As the number of older adults in Japan continues to increase exponentially, the number of patients diagnosed with advanced or metastatic disease is also expected to increase further (1). In routine practice, metastatic urothelial carcinoma (mUC) diagnosis or systemic therapy requirement at diagnosis is common among patients aged ≥80 years (2, 3), making treatment decisions in this population increasingly important.

In recent years, systemic therapy for mUC has evolved substantially. Maintenance avelumab after platinum-based chemotherapy (PBC), antibody–drug conjugates, and PBC combinations have expanded treatment options (4-7). However, older patients often have multiple comorbidities and age-related organ dysfunction (8), limiting the applicability of clinical trial results to real-world practice. Moreover, the efficacy, safety, and feasibility of these newer regimens in patients aged ≥80 years remain insufficiently reported.

PBC has long been the cornerstone of first-line treatment for mUC (9). Nevertheless, real-world data on PBC for octogenarians with mUC remain limited (3, 10), with poor characterization of the balance between potential anti-tumour benefit and treatment-related toxicity in this age group.

Accordingly, this study aimed to describe treatment outcomes in patients aged ≥80 years with mUC eligible for first-line PBC, focusing on treatment efficacy, survival outcomes, and treatment-related adverse events (TRAEs).

Patient population. This single-centre retrospective observational study was based on treatment decisions made in routine clinical practice. We included 30 consecutive patients with mUC aged ≥80 years who received PBC between May 2005 and October 2022. In this cohort, first-line systemic therapy included PBC alone; no patients received subsequent avelumab maintenance therapy or enfortumab vedotin. The study protocol obtained approval from the University of Occupational and Environmental Health Institutional Review Board (approval number: UOEHCRB21-048) and conformed to the principles of the Declaration of Helsinki. Given the retrospective study design, individual consent for study participation was waived, although we provided an opt-out option through the institutional website.

Treatment. PBC included a gemcitabine plus platinum regimen (gemcitabine plus cisplatin or gemcitabine plus carboplatin) or the regimen consisting of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC). Cisplatin was generally administered if the estimated glomerular filtration rate (eGFR) ≥60 ml/min/1.73 m², and carboplatin if the eGFR <60 ml/min/1.73 m² (11). The PBC dosing schedule and dosage were based on previously established standard regimens (9, 12). Dose modifications and schedule adjustments were made at the attending physician’s discretion, considering patients’ advanced age, overall condition, and TRAEs.

Outcomes. Treatment response and survival were the study’s main outcomes. Tumour response was evaluated according to the Response Evaluation Criteria in Solid Tumours, version 1.1, and classified as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) (13). The proportion of patients achieving CR or PR defined the objective response rate (ORR), whereas the proportion achieving CR, PR, or SD defined the disease control rate (DCR).

For survival analyses, the time from PBC initiation to radiographic or clinical disease progression was defined as progression-free survival (PFS). Overall survival (OS) referred to the time from PBC initiation to death from any cause or the last follow-up data.

Safety assessment. TRAEs were graded according to the Common Terminology Criteria for Adverse Events, version 5.0 (14). We evaluated treatment feasibility indicators such as reasons for treatment discontinuation (caused by adverse events or patient preference), dose reduction, and the use of supportive care measures, including red blood cell and/or platelet transfusion and granulocyte colony-stimulating factor (G-CSF).

Statistical analysis. Continuous variables are expressed as median with range or interquartile range (IQR), as appropriate, and categorical variables as number and percentage. We estimated survival curves using the Kaplan–Meier method and calculated the median PFS and OS with 95% confidence intervals (CIs). For descriptive purposes, survival curves were generated separately by metastatic site. No formal statistical comparison was conducted.

Patient characteristics. This study included 30 participants aged ≥80 years with mUC. The median age was 83 years (range=80-92 years), and 20 (66.7%) of them were male. The Eastern Cooperative Oncology Group performance status was 0 in 15 patients (50%) and 1 in 15 (50%). Furthermore, 18 patients (60.0%) had lymph node–only metastasis, whereas nine patients (30%) had visceral metastases involving the lung, liver, or bone. Regarding the chemotherapy regimens, 24 patients (80%) received gemcitabine plus platinum, while six (20%) received MVAC; cisplatin and carboplatin were administered to 15 patients each (Table I). None received subsequent avelumab maintenance therapy or enfortumab vedotin.

