Management of Advanced Urothelial Carcinoma in Older and Frail Patients: Have Novel Treatment Approaches Improved Their Care?

Abstract

Patients with urothelial carcinoma (UC) tend to be older and frailer with a large number of chronic medical conditions. This is particularly pronounced in those with locally advanced or metastatic UC. Prior to 2016, treatment options in advanced urothelial carcinoma (aUC) were limited to chemotherapy, and as a result, a large number of patients were not receiving diseasedirected therapy. Over the last six years, multiple alternative modalities including immune checkpoint inhibitors, enfortumab vedotin, sacituzumab govitecan and erdafitinib have been introduced. They are being used clinically in older and frail patients, but their efficacy and safety profiles remain underexplored in these populations. Based upon available evidence, age does not appear to impact the efficacy and tolerance of immune checkpoint inhibitors if patients are fit enough to receive therapy. There is still not enough evidence to draw specific conclusions regarding the use of enfortumab vedotin, sacituzumab govitecan and erdafitinib in older and frail patients. Regardless, in all older patients with aUC, it is critical to evaluate for frailty through geriatric screening tools and comprehensive assessments. Combining these evaluations with consideration of an individual patient's goals should be the foundation upon which therapeutic decisions are made in this population of patients. Key Points Age is not an independent predictor of safety or efficacy in the management of aUC, but instead, should serve as a signal to providers to assess for frailty, which can have a significant impact on outcomes.  In older and frailer patients with advanced urothelial carcinoma, immune checkpoint inhibitors appear to be a well-tolerated treatment modality in the first and second line settings.  At present, there is not enough data to comment definitively on the efficacy and safety of enfortumab vedotin, sacituzumab govitecan and erdafitinib in older and frail patients.2 Setting the Stage: The Introduction of ICIs, Enfortumab Vedotin, Sacituzumab Govitecan and Erdafitinib Since the 1980's, cisplatin has been the primary agent in aUC. It is the foundation upon which multiple combination regimens have been developed including methotrexate, vinblastine, adriamycin and cisplatin (MVAC) as well as gemcitabine plus cisplatin (GC) [13]. Ultimately, a head-to-head phase III trial of GC versus MVAC demonstrated similar overall response rate, progression free survival (PFS) and overall survival (OS), but given less adverse effects associated with GC, it has been the preferred first-line (1L) regimen in cisplatin-eligible patients [14][15]. Prior to 2016, the preferred therapy in cisplatin-ineligible patients was carboplatin and gemcitabine. Carboplatin-based regimens are inferior to cisplatin-based regimens with worse objective and complete responses, but they are better tolerated in frailer patients [16][17]. In those deemed platinum-ineligible, non-platinum-based regimens centered on the use of gemcitabine, but even still, as much as 23.8% -48.4% of patients were n...

Effect of Antacid Use on Immune Checkpoint Inhibitors in Advanced Solid Cancer Patients: A Systematic Review and Meta-analysis

“…[102][103][104] Previous studies indicated that age does not affect the efficacy and tolerance of ICIs if patients are fit enough to receive therapy. 105 Advanced cancer patients older than 65 years may suffer from more underlying diseases and accept more concomitant medication than those younger than 65 years, resulting in shorter OS and PFS. 106,107 Our results show that only patients older than 65 years have a better response to ICIs.…”

“…In the age subgroup, patients older than 65 years had a higher risk of progression and death than those younger than 65 years, which may be attributed to age-associated decline in immune function, known as immunosenescence or age-related immune dysfunction 102–104. Previous studies indicated that age does not affect the efficacy and tolerance of ICIs if patients are fit enough to receive therapy 105. Advanced cancer patients older than 65 years may suffer from more underlying diseases and accept more concomitant medication than those younger than 65 years, resulting in shorter OS and PFS 106,107.…”

Treatment Patterns and Outcomes by Age in Metastatic Urinary Tract Cancer: A Retrospective Tertiary Cancer Center Analysis

“…Treatment decision-making for older patients with mUTC is complex and driven by multiple factors, such as patient preference, physician’s assessment for treatment tolerability, and patient frailty [ 27 ]. Though age may be associated with increased frailty and treatment toxicity, it does not constitute a reliable prognostic factor [ 28 ]. Our study showed that older patients had comparable outcomes to their younger counterparts regardless of the systemic treatment received.…”