Site-specific heterogeneity in treatment response among patients with metastatic bladder cancer: implications for oligometastatic disease—a retrospective cohort study

Introduction

Bladder cancer is one of the most common malignancies worldwide and has the ninth-highest 5-year prevalence among all cancers (1). Approximately 25% of patients with bladder cancer present with muscle-invasive disease or distant metastasis (2). Although cisplatin-based chemotherapy remains the standard first-line treatment for metastatic bladder cancer, immunotherapy and targeted therapies have shown survival benefits in certain patient subsets. In particular, immune checkpoint inhibitors targeting PD-1 or programmed death-ligand 1 (PD-L1) have emerged as first-line options for patients who are ineligible for cisplatin and whose tumors exhibit high PD-L1 expression, offering a viable immunotherapy-based alternative (3). However, management of metastatic bladder cancer remains challenging because of platinum intolerance, limited survival benefits from chemotherapy, and poor therapeutic responses in certain histological subtypes (4).

The concept of oligometastatic bladder cancer (OMBC) has been proposed to improve outcomes in patients with limited metastatic burden. Although no universally accepted definition currently exists, metastasectomy and metastasis-directed radiotherapy have been proposed as potential treatment strategies in selected patients (5). A recent Delphi consensus study defined OMBC as a maximum of three metastatic sites, irrespective of the number of organs involved, provided that all metastatic sites are amenable to resection or stereotactic radiation (6). However, uncertainties remain regarding the number and location of lymph nodes involved, the maximum number of organs affected, and whether specific metastatic sites should be excluded from this definition.

Whether prognosis and treatment response differ among bladder cancer patients with metastases to different anatomical sites, and whether all metastatic sites should be included within the oligometastatic framework, remain unresolved questions. To address these issues, we conducted a large population-based retrospective analysis using Surveillance, Epidemiology, and End Results (SEER)-Medicare data to evaluate site-specific prognostic impact and treatment response patterns in metastatic bladder cancer. This study aims to provide evidence to inform future research and conceptual frameworks for OMBC. We present this article in accordance with the STROBE reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-2026-1-0059/rc).

Methods

Data source

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Data were obtained from the SEER-Medicare database using the Incidence-SEER Research Data, 17 Registries, November 2023 submission (2000–2021), accessed through SEER*Stat version 8.4.3. Eligible cases were identified using ICD-O-3 site and morphology codes for urinary bladder cancer, excluding benign tumors and cases with missing or unknown distant lymph node metastasis information. For variables with missing data, missing values were either combined with “none” or treated as a separate category, as appropriate, to reduce potential bias and retain all cases in the analysis. The inclusion and exclusion criteria are summarized as follows: (I) pathologically confirmed urinary bladder cancer; (II) available information on metastatic sites; and (III) complete data for variables included in the multivariate analysis. A total of 105,554 cases were included. This study was designed as a retrospective population-based cohort study.

Study design and analytical framework

This study aimed to evaluate whether different metastatic sites in bladder cancer are associated with differences in survival and treatment response, with the goal of informing research on oligometastatic disease. To allow for meaningful comparisons, we included both metastatic and non-metastatic patients, using the non-metastatic group as a reference.

We first conducted univariate survival analyses to assess the relationship between metastasis at each anatomical site and overall survival. Metastatic sites that showed significant associations were then included in subgroup analyses to further explore potential differences in treatment response.

Metastatic sites (bone, brain, liver, lung, and distant lymph nodes) were analyzed separately to account for potential biological and clinical heterogeneity. This site-specific approach allows for a more precise evaluation of prognostic differences and helps avoid confounding effects from combining single-site and multi-site metastases. Patients with metastases at multiple sites were not excluded and could be included in more than one site-specific subgroup. Each metastatic site (bone, brain, liver, lung, and distant lymph nodes) was analyzed as an independent variable based on its presence or absence. As a result, overlap between metastatic sites was not explicitly modeled, and the potential interaction between multiple metastatic sites was not accounted for in the analysis.

All analyses were performed using a consistent modeling approach, and relevant clinicopathological variables were considered to reduce potential confounding. This stepwise strategy allowed us to first identify prognostically relevant metastatic sites and then evaluate their clinical implications.