Treatment response. Figure 1A illustrates a waterfall plot of the maximum percentage change in target lesions. For the best overall response, CR was observed in two patients (6.7%), PR in 10 (33.3%), SD in 11 (36.7%), and PD in seven (23.3%) (Figure 1B). The ORR was 40.0%, while the DCR was 76.7% (Figure 1B).

Survival outcomes. The median follow-up duration was 12.6 months (IQR=7.5-26.7). During follow-up, disease progressed in 24 patients, with death reported in 21. Figure 2 shows Kaplan–Meier curves for PFS and OS from PBC initiation. The median PFS was 5.2 months (95% CI=4.1-6.3), and the median OS was 11.3 months (95% CI=9.1-26.4). Figure 3 depicts OS based on the metastatic pattern. The median OS was 20.7 months (95% CI=9.0-27.8) in patients with lymph node–only metastasis, and 7.6 months (95% CI=2.8-not estimable) in those with visceral metastases.

Adverse events and treatment feasibility. All patients experienced TRAEs. Grade ≥3 TRAEs occurred in 23 patients (76.7%), with neutropenia (63.3%), thrombocytopenia (40.0%), and anaemia (20.0%) being the most common. Febrile neutropenia occurred in three patients (10.0%) and required hospitalization. No cases of interstitial pneumonitis were observed, and no grade 5 TRAEs occurred (Table II).

The median number of PBC cycles administered was three (range=1-6). Dose was reduced in 21 patients (70.0%), while treatment was discontinued in 14 patients (46.7%) because of adverse events and patient preference [7 (23.3%) patients each]. Supportive care measures, including red blood cell, platelet, and G-CSF administration, were provided as clinically indicated (Table III).

This single-institution retrospective study provides real-world data on the effectiveness and tolerability of first-line PBC in patients aged ≥80 years with mUC in the era before the widespread adoption of avelumab maintenance therapy and enfortumab vedotin. Only patients deemed eligible for PBC were included in this study; hence, the findings should be interpreted in this context. Nevertheless, PBC exhibited measurable anti-tumour activity and demonstrated modest survival outcomes in this cohort. However, dose reductions, treatment discontinuation, and supportive care were frequently required, making PBC delivery challenging in this age group. The present data may serve as a practical benchmark for the tolerability and treatment delivery of first-line PBC in patients aged ≥80 years and may provide useful information for planning emerging first-line strategies, particularly as novel combination therapies become increasingly available in this population.

Comorbidities and age-related organ dysfunction often influence systemic chemotherapy in older patients with urothelial carcinoma (8); hence, treatment eligibility and goals should be carefully considered. Conversely, our findings suggest that chronological age alone should not automatically preclude PBC use in patients aged ≥80 years with preserved performance status. However, given the retrospective design of this study and the selected nature of this cohort, the generalizability of our findings is limited. Rather than viewed as equivalent to strategies used in younger individuals, PBC for patients with a more advanced age should be considered cautiously as one therapeutic option tailored to individual clinical factors, including organ function, comorbidities, metastatic pattern, and patient preference.

The cut-off age of 70 years is primarily used when evaluating PBC outcomes in older patients. In a retrospective study of 381 patients, the median OS was 9.3 months in those aged ≥70 years and 10.5 months in those <70 years, showing no significant difference (p=0.16); thus, chronological age may not be an independent prognostic factor (15). Similarly, an international meta-analysis including 543 patients from eight trials demonstrated that OS did not significantly differ between patients aged ≥70 and <70 years (12.1 vs. 12.8 months, p=0.91) (16). However, data focusing on patients aged ≥80 years remain limited, with prior reports restricted to small case series and small-scale retrospective cohorts (3, 10).

In this cohort, active toxicity management and supportive care were frequently needed to maintain treatment delivery. Hematologic adverse events, particularly myelosuppression, were common. Many patients also required dose reduction, G-CSF support, or blood transfusion. TRAEs and patient preference often led to treatment discontinuation, underscoring treatment feasibility as a key consideration in patients of advanced age with mUC.

