Trimodal therapy (TMT), combining optimal transurethral resection of bladder tumour (TURBT) and concurrent chemoradiotherapy, has garnered significant attention for managing muscle-invasive bladder cancer (MIBC). This approach offers the potential for bladder preservation while delivering oncological outcomes comparable to radical cystectomy. Achieving such results hinges on robust local control, which may necessitate salvage cystectomy in cases of invasive local recurrence. Contemporary studies report salvage cystectomy rates of 10–40% in heterogeneous TMT series, with local relapses often occurring at the original disease site, referred to as the index lesion. Evidence supporting a radiotherapy (RT) dose-response effect provides a rationale for focal dose escalation to the index tumour during RT delivery. However, implementing dose escalation is challenged by bladder motion, which causes variations in the organ’s position, volume, and shape both between and within treatment fractions. Image-guided adaptive RT addresses these variations through real-time dose modifications, with the ‘plan of the day’ (PoD) approach emerging as a particularly effective adaptive strategy. The RAIDER trial, a phase 2 non-comparative randomised controlled study led by Huddart et al., assessed the feasibility and safety of dose escalation to the index tumour using image-guided adaptive RT via the PoD approach for patients with T2–4a N0 M0 MIBC. Participants were randomised into three groups: standard whole-bladder RT, standard-dose adaptive RT, and dose-escalated adaptive RT (DART), with two radiation schedules of 20 or 32 fractions. Stage I of the trial evaluated the proportion of DART patients whose RT plans adhered to protocol-specific radiation dose constraints, while stage II focused on the rate of grade 3 late toxicity, as defined by the Common Terminology Criteria for Adverse Events (CTCAE), occurring 6–18 months post-RT. Among 345 patients enrolled, 81% had cT2 tumours, 70% received concurrent radio-sensitising therapy, and 49% underwent neoadjuvant chemotherapy. Stage I results demonstrated that DART could be delivered successfully in over 80% of patients regardless of the radiation schedule, aligning with outcomes from other prospective DART studies. In terms of safety, stage II data revealed radiation-related grade 3 CTCAE toxicity rates of less than 1% for both fraction schedules, with a 90% confidence interval (CI) upper bound excluding rates above 20%. The two-year cumulative incidence of Radiation Therapy Oncology Group (RTOG) grade 3 toxicity was 2.4% (95% CI 0.8–7.4%) for 20 fractions and 1.0% (95% CI 0.1–6.7%) for 32 fractions, favourably comparing with the BC2001 trial’s 5% rate and the RTOG pooled analysis’s 7% rate at a median follow-up of 5.4 years. Notably, the RAIDER study’s follow-up period for late toxicity (6–18 months) was shorter than in prior studies, highlighting the need for extended monitoring. Regarding efficacy, DART achieved a promising two-year locoregional control rate of 84%, surpassing the BC2001 trial’s 67% rate. These findings suggest that advances in radiation delivery, such as those employed in DART, can enhance clinical outcomes within TMT regimens. Despite these advancements, implementing tumour-focused DART presents significant challenges. The approach requires intensity-modulated RT (IMRT) combined with image guidance, technologies not widely available in low- and middle-income countries. The PoD adaptive strategy demands daily plan selection and specialised training for physicians and radiotherapists. Future adoption of online replanning, potentially via magnetic resonance imaging (MRI)-guided RT, could streamline this process. Additionally, accurately identifying the index tumour remains complex and necessitates integration of imaging and pathological data. Emerging techniques, such as the use of gold fiducial markers or suburothelial lipiodol injection, may improve precision in dose delivery. Tumour-focused dose escalation should be limited to unifocal lesions outside the bladder dome with favourable index-tumour-to-bladder ratios to ensure optimal post-treatment bladder function and quality of life. The next generation of TMT will likely incorporate innovations in RT delivery, exemplified by the RAIDER trial, alongside novel systemic therapies. Future clinical trials should integrate advanced radiation techniques while exploring new neoadjuvant, concurrent, and maintenance strategies to optimise outcomes. Selection of suitable candidates for tumour-focused DART may be enhanced through second TURBT procedures after neoadjuvant therapy and genomic profiling for alterations in DNA repair-associated genes, such as ATM, RB1, and FANCC, which predict tumour response to chemotherapy. Together, these developments promise to refine bladder-sparing approaches for MIBC, making them a viable alternative to radical cystectomy in appropriately selected patients.
The future of bladder-sparing therapy is bright
Reviewed by Asif H Ansari
From a storm to sunshine: the future of bladder-sparing therapy is bright.
