Francois Quenet, MD
The addition of heated chemotherapy delivered to the abdomen during surgery delivered no survival benefit to patients with peritoneal carcinomatosis, according to phase III study results presented at the 2018 ASCO Annual Meeting.
After a median follow up of 63.8 months, the difference in median overall survival (OS) was not statistically significant, with 41.2 months (95% CI, 35.1-49.7) reported in the non-HIPEC arm compared with 41.7 months (95% CI, 36.2-52.8) in the HIPEC arm (HR, 1.00; 95% CI, 0.73-1.37; P
One-year (88.3% vs 86.9%, respectively) and 5-year (36.7% vs 39.4%, respectively) OS rates were also similar among the non-HIPEC and HIPEC groups.
“The addition of HIPEC with oxaliplatin does not influence the survival results,” said lead study author Francois Quenet, MD, head of the hepato-biliary and peritoneal surface malignancy unit at the Regional Cancer Institute in Montpellier, France. “The survival rate of the surgery alone group was unexpectedly high, which means every colorectal cancer patient with an isolated peritoneal carcinomatosis should be considered for surgery.”
The addition of hyperthermic intra-peritoneal chemotherapy (HIPEC)oxaliplatin heated to 43C in an attempt to increase chemotherapy efficacyto complete surgical removal of peritoneal carcinomatosis is either an accepted option or a standard of care in many countries.
“In the natural history of the disease, [there has been] less than 6 months survival,” Quenet explained. “Today, when the patient is not resected, patients have a prognosis of 16 months survival with modern systemic chemotherapy alone. If the patient is amenable to complete surgical removal of the tumors and HIPEC, the prognosis is 40 months survival, and in best cases, we are able to cure 16% of the patients.”
The randomized phase III PRODIGE 7 trial enrolled 265 patients who had stage IV colorectal cancer with isolated peritoneal carcinomatosis at 17 centers in France. Patients underwent surgery, which consisted of complete surgical resection ≤1 mm. They were then randomized 1:1 to receive surgery plus HIPEC (n = 133) or surgery alone (n = 132). For both arms, 96% also received systemic chemotherapy per physician choice for 6 months before surgery, after surgery, or both.
OS served as the primary endpoint, and secondary endpoints included relapse-free survival (RFS) and toxicity. In total, 264 patients were required to show a gain in median OS from 30 to 48 months (HR = 0.625) with a two-sided α of 0.046 and 80% power.
At 30 days, the postoperative mortality rate was 1.5% in both arms, and there was no difference in the rate of side effects. However, at 60 days, the rate of grade ≥3 morbidity was significantly higher in the HIPEC group compared with those who did not receive heated chemotherapy (24.1% vs. 13.6%; P
= .030), which typically consisted of extra abdominal complications, Quenet said.
Similarly, median RFS was 11.1 months (95% CI, 9-12.7) in the non-HIPEC arm compared with 13.1 months (95% CI, 12.1-15.7) in the HIPEC arm (HR, 0.90; 95% CI, 0.69-1.90; P
= .486). One-year RFS rates were 46.1% in the non-HIPEC arm and 59% in the HIPEC arm, while 5-year rates were 13.1% and 14.8%, respectively.
Results from a subgroup analysis of the ranges of peritoneal cancer index suggested that HIPEC was beneficial for patients with a medium amount of disease in the peritoneal cavity. However, Quenet et al noted these numbers from the subgroup analysis were too small to be conclusive and should be further studied.
“My impression is that for patients with a very small amount of disease, HIPEC is not necessary, and they can forgo it,” Quenet said. “For patients with high disease, HIPEC plus surgery is not necessary because the disease is too severe. But for the medium patient, we have to go further into the study to be aware if there is an effect from this.”
ASCO expert Andrew Epstein, MD, noted that this study is an “excellent example about how less is more.”
“It is very important to have a study like this to show the lack of [benefit] from the addition of HIPEC to surgery,” he said. “All patients with peritoneal carcinomatosis of colorectal cancer should be considered for surgery. That is fair to say, and I would argue that they should be put in studies like this, if possible, in order to further demonstrate what helps.”
During the question-and-answer portion of the presentation, Epstein also highlighted the importance of this data in the US.
“[HIPEC in the US] is variable, but it has to be underscored that there is this kind of data to be able to show or demonstrate what the additional benefit or detriment is, so that is why this is critical because it is used not infrequently,” he added. “And when patients hear about this treatment and have questions, it is important to have this data to show them.”
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; abstr LBA3503).
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