Data management

Age was categorized as <65 or ≥65 years. Tumor size was grouped as ≤3.0 cm, >3.0 cm, or unknown. Transitional cell carcinomas were classified as papillary or non-papillary, and all other histological types were categorized as non-transitional carcinomas. Histological grades were harmonized across database versions by classifying grade I–II as low grade and grade III–IV as high grade. Radiotherapy was categorized as postoperative radiotherapy, other radiotherapy sequences, or no/unknown radiotherapy. Due to the inherent constraints of the SEER database, information on the number of metastatic lesions and overall metastatic burden is not available. Therefore, metastatic disease was defined based solely on the presence or absence of metastasis at specific anatomical sites. As a result, we were unable to stratify patients according to metastatic burden or to apply a strict definition of oligometastatic disease based on lesion count. To address this limitation, our analyses focused on site-specific patterns of metastasis rather than quantitative measures of disease extent. This approach allowed for a consistent evaluation of the prognostic impact of different metastatic sites within the available data structure.

Covariates and outcomes

Demographic and clinicopathological variables included age, sex, race, tumor size, histology, grade, primary tumor site, tumor (T) stage, node (N) stage, primary tumor surgery, and extent of regional lymph node dissection. Metastatic sites included lung, bone, liver, brain, lymph nodes, and other sites. Treatment modalities for metastatic disease included radiotherapy, chemotherapy, systemic therapy, and surgery. The primary endpoint was overall survival.

Statistical analysis

Categorical variables are presented as frequencies and proportions. Survival analyses were performed using univariable and multivariable Cox proportional hazards regression models. A two-sided P value <0.05 was considered statistically significant. Data processing and visualization were performed using R version 4.3.2, and statistical analyses were conducted using IBM SPSS Statistics 27.

Results

A total of 105,554 patients were included in the analysis, and baseline characteristics of the study cohort are summarized in Table 1. Elderly patients (≥65 years; 80,035, 75.8%) and males (81,001, 76.7%) constituted the majority of the cohort. In the United States, the vast majority of bladder cancer patients are white (91,649, 86.8%). Papillary transitional cell carcinoma accounts for 69.7% of histological types. Tumors most commonly occur on the lateral wall of the bladder (22.6%). Common sites of distant metastasis include the bone (1.70%), lymph nodes (1.70%), lung (1.60%), liver (1.20%), and brain (0.10%). Surgery, chemotherapy, systemic therapy, and radiotherapy are the major treatment options.

The results of the multivariate Cox regression analysis showed that bladder cancer metastasis to the lymph nodes did not affect overall survival [hazard ratio (HR) 1.053, 95% confidence interval (CI): 0.983–1.127], while metastasis to the bone (HR 1.789, 95% CI: 1.680–1.904), brain (HR 1.799, 95% CI: 1.482–2.184), liver (HR 1.884, 95% CI: 1.751–2.028), lung (HR 1.825, 95% CI: 1.713–1.944), and other sites (HR 1.706, 95% CI: 1.584–1.837) significantly impacted patient survival. The survival curves are shown in Figure 1. Both radiotherapy (HR 0.643, 95% CI: 0.572–0.724) and chemotherapy (HR 0.857, 95% CI: 0.820–0.895) help improve the prognosis of patients with bladder cancer. However, surgery targeting distant metastases (HR 1.044, 95% CI: 0.969–1.124) did not improve the prognosis of bladder cancer patients, and surgery on lymph nodes with distant metastases (HR 1.643, 95% CI: 1.321–2.045) reduced overall survival time. The use of systemic therapy, whether administered preoperatively (HR 0.529, 95% CI: 0.497–0.564), intraoperatively (HR 0.697, 95% CI: 0.651–0.745) or postoperatively (HR 0.574, 95% CI: 0.552–0.596), contributes to extending patient survival. Details can be found in Table S1.

Figure 1 Overall survival curves of bladder cancer patients with metastases (log-rank test), stratified according to whether metastases occurring in distant lymph node (A), bone (B) ,brain (C), liver (D) or lung (E). LN, lymph node.

