Abstract
Background/Aim: Intravesical bacillus Calmette-Guérin (BCG) therapy is the standard adjuvant treatment for high-risk non-muscle-invasive bladder cancer (NMIBC). However, the impact of advanced age, particularly ≥80 years, on oncological outcomes of BCG therapy remains controversial. This study evaluated age-stratified outcomes and real-world BCG delivery in patients with NMIBC.
Patients and Methods: We retrospectively reviewed 120 consecutive patients with NMIBC who initiated intravesical BCG therapy between June 2019 and May 2025 at a single center. Patients were stratified by age at BCG initiation into <80 years (n=91) and ≥80 years (n=29). High-risk recurrence-free survival (HR-RFS), progression-free survival (PFS), metastasis-free survival (MFS), and overall survival (OS) were assessed. HR-RFS was defined as the time from BCG initiation to recurrence of high-risk NMIBC or disease progression. Survival outcomes were estimated using the Kaplan-Meier method and compared between groups.
Results: Baseline clinicopathological characteristics and the rate of achieving the institution-defined minimum BCG exposure were similar between the two age groups. During a median follow-up of 33.5 months, there were no significant differences in HR-RFS (p=0.803), PFS (p=0.700), MFS (p=0.750), or OS (p=0.065) between the groups. Although HR-RFS was numerically lower in the ≥80 years group, progression to muscle-invasive disease and distant metastasis remained infrequent and comparable between groups.
Conclusion: In this real-world cohort, intravesical BCG therapy achieved comparable oncological outcomes in patients aged ≥80 years and younger patients with NMIBC. Chronological age alone was not associated with inferior clinically meaningful disease control, supporting BCG use in older patients when clinically indicated, with treatment decisions guided by tolerability and patient preference.
- Non-muscle-invasive bladder cancer
- intravesical bacillus Calmette-Guérin
- older patient
- real-world outcome
- recurrence-free survival
- disease progression
Introduction
Non-muscle-invasive bladder cancer (NMIBC) represents the most common clinical presentation of bladder cancer and comprises a biologically diverse disease entity with variable risks of recurrence and progression (1, 2). While many tumors follow an indolent clinical course, patients with high-risk disease experience substantial rates of recurrence and progression to muscle-invasive bladder cancer, which adversely affect survival and quality of life (3, 4). For several decades, intravesical bacillus Calmette-Guérin (BCG) therapy has remained the standard adjuvant treatment for high-risk NMIBC and continues to be recommended by major international guidelines (1, 5-7).
With the aging of the global population, NMIBC is increasingly diagnosed in older patients, who currently represent a large proportion of candidates for intravesical BCG therapy (8, 9). Unlike systemic anticancer treatments, intravesical BCG is generally initiated even in older patients, with subsequent continuation or discontinuation commonly guided by individual tolerability and, when applicable, patient preference rather than chronological age alone (10-12). Consequently, advanced age is not typically regarded as a strict contraindication to BCG therapy in routine clinical practice. However, concerns regarding treatment adherence, tolerability, and the balance between oncological benefit and treatment burden remain particularly relevant in older populations (12, 13).
Several retrospective studies have investigated the effect of age on the efficacy and safety of intravesical BCG therapy, but the results have been inconsistent (14-16). These discrepancies between studies may be attributable to differences in the definition of older populations, variability in treatment schedules, and heterogeneity in endpoint definitions, particularly regarding recurrence-free survival (RFS) (17, 18). Moreover, many studies have focused primarily on recurrence outcomes without adequately distinguishing between clinically indolent recurrences and high-risk events or evaluating progression-related endpoints, such as progression-free survival (PFS) or metastasis-free survival (MFS), which may be of greater clinical relevance in older patients (19-21). To address these unresolved issues, we conducted a retrospective, single-center analysis of patients with NMIBC who were treated with intravesical BCG therapy, stratified by age at treatment initiation (<80 years vs. ≥80 years). The objectives of this study were to compare oncological outcomes, including high-risk recurrence-free survival (HR-RFS) defined by high-risk recurrence or disease progression, PFS, MFS, and overall survival (OS), as well as to evaluate patterns of BCG treatment delivery in routine clinical practice. By focusing on clinically meaningful endpoints and real-world treatment patterns, this study aimed to clarify the role of intravesical BCG therapy in older patients with NMIBC.
Patients and Methods
Patient population. This retrospective, single-center, observational study enrolled patients with NMIBC who initiated intravesical BCG therapy at the Kyushu Cancer Center. Consecutive patients treated between June 2019 and May 2025 were screened for eligibility. This study period was chosen because maintenance BCG therapy had been routinely implemented at our institution since June 2019. Patients were excluded if they had concurrent upper tract urothelial carcinoma at the time of BCG initiation, insufficient clinical data for outcome evaluation, or if intravesical BCG therapy was administered during systemic treatment for metastatic urothelial carcinoma. After applying these criteria, 120 patients were included in the final analysis.
