At the South Central Section meeting of the AUA in Austin, Texas, in September 2023, the AUA Course of Choice was Trimodality Therapy for Management of Muscle-Invasive Bladder Cancer. Adam S. Feldman, MD, MPH, along with Jason Efstathiou, MD, DPhil of radiation oncology, Richard J. Lee, MD, PhD of medical oncology, and Matthew Wszolek, MD of urology, had previously given the full-length version of this instructional course at the national AUA Annual Meetings from 2018 to 2023. This truly multidisciplinary course highlights the rationale for bladder-sparing trimodality therapy (TMT) for muscle-invasive bladder cancer (MIBC), appropriate patient selection, the importance of coordinated multidisciplinary care, the critical role of aggressive initial and repeat transurethral resection of bladder tumor (TURBT), TMT paradigm and outcomes, cystoscopic surveillance, and how to address local recurrences after TMT. This course also briefly touches on quality of life (QOL), predictive biomarkers, involvement of immunotherapy, and future advances.

This course at the South Central Section meeting begins with the question, why should we even consider TMT for MIBC? As urologists, we know from our experience and from evidence in the literature of the relatively high morbidity and short- and long-term complication risks of radical cystectomy (RC).¹ We also have evidence from the National Cancer Database that many patients with MIBC in the United States, especially in the 7th, 8th, and 9th decades of life, are undertreated and not receiving standard of care curative treatment.² TMT is clearly listed as a treatment option in AUA and National Comprehensive Cancer Network guidelines, as well as listed in our publicly available patient education information.^3,4

We highlight the critical role of the urologist throughout the course of TMT, including proper patient selection, maximal TURBT and re-resection, post-chemoradiation (chemoRT) cystoscopy and biopsy, and ongoing long-term cystoscopic surveillance. Regarding proper patient selection, one must consider both patient factors and tumor factors. Patient factors include the ability to tolerate concurrent radiosensitizing chemotherapy, as well as their candidacy for pelvic radiation therapy, as assessed by any history of prior pelvic radiation, inflammatory bowel disease, or poor baseline bladder or bowel function. Tumor factors which may preclude TMT as an option include the inability to achieve a complete resection, a large tumor burden involving the majority of the bladder, the presence of hydronephrosis, extensive carcinoma in situ, high-grade tumor in a bladder diverticulum, upper tract involvement, or prostatic urethra involvement. Certainly not all cases of MIBC are candidates for TMT, and our experience has demonstrated that approximately one-third of all MIBC cases will be candidates.

Multiple series have demonstrated the importance of a maximal complete TURBT as a key predictor of disease-specific survival (DSS) after TMT for MIBC.^5-7 Prior to starting chemoRT, the treating urologist must be confident that all grossly visible disease has been resected, and especially in a referral setting when the initial TURBT has been performed elsewhere, a repeat TURBT is often advised.

The TMT paradigm historically had proceeded with a split course of chemoRT, with an induction course to 40 Gy, a cystoscopic rebiopsy to assess for response, followed by consolidation chemoRT with an additional 25 Gy. More commonly now, our contemporary paradigm is a single course of chemoRT of 55 to 65 Gy, followed by a cystoscopic rebiopsy at 2 to 3 months post-chemoRT. We strongly advocate for a TURBT-style rebiopsy, rather than cold cup, such that the underlying muscularis propria is assessed microscopically.

The Massachusetts General Hospital experience with TMT has demonstrated DSS for clinical T2 disease of 74% at 5 years and 66% at 10 years.⁵ We have also observed an improved 5-year DSS of 84% in the contemporary experience from 2005 through 2013, compared with the previous 2 decades, likely explained by improved patient selection.⁵ In this contemporary cohort, we also have observed a rate of cystectomy at any point post-TMT of less than 15%.

The direct comparison of survival between TMT and RC is an ongoing challenge. The SPARE Trial in the United Kingdom, which randomized patients with MIBC to RC or chemoRT, failed to accrue.⁸ A SEER (Surveillance, Epidemiology, and End Results)-Medicare population-based study by Williams et al suggested lower overall survival and DSS with TMT compared to RC; however, due to data limitations this analysis was unable exclude patients unfit for surgery or exclude those who had lower overall RT doses, and had unavoidable selection bias.⁹ Importantly, however, this study did demonstrate a greater overall cost with TMT, and raises health care expenditures as an important consideration for TMT moving forward. The South Central Section meeting was fortunate to have in the audience the lead author, Stephen B. Williams, MD, MBA, who could comment on TMT from a cost perspective. Other population-based studies have shown similar overall survival and DSS between TMT and RC, as has a retrospective propensity score–matched analysis at Princess Margaret Hospital in Toronto.^10-12 A recent multi-institutional retrospective propensity score–matched analysis from Massachusetts General Hospital, the University of Toronto, and the University of Southern California demonstrated similar metastasis-free survival and DSS, with still no difference specifically in the subgroup of RC patients who received neoadjuvant chemotherapy.¹³

Cystoscopic surveillance post-TMT is performed every 3 months within the first 2 years, every 6 months in years 3 to 5, and then annually indefinitely, as late recurrences can occur in these patients who retain their bladders. Local recurrences can occur as nonmuscle-invasive bladder cancer (NMIBC) in 25% to 36% of patients and as MIBC in 14% of patients.^7,14 Although many NMIBC recurrences can be treated similar to de novo NMIBC with intravesical therapies, high-risk recurrences that are T1, have carcinoma in situ, lymphovascular invasion, or variant histology should be strongly considered for immediate salvage RC. Salvage RC for MIBC recurrences after complete response to TMT are for curative intent with 5- and 10-year DSS rates of 64% and 55%, respectively.⁵ We have also demonstrated that salvage RC can be safely performed with only marginally higher late complication rates.¹⁵

QOL after TMT is high with minimal high-grade toxicity and low rates of clinically significant radiation cystitis.^16,17 Comparative QOL outcomes demonstrate better sexual QOL, less concern about appearance, and less life interference from cancer with TMT than with RC.¹⁸ Although there are multiple biomarkers under investigation for selection of patients for TMT vs RC, there are unfortunately none currently that are ready for clinical use.

Prior to concluding, the final slides of this AUA Course of Choice at the South Central Section meeting briefly touched on current ongoing clinical trials including a combination of current standard of care chemoRT regimens with immunotherapy vs chemoRT alone, including SWOG/NRG 1806, Keynote-992, and ECOG-ACRIN/NRG EA8185. It is hoped that the combination of immunotherapy with standard chemoRT, potentially with biomarker-directed care, may ultimately improve outcomes and expand the inclusion criteria for bladder preservation.