusive. As such, the investigators concluded that patients with a low peritoneal cancer index could likely forgo HIPEC, whereas those with a high index may not benefit from either surgery or HIPEC. In addition to this, other types of chemotherapy may be more effective than oxaliplatin, the type of chemotherapy used in HIPEC for this study. Of note, the survival rate of the surgery alone patients in this trial was unexpectedly high. This underlines that every patients with an isolated peritoneal carcinomatosis should be considered for surgery.

Reference

Quenet F, et al. A UNICANCER phase III trial of hyperthermic intra-peritoneal chemotherapy (HIPEC) for colorectal peritoneal carcinomatosis (PC): PRODIGE 7. Presented at ASCO 2018; Abstract LBA3503.