To perform the prespecified analysis, the patients were stratified according to age at the initiation of BCG therapy into two groups: those aged <80 years and those aged ≥80 years. Clinical, pathological, and treatment-related variables extracted from electronic medical records included age, sex, tumor status, tumor size, tumor multifocality, pathological stage, presence of concomitant carcinoma in situ, tumor grade according to the World Health Organization 2004 classification (22), histological variants, prior intravesical BCG therapy, and a history of upper tract urothelial carcinoma.
Intravesical BCG treatment protocol. Intravesical BCG therapy was administered using the Tokyo 172 strain (23) according to an institutional protocol based on the Southwest Oncology Group 8507 regimen (24). Induction therapy consisted of weekly intravesical instillations for six consecutive weeks, followed by maintenance therapy when feasible. The standard initial dose was 80 mg per instillation. In cases of treatment-related adverse events, dose reduction was not performed, and the interval between instillations was adjusted according to the patient’s tolerability instead. Maintenance therapy was withheld or discontinued in cases of disease recurrence or progression, unacceptable adverse events, or the patient’s refusal. To describe treatment exposure in routine practice, we used an institution-defined minimum BCG exposure, defined as completion of induction therapy (≥5 of six instillations) followed by at least one cycle of maintenance therapy (≥2 of three instillations) or BCG re-induction therapy (≥2 instillations) (25, 26).
Statistical analysis. HR-RFS, PFS, MFS, and OS were evaluated as study endpoints. HR-RFS was defined as the time from the initiation of intravesical BCG therapy to the first recurrence of high-risk NMIBC or disease progression. High-risk recurrence was defined according to the Japanese Urological Association guidelines and included tumors with pathological stage T1, high-grade disease, or carcinoma in situ. PFS was defined as the time from BCG initiation to progression to muscle-invasive disease or the development of distant metastasis. MFS was defined as the time from BCG initiation to the first documentation of distant metastasis. OS was defined as the time from BCG initiation to death from any cause. Patients without an event were censored at the date of last follow-up.
Baseline characteristics were compared between the age groups using Fisher’s exact test for categorical variables and the Mann-Whitney U test for continuous variables. Survival outcomes were estimated using the Kaplan-Meier method and compared using the log-rank test. Multivariable analyses were not performed to avoid model overfitting because of the limited number of events (24 HR-RFS events). All statistical analyses were performed using EZR (version 1.68; Saitama Medical Center, Jichi Medical University, Saitama, Japan) (27). A two-sided p-value <0.05 was considered statistically significant.
Ethics statement. This study was conducted in accordance with the Declaration of Helsinki and was approved by the ethics review board of the National Hospital Organization Kyushu Cancer Center (approval no. 2014-99). The requirement for written informed consent was waived owing to the retrospective nature of the study, and an opt-out consent process was implemented in accordance with institutional and national ethical guidelines.
Results
Patient characteristics according to age groups. A total of 120 patients with NMIBC who initiated intravesical BCG therapy were included in this analysis. The patients were stratified into two groups according to age at the initiation of BCG therapy: those aged <80 years (n=91) and those aged ≥80 years (n=29). Baseline clinicopathological characteristics according to age group are summarized in Table I.
Baseline clinicopathological characteristics of the patients according to age.
The median age was 71 years (interquartile range=66-75) in the <80 years group and 82 years (interquartile range=81-83) in the ≥80 years group (p<0.001). The sex distribution was not significantly different between the two groups (men: 85.7% vs. 82.8%, p=0.767). The tumor status (primary vs. recurrent), tumor size, tumor multifocality, pathological stage, and presence of concomitant carcinoma in situ were also similar between the age groups, with no significant differences.
Regarding pathological features, pT1 disease was observed in 46.2% of patients aged <80 years and in 44.8% of those aged ≥80 years, while concomitant carcinoma in situ was present in 26.4% and 39.3% of patients, respectively (p=0.236). According to the World Health Organization 2004 classification, the majority of tumors in both groups were high grade. Histological variants, prior intravesical BCG therapy, and a history of upper tract urothelial carcinoma were infrequent, and were not significantly different between the two age groups. Overall, both cohorts were characterized by a high prevalence of adverse pathological features, including pT1 disease, concomitant carcinoma in situ, high-grade tumors, and multifocal disease. Most patients in this cohort were classified as high risk according to institutional criteria; therefore, risk-stratified analyses were not performed.
