Hyperthermic Mitomycin C in Intermediate-risk Non–muscle-invasive Bladder Cancer: Results of the HIVEC-1 Trial

Abstract

BackgroundOptimising therapeutic strategies of intermediate-risk non–muscle-invasive bladder cancer (IR-NMIBC) is needed. ObjectiveTo compare recurrence-free survival (RFS) with adjuvant intravesical mitomycin C (MMC) at normothermia or hyperthermia using the COMBAT bladder recirculation system at 43 °C for 30 and 60 min. Design, setting, and participantsA prospective open-label, phase 3 randomised controlled trial (HIVEC-1) accrued across 13 centres between 2014 and 2020 in Spain. After complete transurethral resection of the bladder and immediate postoperative MMC instillation, patients with IR-NMIBC were randomised (1:1:1) to four weekly followed by three monthly 40-mg MMC instillations at normothermia (control; n = 106), 43 °C for 30 min (n = 107), or 43 °C for 60 min (n = 106) were investigated. Therapeutic compliance was defined as four or more instillations. Outcome measurements and statistical analysisThe primary outcome was RFS at 24 mo in the intention-to-treat (ITT) and per-protocol (PP) populations. The secondary outcomes included progression-free survival at 24 mo, safety outcome measures, and changes in health-related quality of life. Log-rank, Fisher, χ2, and analysis of variance tests were used. Results and limitationsThe ITT 24-mo RFS was 77% for control, 82% for 43 °C-30 min, and 80% for 43 °C–60 min (p = 0.6). The PP 24-mo RFS was 77% for control, 83% for 43 °C–30 min, and 80% for 43 °C-60 min (p = 0.59). Six patients progressed to muscle-invasive disease in the ITT population (four in the control, 43 °C–30 min, and 43 °C–60 min groups each) and four in the PP population (all controls). Serious adverse events occurred in 26 patients (8.1%), and we were unable to demonstrate a difference between groups (p = 0.5). Adverse events, mainly dysuria and spasms, occurred in 124 patients (33% in control, 35% in 43 °C–30 min, and 48% in 43 °C–60 min; p = 0.05). The total International Prostate Symptom Score worsened by 1.2 ± 7.3 points, similarly across groups (p = 0.29). The Functional Assessment of Cancer Therapy—Bladder domains and indexes showed no significant change. ConclusionsFour-month adjuvant hyperthermic MMC using the COMBAT system for 30 and 60 min in IR-NMIBC is well tolerated, but we did not find it to be superior to normothermic MMC at 24 mo. Patient summaryWe were unable to demonstrate the effectiveness of hyperthermia using the COMBAT system in intermediate-risk non–muscle-invasive bladder cancer. Further evaluation of long-term recurrence and progression, and maintenance regimens appears mandatory.