As shown in Table S2 and Figure 2, patients with distant lymph node metastasis are sensitive to systemic therapy, but intraoperative systemic therapy (HR 0.735, 95% CI: 0.406–1.330) does not offer benefits. While these patients also respond to chemotherapy (HR 0.428, 95% CI 0.373–0.490) and surgery of distant site (HR 1.406, 95% CI: 1.078–1.833) . Radiotherapy (HR 0.981, 95% CI: 0.846–1.139) targeting metastatic lymph nodes does not improve their prognosis. Table S3 and Figure 3 indicated that bladder cancer patients with bone metastases are responsive to chemotherapy (HR 0.444, 95% CI: 0.387–0.509), radiation (HR 0.606, 95% CI: 0.497–0.739) and both preoperative (HR 0.493, 95% CI: 0.335–0.725) and postoperative (HR 0.667, 95% CI: 0.570–0.781) systemic therapy. The results of the multivariate analysis suggest that patients with brain metastases respond only to chemotherapy (HR 0.485, 95% CI: 0.240–0.979), while other treatment options are ineffective (Table S4 and Figure 4). Patients with lung metastases are sensitive to chemotherapy (HR 0.498, 95% CI: 0.432–0.574) and systemic therapy (Table S5 and Figure 5). As shown in Table S6 and Figure 6, radiotherapy (HR 0.820, 95% CI: 0.677–0.993), chemotherapy (HR 0.436, 95% CI: 0.370–0.514), and systemic treatments administered preoperatively (HR 0.353, 95% CI: 0.200–0.620) and postoperatively (HR 0.680, 95% CI: 0.559–0.828) can significantly enhance the prognosis for patients with liver metastases.

Figure 2 Multivariable Cox regression analysis of therapeutic strategies for overall survival in bladder cancer patients with distant lymph node metastases. *, including intraoperative radiation with other radiation before/after surgery, intraoperative radiation, radiation before and after surgery, radiation prior to surgery, surgery both before and after radiation and sequence unknown, but both were given. CI, confidence interval; HR, hazard ratio.

Figure 3 Multivariable Cox regression analysis of therapeutic strategies for overall survival in bladder cancer patients with bone metastases. CI, confidence interval; HR, hazard ratio.

Figure 4 Multivariable Cox regression analysis of therapeutic strategies for overall survival in bladder cancer patients with brain metastases. CI, confidence interval; HR, hazard ratio.

Figure 5 Multivariable Cox regression analysis of therapeutic strategies for overall survival in bladder cancer patients with lung metastases. CI, confidence interval; HR, hazard ratio.

Figure 6 Multivariable Cox regression analysis of therapeutic strategies for overall survival in bladder cancer patients with liver metastases. CI, confidence interval; HR, hazard ratio.

Discussion

This large population-based study demonstrates marked site-specific heterogeneity in prognosis and treatment response among patients with metastatic bladder cancer. Notably, distant lymph node metastases were not independently associated with overall survival in the multivariate analysis. In contrast, surgical intervention targeting distant lymph nodes was associated with poorer survival outcomes. These findings are consistent with previous reports indicating that extended lymph node dissection does not confer additional survival benefits compared with standard dissection (7,8). The lack of an independent association may reflect a lower tumor burden and less aggressive disease compared with visceral metastases. The observed association between surgery and poorer survival is more likely attributable to selection bias, as patients undergoing surgery may have more advanced, aggressive, or symptomatic disease, rather than a direct detrimental effect of the procedure. Although some small retrospective studies have suggested potential benefits of stereotactic body radiotherapy for nodal metastases (9,10), our population-level analysis did not demonstrate a survival advantage from radiotherapy in patients with distant lymph node metastases. Differences between studies may reflect heterogeneity in patient selection, treatment protocols, and sample size limitations. Collectively, these findings suggest that metastasis-directed local therapy for distant lymph node involvement may have limited prognostic value and should be interpreted cautiously in the context of OMBC.

In contrast, patients with bone metastases appeared to benefit from chemotherapy, systemic therapy, and radiotherapy, though these associations may reflect patient selection rather than a direct treatment effect. Prior studies have similarly reported improved outcomes with radiotherapy in patients with bone metastases (11), although conflicting results have also been described (12). Such discrepancies may reflect sample size limitations and selection bias in smaller cohorts. Our large population-based analysis provides supportive evidence that bone metastases may represent a subgroup of metastatic bladder cancer with relative sensitivity to local treatment, suggesting their potential relevance in future oligometastatic research frameworks.

