Association of higher thermal dose with improved 5-year recurrence-free survival after locoregional hyperthermia combined with intravesical chemotherapy for non-muscle-invasive bladder cancer.

190

Background: To investigate the continuous thermal dose (TD)-effect relationship for estimating the probability of 5-year recurrence-free survival (RFS) in patients with non-muscle-invasive bladder cancer (NMIBC) treated with locoregional chemohyperthermia (CHT). Methods: In this cohort follow-up study (2009−2020; CHIB2; Netherlands Trial Register NL2429), patients with recurrent intermediate- or high-risk NMIBC received 6 weekly sessions of locoregional CHT combined with mitomycin C (MMC), followed by 4 monthly maintenance instillations. Intravesical and perivesical temperatures (urethra, rectum, and, if applicable, vagina) were recorded. Hyperthermia TD was expressed as cumulative equivalent minutes at 43°C (CEM43). Among continuous TD parametrizations, log-transformed Average CEM43T50 was selected using Weibull univariate and stepwise regression analyses, adjusting for recurrence rate, multifocality, and WHO 2004/2016 grade classification. The association between TD and 5-year recurrence risk was additionally evaluated using Fine and Gray competing risks analysis. Results: Sixty patients were included; 83% (n=50) were high-risk and 17% (n=10) intermediate-risk. Thirty patients experienced recurrence after locoregional CHT, with a median time to recurrence of 2.1 years (IQR 0.8−6.5 years). Median Average CEM43T50 was 2.5 minutes, ranging from 0.09−15.2 minutes. Higher TD was significantly associated with increased RFS ( P =<.001). In the Weibull regression, a twofold increase in TD was associated with a 32% decrease in the hazard of recurrence in univariate analysis (95% CI 15%−45%; P =<.001) and a 31% decrease after adjustment (95% CI 12%−45%; P =.002). Fine and Gray analysis confirmed that increasing Average CEM43T50 TD was significantly associated with reduced recurrence risk (unadjusted P =.002; adjusted P =.003). Conclusions: Across the continuous TD range, higher hyperthermia TD (Average CEM43T50) was independently associated with improved 5-year RFS in patients with NMIBC treated with locoregional hyperthermia combined with MMC, showing the paramount importance of achieving high TD in locoregional chemohyperthermia. Clinical trial information: NL2429 .