Delivery of intravesical BCG therapy. The details of intravesical BCG treatment delivery stratified by the age groups are shown in Table II. The initial BCG dose was 80 mg in nearly all patients, with no significant difference between those in the <80 years group and those in the ≥80 years groups (98.9% vs. 100%, p>0.999). The completion of induction BCG therapy (defined as ≥5 instillations) was achieved in 94.5% of patients in the <80 years group and in 93.1% of those in the ≥80 years group (p=0.675). Regarding maintenance therapy during the first cycle, 69.2% of patients in the <80 years group and 65.5% of those in the ≥80 years group received at least two instillations, whereas 22.0% and 34.5%, respectively, did not receive any maintenance instillations during cycle 1 (p=0.119).
Delivery of intravesical bacillus Calmette-Guérin therapy according to age group.
Overall, the institution-defined minimum BCG exposure was achieved in 73.6% of patients in the <80 years group and 72.4% of those in the ≥80 years group, with similar frequencies between groups (p>0.999). Among patients who did not achieve the minimum exposure, treatment-limiting adverse events and patient refusal were the most frequently documented reasons. Patient refusal appeared more common in the ≥80 years group; however, formal statistical testing was not performed because of the small number of cases.
Survival outcomes according to age groups. Kaplan-Meier survival curves for HR-RFS, PFS, MFS, and OS stratified by the age groups are shown in Figure 1. During a median follow-up of 33.5 months (range=4.4-70.3 months), there were no significant differences in any of the evaluated survival endpoints (RFS: p=0.803; PFS: p=0.700; MFS: p=0.750; OS: p=0.065) between the two groups.
Survival outcomes according to age groups. Kaplan-Meier curves showing (A) high-risk recurrence-free survival (HS-RFS), (B) progression-free survival (PFS), (C) metastasis-free survival (MFS), and (D) overall survival (OS) stratified by age at the initiation of intravesical bacillus Calmette-Guérin (BCG) therapy (<80 years vs. ≥80 years).
Patients in the ≥80 years group showed a numerically lower HR-RFS rate than those in the <80 years group, but this difference was not significant (Figure 1A). PFS and MFS remained high and were similar between the two age groups throughout the observation period (Figure 1B and C). The OS rate was numerically lower in the ≥80 years group than in the <80 years group, but this was not significant (Figure 1D). During the follow-up period, five deaths were observed, with two in the <80 years group and three in the ≥80 years group. Among the two deaths in patients in the <80 years group, one occurred after recurrence or progression to muscle-invasive bladder cancer, for which best supportive care was selected. In the ≥80 years group, two patients selected best supportive care following recurrence or progression to muscle-invasive bladder cancer, and one patient died of causes unrelated to bladder cancer.
Discussion
In this retrospective, single-center analysis, we evaluated the oncological outcomes of intravesical BCG therapy in patients with NMIBC who were stratified by age at treatment initiation. No significant differences in HR-RFS, PFS, MFS, or OS were observed between patients aged <80 years and those aged ≥80 years. These findings indicated that advanced chronological age alone was not associated with inferior oncological outcomes following intravesical BCG therapy in routine clinical practice. Notably, progression to muscle-invasive bladder cancer and the development of distant metastasis were infrequent in both age groups. This finding suggested that intravesical BCG therapy maintained its capacity to suppress clinically meaningful disease progression irrespective of age. Baseline clinicopathological characteristics and the frequency of the institution-defined minimum BCG delivery were mostly similar between younger and older patients. Therefore, the observed outcomes appear to reflect genuine treatment effectiveness rather than differences in disease burden or treatment exposure. Although OS was numerically lower in patients aged ≥80 years than in those aged <80 years, this appeared to be affected by treatment selection after progression and competing causes of death rather than by inadequate oncological control. Collectively, these results support the notion that intravesical BCG therapy remains a reasonable and potentially beneficial bladder-preserving treatment option for carefully selected older patients with NMIBC, and that chronological age alone should not preclude its use.
RFS is a sensitive endpoint for assessing intravesical disease activity in NMIBC, but interpretation of RFS requires careful contextualization, particularly in older patients. To focus on clinically meaningful events, we used HR-RFS, defined as the time from BCG initiation to recurrence of high-risk NMIBC or disease progression, thereby excluding low-grade or clinically indolent intravesical recurrences. Within this framework, recurrence-related events observed in patients aged ≥80 years were not accompanied by an increased risk of progression to muscle-invasive disease or distant metastasis. This dissociation between intravesical recurrence and disease progression has been consistently reported in BCG-treated cohorts and reflects the biological heterogeneity of NMIBC, in which not all recurrences carry equivalent prognostic significance (3, 4, 17-19). This concept has also been emphasized in commentaries and reviews discussing the limitations of recurrence-based risk prediction in NMIBC (20). Previous studies have demonstrated that the principal clinical benefit of intravesical BCG therapy lies in suppressing biologically aggressive disease rather than completely preventing all intravesical tumor recurrences, particularly in patients with high-risk pathological features (19). Accordingly, modest differences in HR-RFS, as defined by clinically meaningful high-risk events, do not necessarily indicate compromised oncological control when progression and metastasis remain infrequent.
