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Adding hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin C to surgery for locally advanced colorectal cancer (CRC) significantly reduced the risk of locoregional recurrence, the randomized HIPECT4 trial showed.

At 3 years, patients who underwent cytoreduction plus HIPEC with mitomycin C had a 10% absolute improvement in locoregional control (LC) -- 97.6% versus 87.6% for those who underwent cytoreduction alone. The absolute benefit increased to 16% among patients with pathologic (p)T4 disease. Disease-free survival (DFS) and overall survival (OS) did not differ between the two treatment groups.

Surgery with or without HIPEC led to similar rates of morbidity and toxicity, reported Alvaro Arjona-Sánchez, MD, PhD, of University Hospital Reina Sofia in Córdoba, Spain, and co-authors in .

"To our knowledge, this trial is the first to investigate the specific role of HIPEC with mitomycin C in reducing the risk of peritoneal relapse after resection in patients with locally advanced colorectal cancer," the authors wrote of their findings. "These results suggest that this HIPEC regimen confers an additional benefit to cytoreductive surgery and thus has important implications for clinical practice."

The HIPEC-mitomycin C regimen addressed several criticisms of HIPEC with oxaliplatin, according to the authors of an . Specifically, the trial showed no increase in adverse events or toxicity, noted Sara K. Daniel, MD, and Byrne Lee, MD, of Stanford University School of Medicine in California. Additionally, intraoperative HIPEC with mitomycin C did not delay adjuvant chemotherapy because of complications, as a similar proportion of patients in both groups started adjuvant treatment within 12 weeks of surgery.

Whether the HIPEC regimen reduces the risk of distant metastasis remains to be seen and will be addressed in the randomized trial, Daniel and Lee added.

"Overall, HIPECT4 provided additional evidence reinvigorating further research into the use of HIPEC for both prophylaxis and treatment of PC [peritoneal carcinomatosis] in colorectal cancer," they concluded.

About 10% of patients with CRC develop peritoneal metastases, which significantly reduce overall survival. Multiple clinical trials evaluated the efficacy of cytoreductive surgery with adjuvant HIPEC, leading to mixed results, Arjona-Sánchez and co-authors noted.

Locally advanced (pT4) CRCs have a prognosis similar to that of patients with N2 and M1 disease, associated with a 5-year OS of about 20%. As many as 36% of patients with pT4 disease have metachronous peritoneal metastases, the authors said. Patients often receive adjuvant chemotherapy, which does not eliminate the risk of metastasis.

The only phase III trial of prophylactic HIPEC with oxaliplatin in pT4 CRC showed no effect on the risk of peritoneal metastasis. Investigators at 17 Spanish centers continued the evaluation of HIPEC in HIPECT4, comparing cytoreduction plus HIPEC with mitomycin C (30 mg/m² over 60 minutes) or cytoreduction alone. Both groups also received adjuvant chemotherapy.

Eligible patients had clinical T4N02M0 CRC. Lymph node involvement (N0-2) was allowed with complete resection. The study included 184 patients, all of whom had extensive cytoreductive and target surgery that included complete tumor resection, extensive lymph node resection, omentectomy, and appendicectomy. Postmenopausal women also had bilateral oophorectomy. Patients in both arms received the same chemotherapy, FOLFOX with oxaliplatin and capecitabine (XELOX).

The primary endpoint was LC. After a median follow-up of 36 months, LC had occurred in two patients in the HIPEC arm versus 10 in the surgery-only arm, representing a 79% reduction in the risk of LC (95% CI 0.05-0.95, P=0.03). The 3-year DFS rate was 81.2% with HIPEC and 78.0% with surgery alone. The 3-year OS rate was also similar -- 91.7% with HIPEC and 92.9% for surgery without HIPEC.

Pathology showed that 41.8% of patients had pT4a disease, and 26.1% had pT4b disease. An exploratory analysis looked at the pT4 subgroup and showed a 3-year LC rate of 98.3% with HIPEC and 82.1% with surgery only, representing a 91% reduction in the hazard (95% CI 0.01-0.70, P=0.003).

"Despite the potential benefit of prophylactically treating patients at high risk of developing peritoneal metastases, there is currently only one prevented strategy used in this context: the administration of adjuvant systemic chemotherapy," Arjona-Sánchez and team wrote. "This strategy is controversial because no studies, to our knowledge, have demonstrated that its use for high-risk, stage II (pT4) colon cancer reduces the rate of peritoneal relapse or improves disease-free survival. ... These findings support the need for different strategies to prevent peritoneal relapse in patients at high risk."