Background
Adjuvant intravesical chemotherapy following tumour resection is recommended for intermediate-risk non–muscle-invasive bladder cancer (NMIBC).
Objective
To assess the efficacy and safety of adjuvant intravesical chemohyperthermia (CHT) for intermediate-risk NMIBC.
Design, setting, and participants
HIVEC-II is an open-label, phase 2 randomised controlled trial of CHT versus chemotherapy alone in patients with intermediate-risk NMIBC recruited at 15 centres between May 2014 and December 2017 (ISRCTN 23639415). Randomisation was stratified by treating hospital.
Interventions
Patients were randomly assigned (1:1) to adjuvant CHT with mitomycin C at 43°C or to room-temperature mitomycin C (control). Both treatment arms received six weekly instillations of 40 mg of mitomycin C lasting for 60 min.
Outcome measurements and statistical analysis
The primary endpoint was 24-mo disease-free survival as determined via cystoscopy and urinary cytology. Analysis was by intention to treat.
Results
A total of 259 patients (131 CHT vs 128 control) were randomised. At 24 mo, 42 patients (32%) in the CHT group and 49 (38%) in the control group had experienced recurrence. Disease-free survival at 24 mo was 61% (95% confidence interval [CI] 51–69%) in the CHT arm and 60% (95% CI 50–68%) in the control arm (hazard ratio [HR] 0.92, 95% CI 0.62–1.37; log-rank p = 0.8). Progression-free survival was higher in the control arm (HR 3.44, 95% CI 1.09–10.82; log-rank p = 0.02) on intention-to-treat analysis but was not significantly higher on per-protocol analysis (HR 2.87, 95% CI 0.83–9.98; log-rank p = 0.06). Overall survival was similar (HR 2.55, 95% CI 0.77–8.40; log-rank p = 0.09). Patients undergoing CHT were less likely to complete their treatment (n =75, 59% vs n = 111, 89%). Adverse events were reported by 164 patients (87 CHT vs 77 control). Major (grade III) adverse events were rare (13 CHT vs 7 control).
Conclusions
CHT cannot be recommended over chemotherapy alone for intermediate-risk NMIBC. Adverse events following CHT were of low grade and short-lived, although patients were less likely to complete their treatment.
Adjuvant intravesical chemotherapy following tumour resection is recommended for intermediate-risk (IR) non-muscle-invasive bladder cancer (NMIBC). The benefit of hyperthermia to increase the efficacy of chemotherapy has been already described in in vitro and in vivo studies.
Previously, only chemohyperthermia (CHT) delivered through a system that uses radiofrequency-induced hyperthermia has shown efficacy in intermediate-risk (IR) and high-risk (HR) papillary NMIBC. Due to the toxicity and the cost of such treatments alternative systems, delivering CHT via convection hyperthermia has been developed and used throughout Europe. However, its use is based on retrospective data only; more robust data with strong evidence is anticipated.
HIVEC-II is an open-label, phase 2 randomised controlled trial of CHT versus chemotherapy alone in patients with IR-NMIBC recruited at 15 centres between 2014 and 2017. The primary objective of the study was to assess the efficacy and safety of adjuvant intravesical CHT for IR-NMIBC.
Patients were randomly assigned (1:1) to adjuvant CHT with mitomycin C at 43°C using a Combat bladder recirculating system (Combat Medical, St. Albans, UK) or to room-temperature mitomycin C (control). Patients in both arms were planned to received six weekly instillations of 40 mg of mitomycin C.
The primary endpoint was a 24-mo disease-free survival (DFS) defined as days between the date of randomisation and the earliest date of identification of recurrent disease (histology or positive cytology), including disease progression or death from any cause.
HIVEC-II was powered as a superiority trial to detect an absolute difference in 24-mo DFS of 12.2% favoring CHT. A total of 259 patients (131 CHT vs 128 control) were randomised. The median follow-up in the absence of disease recurrence or death (n = 158) was 24 mo. At 24 mo, 42 patients (32%) in the CHT group and 49 (38%) in the control group experienced recurrence.
Regarding the primary endpoint, DFS at 24 mo was 61% in the CHT arm and 60% in the control arm (hazard ratio [HR] 0.92, 95% CI 0.62-1.37; log-rank p = 0.8). Progression-free survival was higher in the control arm (HR 3.44, 95% CI 1.09-10.82; log-rank p = 0.02) on intent-to-treat but not on per-protocol analysis (p = 0.06). Overall survival was similar (p = 0.09).
Regarding the safety and the tolerance of the treatment, the tolerability was lower in CHT. Indeed, patients undergoing CHT were less likely to complete their treatment (59% vs 89%) especially due to equipment-related issues. Adverse events (AEs) were reported by 164 patients (87 CHT vs 77 control). Major (grade III) AEs were rare (13 CHT vs 7 control).
The HIVEC-II trial is the first published randomised controlled trial (RCT) to use conductive hyperthermia for bladder cancer. We commend the authors for providing the first substantial study that investigated the role of heated chemotherapy instillations in the bladder for treatment of IR-NMIBC. Moreover, despite low-grade and short-lived AEs after CHT, patients were less likely to complete their treatment. These results ultimately allow us to not recommend CHT over chemotherapy alone for IR-NMIBC.
More data are expected in the future to assess the use of CHT in the setting of HR-NMIBC such as the one presented in the HIVEC-HR RCT published earlier this year by Guerrero Ramos et al.
Furthermore, the use of new drugs including checkpoint inhibitors, as well as, new devices such as releasing intravesical system may be more effective for the patients although studies are still enrolling patients in these settings.