In patients of advanced age, the number of induction PBC cycles and the timing of transition to maintenance therapy are clinically relevant considerations. In our previous real-world study of first-line PBC for mUC, the number of PBC cycles was associated with subsequent treatment outcomes, supporting the clinical relevance of optimizing induction chemotherapy duration (2). The phase II randomized DISCUS trial compared three and six cycles of PBC followed by avelumab maintenance and incorporated patient-reported outcomes as a co-primary endpoint. Results showed that quality-of-life outcomes were better in the three-cycle group, at the time when the six-cycle group completed the therapy (17). Accordingly, initiation of PBC in patients of advanced age requires early dose optimization, proactive supportive care, and flexible management that accounts for treatment burden and care environment. Such approaches may also facilitate a timely transition from induction chemotherapy to subsequent maintenance strategies in selected patients.

Survival curves based on metastatic pattern are also presented to descriptively illustrate outcome distribution in patients with lymph node–only metastasis and those with visceral metastases. Patients with lymph node–only metastasis showed relatively longer survival than those with visceral metastases. However, this analysis was limited by the small sample size and was not intended to formally compare between such patient groups or identify independent prognostic factors. Rather, it provides a clinical perspective that metastatic pattern, along with age and general condition, may influence treatment selection and goal setting in patients aged ≥80 years with mUC.

Only patients whose disease is controlled after first-line PBC can receive avelumab as maintenance therapy; therefore, both treatment response and tolerability during induction PBC may influence the feasibility of subsequent treatment transition (18). In the JAVELIN Bladder 100 trial, maintenance therapy was associated with improved PFS in patients with lymph node–only metastasis (19). The relatively high proportion of lymph node–only metastasis cases in our cohort provides clinical context when selecting individuals who may transition from induction PBC to maintenance strategies. In addition, Furubayashi et al. (20) reported that outcomes of avelumab treatment may differ according to age, performance status, and treatment timing in real-world practice, underscoring the importance of patient selection and optimal timing when considering maintenance therapy in older patients. Although the efficacy of maintenance therapy in patients aged ≥80 years has been reported (21), real-world data focusing on this age group remain limited and warrant further investigation.

Limitations. First, it is a single-centre retrospective study without a comparator group, and the sample size is small. Second, the cohort was restricted to patients deemed eligible for systemic chemotherapy, potentially introducing selection bias. Third, treatment regimens and platinum agents were heterogeneous, and the dose was modified, making the treatment intensity inconsistent. Fourth, although the study period is long, it may have introduced temporal changes in supportive care and the treatment environment. Fifth, adverse events were assessed retrospectively from medical records; therefore, some non-hematologic toxicities, comorbidity exacerbations, and geriatric syndrome-related events may have been overlooked.

Nevertheless, this study describes the real-world effectiveness, safety, and treatment delivery of first-line PBC in patients aged ≥80 years with mUC, providing practical reference data for future therapeutic considerations in this age group.

In treatment-eligible patients aged ≥80 years with mUC, first-line PBC showed measurable anti-tumour activity and survival outcomes in routine practice. However, grade ≥3 myelosuppression was frequent, thereby necessitating dose reduction, treatment discontinuation, and supportive care. Therefore, PBC should be considered cautiously in this age group, with careful patient selection and tailored toxicity management.

The Authors declare that they have no competing interests in relation to this study. Akinori Minato declares honoraria from Merck, Astellas, MSD, Ono, Bristol-Myers Squibb, Nippon Kayaku, Eisai, AstraZeneca, and Fuso, all unrelated to this manuscript, and consulting fees from Janssen, also unrelated to this manuscript.

A.M. contributed to the conceptualization, acquisition of patient data, data curation, statistical analysis, and writing of the original draft. K.J. contributed to the acquisition of patients’ data, reviewing, and editing. Y.T., Y.M., Y.S., and T.M. contributed to data curation and reviewed the draft. I.T. and E.K. reviewed the draft and supervised the study. All Authors discussed, verified, and approved the final version of the article.

The Authors thank Enago (www.enago.jp) for English language editing.

No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.