Bladder preservation strategies are emerging as a modern and effective choice for patients with muscle-invasive bladder cancer (MIBC), challenging the long-held standard of radical cystectomy. Recent data presented at the 2024 American Society for Radiation Oncology (ASTRO) annual meeting and in other publications highlight the growing acceptance and refinement of trimodality therapy (TMT) as a viable alternative.
Trimodality Therapy: An Established Alternative
For decades, radical cystectomy has been the gold standard for MIBC treatment. However, TMT, which combines maximal transurethral resection of the bladder tumor (mTURBT) followed by chemoradiation, has emerged as a promising bladder-sparing approach. The Radiation Therapy Oncology Group (RTOG)/NRG has been instrumental in integrating radiation therapy into bladder preservation strategies, initially for patients unfit for cystectomy.
Prospective trials demonstrate that TMT can achieve similar long-term clinical outcomes to cystectomy, with comparable safety and tolerability, especially with contemporary radiation therapy techniques and chemotherapy combinations. Chemotherapy regimens often include cisplatin-based combinations like 5-FU/cisplatin, MCV/cisplatin, or Taxol/cisplatin, sometimes followed by gemcitabine/cisplatin. In the RTOG 05-24 trial, patients with HER2/neu overexpression received trastuzumab and paclitaxel, achieving complete response rates between 66-88% and overall survival rates comparable to radical cystectomy.
Long-Term Outcomes and Comparative Studies
The BC2001 trial, a large phase 3 randomized controlled trial (n=458), demonstrated that chemoradiotherapy improved locoregional control (HR 0.61, p=0.004) and bladder cancer-specific survival (BCSS) compared to radiotherapy alone, with benefits lasting over two years. TMT also reduced the need for salvage cystectomy (14% vs. 22%, p=0.034). While disease-free survival (DFS), metastasis-free survival (MFS), and overall survival (OS) did not show statistically significant differences, the results support TMT's efficacy.
A multi-institutional propensity score-matched comparison of radical cystectomy versus TMT across three university centers in the USA and Canada (n=1,116) showed that 5-year metastasis-free survival was 74% for radical cystectomy and 75% for TMT. The 5-year disease-free survival was 73% for radical cystectomy and 74% for TMT. Notably, overall survival favored TMT (IPTW: 66% vs. 73%; hazard ratio 0.70 [95% CI 0.53-0.92]; p=0.010). Salvage cystectomy was performed in 13% of TMT-treated patients, with no difference in cancer-specific survival between those who underwent salvage cystectomy and those who did not (p=0.69).
National Guidelines and Expanding Applications
The latest NCCN guidelines now recommend bladder preservation with concurrent chemoradiotherapy and maximal TURBT as a primary treatment option for patients with stage II (cT2N0) and stage IIIA (cT3N0, cT4N0, cT1-cT4N1) MIBC. This shift recognizes that radical cystectomy is no longer the sole standard of care.
Researchers are also exploring TMT's potential in non-muscle invasive bladder cancer (NMIBC) and metastatic bladder cancer. The RTOG 0926 phase II trial in recurrent high-grade NMIBC showed that at 3 years, 88% of patients were free from undergoing cystectomy, with a 5-year overall survival rate of 53%. In metastatic bladder cancer, a retrospective analysis found that consolidative radiotherapy improved overall survival (HR 0.48, p = 0.026) in patients with limited residual metastases after first-line therapy.
Ongoing Research and Future Directions
Several key questions remain, including the optimal integration of immunotherapy with TMT, the role of neoadjuvant chemotherapy, and the necessity of maximal TURBT. The SWOG/NRG 1806 (INTACT) trial is investigating concurrent chemoradiotherapy with or without atezolizumab in localized MIBC, with bladder intact event-free survival (BIEFS) as the primary endpoint.
While the RTOG 89-03 study found no benefit from neoadjuvant methotrexate, cisplatin, and vinblastine (MCV) chemotherapy before TMT, modern techniques and chemotherapeutic agents may warrant a reevaluation. A Canadian study involving 785 patients suggested that neoadjuvant chemotherapy (NAC) was significantly associated with improved CSS and OS. However, a sensitivity analysis among TMT-only patients did not demonstrate a benefit in OS with NAC (HR 0.82, 95% CI 0.54–1.25, p=0.4).
Regarding the completeness of TURBT, a retrospective study of 757 patients found no significant differences in 5-year overall survival (OS), cancer-specific survival (CSS), or metastasis-free survival (MFS) between patients with complete versus incomplete TURBT.
Ongoing trials, including NRG studies in NMIBC and MIBC, and a SWOG trial investigating radiotherapy following neoadjuvant therapy, promise to further refine bladder cancer treatment strategies and improve patient outcomes.
