Is there a role for hyperthermic intraperitoneal chemotherapy (HIPEC) along with cytoreductive surgery (CRS) for colon cancer patients with peritoneal metastases? The answer is maybe, according to two experts who debated this topic at the 2022 Great Debates & Updates in Gastrointestinal Malignancies.
The survival of colon cancer patients with isolated peritoneal metastasis after current era first-line, second-line, or third-line systemic chemotherapy is still relatively unknown. The central hypothesis of HIPEC is that, in selected patients, peritoneal metastases represent the sole site of metastatic disease and, therefore, may be cured with locoregional therapy. The challenges of HIPEC are reduced drug penetration to peritoneal versus visceral metastases and complete cytoreduction is never complete.
Yes to HIPEC
Andrew M. Lowy, MD, FACS, Professor of Surgery and Chief of the Division of Surgical Oncology of the Moores Cancer Center at UC San Diego, presented the rationale for intraperitoneal chemotherapy. The peritoneal/plasma barrier allows for high doses, peritoneal clearance is less than systemic clearance, and systemic toxicities may be reduced because of poor systemic absorption, he noted.
"The benefit of CRS plus HIPEC is supported by preclinical and retrospective clinical data gathered over decades," said Lowy. He asked the question: Is CRS with or without HIPEC beneficial in patients with colorectal peritoneal metastasis or is it just another bad option?
To support his case, Lowy presented data from PRODIGE 7, the first trial to specifically examine HIPEC for colorectal cancer patients with peritoneal metastases (Lancet Oncol 2021; https://doi.org/10.1016/S1470-2045(20)30599-4). This multicenter, open-label, Phase III trial at 17 French centers randomly assigned 133 patients to cytoreductive surgery plus oxaliplatin-based HIPEC and 132 patients to cytoreductive surgery alone.
"Most patients had low peritoneal cancer index (PCI), including PCIs of 1. There was some imbalance in PCI favoring the CRS arm. Also, 15 percent of patients crossed over to receive HIPEC after recurrence," Lowy noted.
His takeaway from PRODIGE 7 was "complete cytoreduction resulted in better-than-predicted overall survival than expected from chemotherapy alone (41 vs. 16 months from historic control). HIPEC with 30 minutes of oxaliplatin provides no survival benefit over CRS alone."
Several questions remain unanswered by PRODIGE 7. "The most commonly used HIPEC regimen was not utilized; therefore, has PRODIGE 7 really proven HIPEC to be ineffective or only the specific regimen studied? The intermediate PCI group (11-15) suggested a benefit from HIPEC and deserves specific study. Is this a real signal? What is the best primary endpoint and what magnitude of benefit is reasonable to posit for HIPEC?" he asked.
Lowy concluded: "The concept of HIPEC as logical strategy to target peritoneal metastases is supported by preclinical data and retrospective series demonstrate prolonged survival and cure for selected patients. Only PRODIGE 7 has examined the specific benefit of HIPEC and it utilized a brief period of treatment with oxaliplatin, which has poor single-agent activity [and] poor peritoneal pharmacokinetic characteristics, and all patients had previously seen oxaliplatin."
He added: "Despite no impact on overall survival for the entire cohort (with some methodologic confounders), there were signals of activity deserving of further investigation. Both groups achieved prolonged survival over most historical controls, suggesting that CRS is an appropriate therapy for fit patients with peritoneal metastases from colon cancer. The value of HIPEC in addition to CRS for colon cancer remains uncertain at this time."
No to HIPEC
"I do think that Dr. Lowy and I are more on the same page as not, but I question the value of HIPEC in this patient situation (peritoneal carcinomatosis)," said Kristen K. Ciombor, MD, MSCI, Associate Professor of Medicine at Vanderbilt-Ingram Cancer Center.
She noted that HIPEC offers a choice of chemotherapy agent, including mitomycin and oxaliplatin. In general, chemotherapy is circulated for 30-120 minutes. Hyperthermia can directly kill tumor cells and enhance efficacy of chemotherapy by increasing penetration depth, she said.
In PRODIGE 7, Ciombor noted that, after a median follow-up of 64 months, the median survival was 41.7 months with HIPEC and 41.2 months without HIPEC. Grade 3 or higher morbidity at 60 days was higher with HIPEC (24.1%) than with no HIPEC (13.6%), and hospital stays were longer with HIPEC (18 days) than with no HIPEC (13 days).
"The overall survival was higher than expected in this selected population," Ciombor noted. "Did the long overall survival mask survival benefit from HIPEC? Power analysis is dependent on the expected 18-month difference in survival with HIPEC, which likely overestimated the presumed benefit."
A post-hoc analysis showed survival benefit with HIPEC in patients with intermediate PCI of 11-15, and 12 percent in the CRS arm crossed over, as compared to 7 percent in the HIPEC arm. "The choice of IP agent, dosing of IV chemotherapy, and duration of perfusate also are controversial. Some 40 percent of all patients had previously received oxaliplatin, which might have led to resistance," she said.
"No randomized data support HIPEC. It's hard to extrapolate from retrospective studies with outdated historical controls. PRODIGE 7 showed no survival benefit of HIPEC over CRS plus chemotherapy," Ciombor concluded.
Moderator David Ilson, MD, PhD, Medical Oncologist at Memorial Sloan Kettering Cancer Center, commented: "Doctors have to make an individual decision for each patient. Both debaters agree more than they disagree."
Mark L. Fuerst is a contributing writer.