Efficacy and Safety of Intraoperative Hyperthermic Intraperitoneal Chemotherapy for Locally Advanced Colon Cancer

Abstract

ImportancePeritoneal metastasis in patients with locally advanced colon cancer (T4 stage) is estimated to recur at a rate of approximately 25% at 3 years from surgical resection and is associated with poor prognosis. There is controversy regarding the clinical benefit of prophylactic hyperthermic intraperitoneal chemotherapy (HIPEC) in these patients.ObjectiveTo assess the efficacy and safety of intraoperative HIPEC in patients with locally advanced colon cancer.Design, Setting, and ParticipantsThis open-label, phase 3 randomized clinical trial was conducted in 17 Spanish centers from November 15, 2015, to March 9, 2021. Enrolled patients were aged 18 to 75 years with locally advanced primary colon cancer diagnosed preoperatively (cT4N02M0).InterventionsPatients were randomly assigned 1:1 to receive cytoreduction plus HIPEC with mitomycin C (30 mg/m2 over 60 minutes; investigational group) or cytoreduction alone (comparator group), both followed by systemic adjuvant chemotherapy. Randomization of the intention-to-treat population was done via a web-based system, with stratification by treatment center and sex.Main Outcomes and MeasuresThe primary outcome was 3-year locoregional control (LC) rate, defined as the proportion of patients without peritoneal disease recurrence analyzed by intention to treat. Secondary end points were disease-free survival, overall survival, morbidity, and rate of toxic effects.ResultsA total of 184 patients were recruited and randomized (investigational group, n = 89; comparator group, n = 95). The mean (SD) age was 61.5 (9.2) years, and 111 (60.3%) were male. Median duration of follow-up was 36 months (IQR, 27-36 months). Demographic and clinical characteristics were similar between groups. The 3-year LC rate was higher in the investigational group (97.6%) than in the comparator group (87.6%) (log-rank P = .03; hazard ratio [HR], 0.21; 95% CI, 0.05-0.95). No differences were observed in disease-free survival (investigational, 81.2%; comparator, 78.0%; log-rank P = .22; HR, 0.71; 95% CI, 0.41-1.22) or overall survival (investigational, 91.7%; comparator, 92.9%; log-rank P = .68; HR, 0.79; 95% CI, 0.26-2.37). The definitive subgroup with pT4 disease showed a pronounced benefit in 3-year LC rate after investigational treatment (investigational: 98.3%; comparator: 82.1%; log-rank P = .003; HR, 0.09; 95% CI, 0.01-0.70). No differences in morbidity or toxic effects between groups were observed.Conclusions and RelevanceIn this randomized clinical trial, the addition of HIPEC to complete surgical resection for locally advanced colon cancer improved the 3-year LC rate compared with surgery alone. This approach should be considered for patients with locally advanced colorectal cancer.Trial RegistrationClinicalTrials.gov Identifier: NCT02614534

Neoadjuvant treatment of colorectal cancer: comprehensive review

“…More positive results were seen in the Spanish multicentre clinical trial HIPECT4, where HIPEC was given as an intraoperative treatment at the time of initial surgical resection 113 . A total of 184 patients with locally advanced primary colon (cT4N0–2M0) were randomized to radical tumour resection plus HIPEC with mitomycin C (30 mg/m 2 ; 60 min) compared to cytoreduction alone.…”

Efficacy, Safety, and Analysis Issues in a Study of Intraoperative Hyperthermic Intraperitoneal Chemotherapy for Locally Advanced Colon Cancer—Reply

“…In Reply I thank all the letter writers for their interest in our work. The multicenter phase 3 HIPECT4 was a randomized clinical trial that showed benefit in locoregional control rate with hyperthermic intraperitoneal chemotherapy (HIPEC) using mitomycin C in locally advanced colon cancer. The design of this study was focused on the surrogate primary end point of locoregional control rate at 3 years.…”

Efficacy, Safety, and Analysis Issues in a Study of Intraoperative Hyperthermic Intraperitoneal Chemotherapy for Locally Advanced Colon Cancer

“…To the Editor We read with great interest the study by Arjona-Sánchez and colleagues regarding the use of intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) for locally advanced colon cancer. In their study, the authors assessed the safety of mitomycin C (MMC)–based chemotherapy and its effect on local recurrence and disease-free survival.…”