Patients with brain metastases exhibited a distinct treatment response pattern, with chemotherapy being the only modality associated with improved survival. Previous small studies and case series have suggested that combined surgery and radiotherapy may improve outcomes (13), and isolated case reports have described responses to immunotherapy (14). However, brain metastases remain rare in bladder cancer and are frequently associated with widespread systemic disease (13). The limited evidence supporting benefit from local therapy and the frequent coexistence of multisite metastases suggest that brain metastases represent a biologically aggressive phenotype, with limited suitability for oligometastatic treatment strategies.

For lung metastases, prior studies have reported variable results regarding the role of surgery and local treatment (15-18). In our analysis, chemotherapy and systemic therapy were independently associated with improved survival, whereas local radiotherapy and surgical treatment of metastatic lesions were not. These findings suggest that lung metastases may benefit more from systemic therapy than from local interventions, though the absence of subgroup analyses limits firm conclusions regarding local treatment efficacy.

Patients with liver metastases appeared to benefit from systemic therapy, chemotherapy, and radiotherapy, although outcomes may be influenced by unmeasured factors such as disease burden or treatment intent, consistent with previous reports (19-23). Surgical treatment of either primary or metastatic lesions was not associated with improved survival in our cohort. Nevertheless, selected subgroups may derive benefit from multimodal treatment approaches, and further prospective research is required to clarify optimal management strategies. Collectively, these findings suggest that liver metastases may represent a subgroup with partial responsiveness to local therapy, meriting consideration in future oligometastatic research.

In addition, the introduction of immunotherapy and targeted therapies has ushered in a new era in bladder cancer treatment, potentially profoundly altering the prognosis of patients with metastatic disease. However, due to the limitations of the database, we are unable to fully assess their impact in the current study. We plan to address in future research how these therapies reshape the prognosis of patients with metastatic urothelial carcinoma and their implications for the management of OMBC.

Several limitations should be acknowledged. A key limitation of this study is the lack of data on metastatic lesion count and burden in SEER, which are important for defining oligometastatic disease. As a result, we could not stratify patients by metastatic volume. To address this, we focused on site-specific prognostic patterns and carefully avoided overinterpreting our findings within a strict oligometastatic framework. Future studies with detailed metastatic burden data are needed to validate these results. Additionally, this retrospective database study is subject to inherent biases, including variations in histological classification, staging systems, and missing data. Detailed treatment information, including specific chemotherapy regimens, radiation doses, number of cycles, and distinctions between immunotherapy and targeted therapy, was unavailable. Overlapping metastatic sites were not explicitly accounted for, and patients with multiple metastases could be included in more than one subgroup. This may introduce residual confounding and should be considered when interpreting the results. The current evidence base for OMBC remains limited, and some conclusions require validation in prospective and mechanistic studies. Besides, the observed associations may partly reflect selection of patients for specific treatments rather than a causal therapeutic effect. Future studies with detailed information on metastatic volume are needed to validate and extend these observations.

Conclusions

Metastatic bladder cancer exhibits substantial biological and clinical heterogeneity, with site-specific differences in prognosis and treatment response. While systemic therapy and chemotherapy remain central components of management, only patients with bone and liver metastases were associated with comparatively greater survival following targeted local radiotherapy, but these findings should be interpreted cautiously given the limitations of registry data. In contrast, patients with distant lymph node, brain, and lung metastases show limited or no survival benefit from local treatment strategies. These observations should be interpreted with caution, as treatment allocation in this retrospective registry-based study is likely influenced by patient condition, disease burden, and physician choice, and unmeasured confounding may bias the observed associations. Nevertheless, These findings indicate that metastatic site represents a critical factor that should be incorporated into future efforts aimed at refining the conceptual definition and clinical research framework of OMBC.

Acknowledgments

We would like to thank the SEER-Medicare database staff and contributors to open-source software, including R, for data access and analytical support.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-2026-1-0059/rc

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2026-1-0059/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2026-1-0059/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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