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

Background: Optimising therapeutic strategies of intermediate-risk non-muscle-invasive bladder cancer (IR-NMIBC) is needed.Objective: To compare recurrence-free survival (RFS) with adjuvant intravesical mito-mycin C (MMC) at normothermia or hyperthermia using the COMBAT bladder recircula-tion system at 43 degrees C for 30 and 60 min.Design, setting, and participants: A prospective open-label, phase 3 randomised con-trolled 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 fol-lowed by three monthly 40-mg MMC instillations at normothermia (control; n = 106), 43 degrees C for 30 min (n = 107), or 43 degrees C for 60 min (n = 106) were investigated. Therapeutic compliance was defined as four or more instillations.Outcome measurements and statistical analysis: The primary outcome was RFS at 24 mo in the intention-to-treat (ITT) and per-protocol (PP) populations. The secondary out-comes included progression-free survival at 24 mo, safety outcome measures, and changes in health-related quality of life. Log-rank, Fisher, v2, and analysis of variance tests were used.Results and limitations: The ITT 24-mo RFS was 77% for control, 82% for 43 degrees C-30 min, and 80% for 43 degrees C-60 min (p = 0.6). The PP 24-mo RFS was 77% for control, 83% for 43 degrees C-30 min, and 80% for 43 degrees C-60 min (p = 0.59). Six patients progressed to muscle -invasive disease in the ITT population (four in the control, 43 degrees C-30 min, and 43 degrees 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 degrees C-30 min, and 48% in 43 degrees 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.Conclusions: Four-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 nor-mothermic MMC at 24 mo.Patient summary: We 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.(c) 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.