Many urologists express a laudable desire to improve patient care. In its traditional sense, the term “research” conjures images of pipettes and test tubes. At its core, however, the goal of any research is to improve patient care and outcomes. In 2017, Waingankar et al provided a framework describing 4 risks that influence surgical outcomes; these included disease risk, patient risk, clinician risk, and system risk.¹ While originally intended to characterize factors associated with surgical quality, this model can be adapted to conceptualize areas where researchers can focus. Treatment decisions and outcomes are affected by disease processes, patient factors, provider skills and knowledge, available tools/treatments, and the health care system. Therefore, researchers can advance knowledge and effect change by focusing on disease biology (basic or translational), patient factors (aging/frailty, competing risk models, quality-of-life preferences), clinician knowledge/ability (education, implementation science), treatment tools (engineering, innovation), and/or health care delivery systems (health services research, policy/advocacy; Figure 1).

Treatment decisions that prioritize the unique characteristics of an individual patient and that patient’s disease over what works best for the average patient in a population result in ideal outcomes. I (BTR) am fortunate that our research at UConn Health is supported both by local and USMART mentorship. It centers on the intersection of bladder cancer treatment with the increasingly aging population in collaboration with the UConn Center on Aging and bladder cancer biology through team science with the Jackson Laboratory for Genomic Medicine.

Bladder cancer is diagnosed at a median age of 73 years, an age projected to increase in coming years. The risk of invasive cancer increases with aging and is reflected in lower 5-year survival rates among patients >75 years. Guidelines for clinically localized, muscle-invasive bladder cancer (MIBC) recommend either neoadjuvant chemotherapy with radical cystectomy and urinary diversion or combination chemoradiation therapy.² Radical cystectomy with urinary diversion is major surgery with up to 64% of patients experiencing a complication within 90 days.³ Importantly, the average risk of complications is similar in octogenarians selected for surgery compared to younger individuals. Nonetheless, many older patients with invasive bladder cancer appear to be undertreated relative to younger cohorts,⁴ and could have benefitted from more aggressive treatment to prevent cancer-related declines in quality of life. In contrast, other individuals of the same chronological age are clearly overtreated, and a more conservative approach incorporating palliative/supportive care may have been preferred as they suffer unacceptable side effects following radical cystectomy.⁵ The current status quo underscores a need to optimize quality of life and health span by more accurately matching treatment intensity with heterogeneity in individual physiology or frailty irrespective of chronological age. Several clinical measures of frailty have been developed, yet none have gained widespread clinical use in older adults with bladder cancer. An approach that emphasizes assessment of frailty and physical performance and that incorporates use of selected biomarkers may be more appropriate for pretreatment assessment of patients with MIBC and may lead to more optimal outcomes. In collaboration with the UConn Center on Aging, we have proposed prospective evaluation of physical frailty and select liquid/tissue biomarkers in older patients with MIBC referred for cystectomy.

Bladder cancer is a heterogenous disease, and there is marked variation in clinical outcome when patients are categorized by traditional stage and grade. Despite creation of recurrence and progression risk scores based on clinical parameters, recurrence for patients with Ta and T1 nonmuscle-invasive bladder cancer ranges from 15%-61% and progression ranges from 1%-17% at 5 years.⁶ Among patients with carcinoma in situ, disease progression is estimated at 54%; however, there are no known clinical parameters that reliably distinguish progressors from nonprogressors.⁷ Similarly, outcomes for patients with MIBC are heterogenous. For example, randomized trials have demonstrated that the complete response rate to neoadjuvant chemotherapy is 38%; however, a surgeon’s ability to predict complete response and avoid radical surgery has been elusive to date.⁸ Furthermore, in those without a complete response to chemotherapy for whom additional treatment is advisable, the decision to proceed with surgery as opposed to chemoradiation bladder-sparing protocols lacks a robust biological basis. While molecular classifications are promising⁹ and have been correlated with clinical outcomes,¹⁰ few of these therapeutic targets have been adopted into routine clinical practice. To date, we have generated preliminary data from single-cell RNA sequencing of transurethral resection of bladder tumor specimens demonstrating that tumors of identical stage and grade are comprised of different cell populations and proportions (Figure 2, A-C). Further, these “identical” tumors show divergent expression profiles (Figure 2, D-G). Despite clear cellular molecular variation, these 2 tumors would be treated identically in clinical practice based on tumor grade and stage. This may be one explanation for observed variations in patient response when only grade and stage are considered during treatment decision-making.

In addition to providing outstanding patient care in the present, there are countless ways in which urologists can contribute to improvements in care. I (BTR) am grateful for support from mentors at UConn Health. In addition, programs through the AUA Office of Research such as the USMART academy and the Early Career Investigators workup are invaluable in extending mentorship networks and facilitating meaningful collaborations for discovery. Our team is committed to the ideal of precision medicine; more accurately matching treatment decisions and intensity to individual patient physiology and unique tumor biology will result in improved patient care and outcomes.