Bladder tumor-focused adaptive radiotherapy shows feasibility in phase 2 trial

Dose-escalated adaptive image-guided radiotherapy (DART) demonstrated safety and initial efficacy while maintaining an acceptable toxicity profile in patients with muscle invasive bladder cancer (MIBC), according to data from the phase 2 RAIDER trial (NCT02447549) published in European Urology.¹

The 2-year overall survival rate was 77% in the WBRT and SART arms and 80% in the DART arms.

In total, the study enrolled 345 patients with MIBC across 49 clinical trial sites in Europe and Australia.²

Participants were randomly assigned 1:1:2 to receive standard whole bladder radiotherapy (WBRT; n = 87), standard-dose adaptive radiotherapy (SART; n = 87), or DART (n = 171). Patients enrolled in the WBRT and SART arms received either a 55 Gy/20f (n = 41 in each) or 64 Gy/32f (n = 46 in each) fractionation schedule. Patients in the DART arm received a fractionation schedule of either 60 Gy/20f (n = 81) or 70 Gy/32f (n = 90).

The primary end point for stage I of the trial was the proportion of DART participants meeting the medium plan mandatory radiotherapy dose constraints. The primary end point for stage II was the proportion of patients with treatment-emergent radiotherapy-related grade 3 or higher CTCAE v4.0 toxicity 6 to 18 months after completing radiotherapy.

The median follow-up was 38.2 to 42.1 months across all treatment arms.

Data showed that among those planned for DART, 86% (66 of 77) of patients in the 20f schedule and 90% (74 of 82) of patients in the 32f schedule met the mandatory medium plan dose constraints. Of those that didn’t meet the medium plan dose constraints, 4 of 11 patients in the 20f schedule and 8 of 8 patients in the 32f schedule received SART. The remaining who did not meet the dose constraint for DART received DART per investigator decision.

Regarding safety, grade 3 or higher treatment-emergent radiotherapy-related toxicity was reported in 1 patient in each of the 20f fractionation schedule arms. In the 32f cohorts, no late CTCAE radiotherapy-related toxicities of grade 3 or higher were observed.

The authors added, “In both cohorts, >20% grade ≥3 radiotherapy-related late toxicity with DART was excluded.”

Further, in the DART cohorts, any late treatment-emergent toxicities of grade 3 or higher were reported among 8.6% of patients in the 20f cohort and 5.4% of patients in the 32f cohort. Any late treatment-emergent toxicities of grade 2 or higher were experienced by 31% of patients in the 20f cohort and 36% of patients in the 32f cohort.

The authors noted, “The 2-yr cumulative incidence of RTOG grade ≥3 toxicity was 2.4% (95% CI 0.8%, 7.4%) for 20f and 1.0% (0.1%, 6.7%) for 32f.”

Regarding efficacy, the 2-year locoregional disease control rate was 66% among those in the WBRT and SART arms and 74% among those in the DART arm, with no statistically significant difference between groups (adjusted HR, 0.81; 95% CI, 0.55-1.19; P = .2). Further, the 2-year invasive locoregional disease control rate was 80% among those in the WBRT and SART arms vs 83% among those in the DART arm (P = 0.4).

The 2-year bladder intact event-free survival rate was estimated to be 67% in the WBRT and SART arms and 72% in the DART arm, though no statistically significant difference was noted between groups (P = .3). In total, 13 patients (3.8%) underwent cystectomy, of which 11 were due to disease recurrence, 1 was due to radical bladder treatment instead of allocated radiotherapy, and 1 was due to an unknown reason. No cystectomies were due to adverse events.

The 2-year overall survival rate was 77% (95% CI, 70-82) in the WBRT and SART arms and 80% (95% CI, 73-85) in the DART arms, with no significant difference noted between groups (unadjusted HR, 0.84; 95% CI, 0.59-1.21; P = .4). In total, there were 64 and 56 deaths in each group, respectively.

Overall, these findings add to phase 1 (NCT01124682) data showing that DART was feasible with an acceptable toxicity profile at doses up to 70 Gy.³ In the phase 1 study, the 5-year overall survival rate was 58% (95% CI, 44%-71%), and the bladder preservation rate was 89% (95% CI, 88%-96%).

Phase 2 of the RAIDER trial remains ongoing, with final completion anticipated for March 2029.²

“In this phase 2 study, an image-guided adaptive strategy enabled radiotherapy dose escalation to over 86% of patients’ bladder tumors without significant increase in toxicity,” the authors concluded.¹ “Dose-escalated therapy achieves promising tumor control and survival rates similar to that achieved with cystectomy, with low rates of salvage cystectomy, and should be studied in future trials.”

References

1. Huddart R, Hafeez S, Griffin C, et al. Dose-escalated adaptive radiotherapy for bladder cancer: Results of the phase 2 RAIDER randomised controlled trial. Eur Urol. 2025;87(1):60-70. doi:10.1016/j.eururo.2024.09.006

2. Study of tumour focused radiotherapy for bladder cancer (RAIDER). ClinicalTrials.gov. Last updated June 9, 2020. Accessed January 9, 2025. https://clinicaltrials.gov/study/NCT02447549

3. Haffeez S, Warren-Oseni K, Jones K, et al. Bladder tumor-focused adaptive radiation therapy: Clinical outcomes of a phase I dose escalation study. Int J Radiat Oncol Biol Phys. 2025;121(1):165-175. doi:10.1016/j.ijrobp.2024.07.2317