Importantly, recurrence outcomes in older patients should be interpreted alongside treatment delivery and continuation in routine practice. A claims-based real-world study has suggested that adherence to BCG maintenance schedules (i.e., guideline-concordant maintenance) is associated with improved oncology-relevant outcomes, underscoring that treatment delivery may be at least as influential as chronological age alone (21). In our cohort, although the overall rate of achieving the institution-defined minimum BCG exposure was similar between the age groups, patient refusal accounted for a larger proportion of non-achievement in older patients than in younger patients. Similar patterns have been reported previously, with a higher discontinuation rate observed in older patients than in younger patients, frequently driven by patient preference or perceived treatment burden rather than severe treatment-related toxicity (11-13, 16). Notably, even limited exposure to intravesical BCG therapy, including induction with abbreviated or incomplete maintenance schedules, has been reported to provide durable protection against disease progression in a substantial proportion of patients (10, 19). These findings suggest that recurrence outcomes defined by high-risk events in older patients with NMIBC are affected not only by tumor biology but also by pragmatic factors related to treatment continuation and patient-centered decision-making.
PFS and MFS are particularly relevant endpoints when evaluating treatment effectiveness in older patients with NMIBC because they reflect the prevention of clinically consequential disease states rather than intravesical tumor activity alone. In this study, PFS and MFS remained favorable in patients aged ≥80 years and were comparable to those observed in younger patients. These findings are consistent with prior reports indicating that intravesical BCG therapy can provide durable protection against disease progression and metastasis, likely through the suppression of biologically aggressive tumor behavior (24, 28, 29). From a clinical perspective, maintaining low risks of progression and metastasis rates may be especially meaningful in older patients, for whom treatment goals often emphasize bladder preservation, avoidance of systemic disease, and preservation of functional independence. In geriatric oncology, therapeutic decision-making increasingly emphasizes individualized risk-benefit assessment, recognizing that chronological age alone is an imperfect surrogate for physiological reserve or treatment tolerance (8, 9). Therefore, the favorable PFS and MFS observed in older patients in this study support a pragmatic treatment approach in which BCG therapy is offered when clinically indicated, with subsequent treatment decisions guided by tolerability and patient preference rather than age-based exclusion.
Limitations. First, it was a retrospective, single-center analysis, which may limit the generalizability of the findings to broader clinical settings. Second, although the cohort size was moderate, the number of outcome events was limited, which precluded multivariable analyses and limited the ability to identify independent prognostic factors. Third, HR-RFS was defined by recurrence of high-risk NMIBC or disease progression, excluding low-grade or clinically indolent recurrences. While this definition was intentionally chosen to focus on clinically meaningful events, it may limit direct comparability with studies using broader recurrence definitions. Finally, information on patient-reported outcomes, quality of life, and comprehensive geriatric assessments was not available, and treatment continuation may have been influenced by physicians’ judgment and patients’ preferences, reflecting inherent limitations of real-world retrospective data.
Conclusion
In this retrospective, single-center study, intravesical BCG therapy was associated with comparable oncological outcomes in patients aged ≥80 years and those aged <80 years with NMIBC. Notably, PFS and MFS remained favorable in older patients, supporting the interpretation that advanced age alone did not compromise clinically meaningful disease control. These findings support the consideration of intravesical BCG therapy in older patients when clinically indicated, with treatment decisions guided by individual tolerability and patients’ preferences rather than chronological age alone. Further studies with larger cohorts and longer follow-up are warranted to validate these observations.
Acknowledgements
The Authors would like to thank J. Ludovic Croxford, PhD, and Ellen Knapp, PhD, from Edanz (https://jp.edanz.com/ac) for professional English language editing of this manuscript.
Footnotes
Authors’ Contributions
Conceptualization was performed by N.F., M.N., and T.N.; methodological design and formal analyses were conducted by N.F. and T.N.; data acquisition and investigation were performed by N.F., J.T., A.T., Y.S., M.N., and T.N.; data curation and visualization were carried out by N.F.; manuscript drafting was undertaken by N.F.; critical revision and editing were performed by all Authors; overall supervision of the study was provided by M.N. and T.N. All Authors reviewed and approved the final manuscript.
Conflicts of Interest
The Authors declare no conflict of interest in relation to this study.
Artificial Intelligence (AI) Disclosure
No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.
- Received February 7, 2026.
- Revision received March 3, 2026.
- Accepted March 6, 2026.
- Copyright © 2026 The Author(s). Published by the International Institute of Anticancer Research.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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