Survival after Trimodal Therapy in Octogenarians with Organ-Confined Urothelial Bladder Cancer

Trimodal therapy (TMT) has emerged as a viable alternative to radical cystectomy (RC) for patients with muscle-invasive bladder cancer (MIBC), particularly those ineligible for surgery or who prefer a bladder-preserving approach.¹ By integrating maximal transurethral resection of the bladder tumor (TURBT) with chemotherapy (CT) and radiation therapy (RT), TMT aims to achieve oncologic outcomes comparable to RC.

Given its less invasive nature, TMT may be especially relevant for elderly patients, who face heightened perioperative risks and a greater likelihood of intensive care following RC. However, robust data evaluating its effectiveness in this population have been lacking.

To address this knowledge gap, our recent study leveraged the Surveillance, Epidemiology, and End Results (SEER) database to assess treatment patterns and cancer-specific mortality (CSM) among octogenarians with organ-confined (T2N0M0) urothelial carcinoma of the bladder.² Between 2004 and 2021, we identified 2,355 such patients, of whom 793 (33.7%) underwent TMT. As expected, those receiving TMT were slightly older than their RC counterparts (median age: 84 vs. 82 years, p<0.001). Notably, both treatment groups were predominantly Caucasian (88.3% in TMT vs. 88.7% in RC). To mitigate confounding, we performed 1:1 propensity score matching (PSM) for age and sex, in addition to multivariable adjustments.

Over the study period, TMT utilization increased substantially, from 53.3% in 2004 to 82.2% in 2021 (EAPC: +2.5%, p<0.001). Despite this trend, TMT was associated with significantly higher five-year CSM compared to RC (50.1% vs. 31.1%). After extensive multivariable adjustment, including PSM, TMT remained an independent predictor of worse CSM, conferring a 1.7-fold higher risk of cancer-specific death. This survival disadvantage persisted even in subgroup analyses restricted to Caucasian patients (HR: 1.7, p<0.001), reinforcing the robustness of our findings.

Our results align with prior population-based studies demonstrating inferior survival outcomes with TMT compared to RC across all age groups.^3,4 For instance, Deuker et al. reported that 10-year CSM after RC was lower than after TMT (25.9% vs. 44.3%, HR: 0.48, p<0.001).³ Interestingly, our findings suggest that this survival disparity may be even more pronounced in octogenarians.

It is worth noting that the majority of studies reporting a TMT survival disadvantage are based on large-scale SEER analyses. Prospective randomized evidence remains scarce, with the only phase III randomized controlled trial (RCT) comparing TMT to RC – the SPARE trial – failing to meet its recruitment target. Among the 45 enrolled patients (20 TMT, 25 RC), five-year CSM rates were 52% for TMT vs. 20% for RC (HR: 3.05, 95% CI: 0.92 – 10.15, p=0.06), but the study was underpowered to confirm statistical significance. The challenges faced by SPARE highlight the inherent difficulties in conducting prospective trials in this setting, particularly given the prevailing perception that TMT offers an advantage over RC.

Recent data from Zlotta et al. further contextualize the debate.⁵ Their PSM analysis of 722 patients with clinical T2-T4N0M0 MIBC found comparable five-year metastasis-free, disease-free, and cancer-specific survival between TMT and RC, with TMT yielding superior overall survival (HR: 0.75, 95% CI: 0.58 – 0.97), likely due to the 2.5% perioperative mortality rate associated with RC. However, their study was conducted in highly selected patients meeting strict eligibility criteria, whereas our SEER-based analysis reflects real-world practice, encompassing diverse patient populations and treatment settings. This distinction underscores the importance of interpreting findings within their respective contexts.

Another critical factor in treatment selection is cost. A SEER-Medicare analysis revealed that TMT incurred $136,935 higher mean costs than RC within one year of diagnosis, driven primarily by outpatient care, radiology, medication, and pathology/laboratory expenses.⁶ Given the financial constraints often faced by elderly patients, this economic burden warrants careful consideration. Furthermore, in our cohort, only approximately 25% of RC-treated patients received chemotherapy – a key factor given the unique challenges and risks associated with systemic therapy in older individuals. Future research should explore strategies to optimize treatment selection and sequencing in this population, balancing oncologic efficacy with quality of life and healthcare resource utilization.

In addition to survival and economic concerns, functional outcomes play a crucial role in treatment decision-making for elderly patients. While TMT preserves the bladder, it is associated with significant long-term toxicity, including urinary dysfunction, hematuria, and radiation-related complications. In contrast, RC eliminates the primary tumor burden but introduces quality-of-life considerations related to urinary diversion. Recent patient-reported outcome studies suggest that while some patients adapt well to urinary diversion following RC, others experience substantial distress, particularly in the absence of adequate preoperative counseling and postoperative support. These findings highlight the importance of individualized discussions regarding functional outcomes when counseling octogenarian patients.

The evolving role of immunotherapy in bladder cancer treatment may further impact the relative viability of TMT and RC.⁷ Immune checkpoint inhibitors have shown promising results in MIBC, particularly as neoadjuvant or adjuvant therapy. The integration of immunotherapy into bladder-sparing approaches could potentially enhance TMT outcomes, mitigating its survival disadvantage relative to RC. Ongoing clinical trials will be instrumental in determining whether novel systemic therapies can improve the oncologic efficacy of TMT, particularly in elderly populations where treatment tolerability is a key concern.⁸

Ultimately, the choice between TMT and RC in octogenarian patients should be guided by a comprehensive assessment of oncologic efficacy, functional outcomes, patient preferences, and healthcare resource availability. While our study provides strong evidence of inferior cancer-specific survival with TMT, it is imperative to acknowledge that some patients may not be candidates for RC due to comorbidities or frailty. In such cases, TMT remains a crucial alternative, albeit with a clear need for transparent discussions regarding its limitations.

In conclusion, our study underscores a consistent survival disadvantage associated with TMT in octogenarians with organ-confined bladder cancer. This finding remains robust across the entire cohort and in subgroup analyses limited to Caucasian patients, regardless of adjustment for age and sex. While patient selection and individualized decision-making remain paramount, it is imperative that clinicians fully inform eligible octogenarians about the higher CSM risk associated with TMT. In cases where RC is not feasible due to absolute contraindications, TMT remains a necessary alternative. However, for those for whom RC is a viable option, our data suggest that its oncologic benefits should be weighed carefully in the shared decision-making process. Additionally, future studies should further explore the integration of emerging systemic therapies into bladder-sparing strategies to refine treatment paradigms for elderly patients with MIBC.

Written by: Mattia Longoni, MD, Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montréal Health Center, Montréal, QC, Canada; Division of Experimental Oncology/Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan, Italy; “Vita-Salute” San Raffaele University, Milan, Italy.

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