Although radical cystectomy (RC) remains the most common treatment approach for patients with nonmetastatic muscle-invasive bladder cancer (MIBC), the competing risks of bladder cancer patients present challenges to this management strategy. With an average age of 73 years and high likelihood of comorbidities at diagnosis, RC (and the significant perioperative morbidity and mortality that come with it) may not be the appropriate treatment option for some MIBC patients after shared decision making.¹ Consequently, bladder sparing approaches that offer the promise of limiting morbidity and maximizing quality of life continue to garner interest from patients both fit and unfit for surgery.

Among the most consistently utilized bladder sparing approaches is trimodal therapy (TMT), which includes maximal transurethral resection of visible bladder tumor followed by radiotherapy in conjunction with radiosensitizing chemotherapy regimens.² Generally accepted criteria for surgically fit patients suitable for this approach include those with small (<4–7 cm) unifocal tumors, well-functioning bladders and an absence of obvious extravesical extension, carcinoma in situ or hydronephrosis. Although stringent, it is estimated that approximately 1 out of every 5 MIBC patients meets these criteria.³

To date, randomized comparisons of TMT to RC are unavailable and are unlikely to be undertaken in the wake of SPARE, a phase III randomized controlled trial which launched in 2007 and prematurely closed due to poor accrual.⁴ Comparative outcomes are therefore limited to observational studies with conflicting results. In a recent systematic review of 12 retrospective single-center and population-based studies, overall survival outcomes varied significantly. Meta-analysis of the included single center studies showed a nonstatistically significant advantage for TMT while the pooled estimate after adding the population-based studies favored RC.⁵ These findings were recently challenged by abstract data from a multicenter retrospective 3:1 matched comparison analysis of TMT (282) and RC (834) showing no difference in 5-year metastasis-free survival between treatments (78% vs 73%, p = 0.07) and a statistically significant cancer-specific and overall survival advantage in those treated with TMT (85% vs 78%, p = 0.02, 78% vs 70%, p <0.001, respectively).⁶ Furthermore, only 13% of patients undergoing TMT required salvage cystectomy for treatment failure or toxicity. As always, cautious interpretation of these findings is warranted. The discrepancy between an insignificant difference in 5-year metastasis and a significant difference in cancer mortality between treatment groups raises concern for errors in classifying cause of death. Intuitively, it would be unlikely for a patient to have a cancer-related death that was not in the setting of metastasis. Similarly, the risk of death once metastases are present is likely to be similar regardless of the modality of localized treatment. While the similar observed efficacy is promising, further methodological detail is needed prior to applying these findings.

In addition to the heterogeneity of clinical stage and patient comorbidity and performance status that exist in these studies, there are several additional limitations important to consider when attempting to translate these data into clinical practice. First, a standard definition of TMT is lacking. Radiotherapy target volumes and fractionation vary in the literature. Similarly, while cisplatin-based regimens, gemcitabine monotherapy, or combination fluorouracil and mitomycin C are most common, there is lack of consensus on which radiosensitizing chemotherapy regimen to employ or how to employ it (ie split course vs continuous course). Inclusion of neoadjuvant or adjuvant therapies to these treatments leads to even greater heterogeneity. Second, each of the 3 components of TMT requires skilled specialists to maximize outcomes. The quality of transurethral resection of bladder tumor, radiation planning, surveillance and chemotherapy management likely vary depending on the provider and introduce further unmeasured confounding. Finally, the criteria for continuing with TMT and management of progression vary between centers. For example, in an analysis of long-term outcomes in patients treated with TMT at Massachusetts General Hospital, a restaging post-induction transurethral resection of bladder tumor was performed.⁷ Patients without a complete response were recommended to receive immediate RC (which was performed in 17% of all patients) instead of finishing the remaining consolidation treatment doses. Understanding the impact of such protocol variations on outcomes is critical.

Lack of data describing long-term functional outcomes and treatment toxicity present additional challenges to shared decision making. Current literature would suggest that late severe toxicities such as end stage bladder and surgically managed bowel complications are rare (1%–3%) and post-treatment quality of life is at least comparable to RC.^8,9 However, the paucity of these data beyond 15 years, including the understudied possibility of secondary malignancy, makes evaluations of the appropriateness of TMT in younger populations with longer life expectancies challenging.

Finally, the impact of these treatment approaches on the health care system as well as patients’ finances must be considered. In an analysis of 2,963 patients included in the Surveillance, Epidemiology, and End Results-Medicare linked database, median total costs were significantly higher for TMT compared to RC resulting in nationwide excess spending of $468 million.¹⁰ The extent to which patients are responsible for this added cost is unknown, but there is a clear need for further evaluation of potential financial toxicity that may influence treatment choice and regret in this population.

Utilization of TMT among other bladder sparing approaches is anticipated to grow as advancements occur. There are currently over half a dozen clinical trials evaluating the potential value of adding immune checkpoint inhibitors to TMT regimens. Biomarker directed therapy, application of novel intravesical drug delivery systems (such as TAR-200), advancements in disease imaging and higher precision radiotherapy technology are just a few of the potential innovations that hold promise for continued improvement of oncologic outcomes and toxicity profiles associated with TMT.

The demographics, comorbidities, and preferences of these MIBC patients along with promising oncologic outcomes are the driving force behind TMT’s expanded use. However, the emergence of improved long-term evaluations of toxicity and quality of life in the context of oncologic outcomes and economic considerations are needed to understand which patients are most appropriate for bladder sparing approaches. We live in an exciting time for bladder cancer care and look forward to therapies which hold the promise of challenging RC and ultimately improving “bladder intact event-free survival.”