Predicting early death in elderly patients with bladder urothelial carcinoma: a population-based study

Introduction

Bladder cancer (BLCA) is the ninth most common malignancy worldwide, second only to prostate cancer among urological malignancies (1). Globally, the estimated number of new cases in 2022 was approximately 614,000, and more than 90% are pathologically classified as urothelial carcinoma (1,2). And BLCA also poses a significant mortality burden, accounting for approximately 220,000 deaths in 2022, making it the 13th leading cause of cancer-related death worldwide (1,3). Tobacco smoking is identified as the primary risk factor for BLCA, contributing to approximately 50% of cases (4). Occupational exposure to industrial chemicals, including aromatic amines, polycyclic aromatic hydrocarbons, and chlorinated hydrocarbons, represents the second most significant risk factor for BLCA (5). The increasing global incidence of BLCA, coupled with the high costs associated with its diagnosis and treatment, underscores the substantial challenges.

BLCA can be categorized into two main groups: non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC). Of these, 75% of patients are initially diagnosed with NMIBC, but MIBC is the leading cause of BLCA-related deaths (6). Notably, in patients with high-risk NMIBC, the 5-year disease-free survival rate after radical cystectomy can be more than 80% (7). For MIBC, the standard treatment regimen is neoadjuvant chemotherapy combined with radical cystectomy and pelvic lymph node dissection, and this treatment strategy has become the current trend. A study has shown that neoadjuvant chemotherapy significantly reduces the risk of death: during a median follow-up of 8 years, the risk of death decreased by 16% and the 10-year survival rate improved from 30% to 36% (8). In addition, pelvic lymph node dissection not only has a therapeutic role, but also provides important information for prognostic assessment and improves the accuracy of pathologic staging and postoperative survival (9). A large-scale clinical study has shown that patients undergoing radical cystectomy have 5-year overall and recurrence-free survival rates of 66% and 68%, respectively, with corresponding 10-year survival rates of 43% and 60% (10).

It is common for patients with BLCA to die within a short period of time after diagnosis. However, there is no consensus in the clinical about the definition of “early death”, and in this study, according to previous research, death from all-cause within 6 months of diagnosis was defined as “early death” (11). Therefore, it is clinically important to explore the risk factors associated with early death, not only to help doctors predict the probability of early death in BLCA patients, but also to provide a scientific basis for the development of personalized treatment plans, so as to reduce the incidence of early death and improve the quality of patient’s prognosis. Currently, there are many studies pointing out that different risk factors have an impact on the prognosis of elderly patients with bladder urothelial cancer, including multiple risk factors such as old age, surgery, and brain tumor metastasis (12-14). However, these studies only focus on a single risk factor and lack a comprehensive and detailed summary. Therefore, there is a great need for this study to provide a comprehensive list of relevant risk factors to better understand the prognosis of elderly patients with bladder urothelial carcinoma. Nomogram, as a statistical model integrating relevant high-risk factors, has been widely used in the development of cancer treatment plans and prognosis assessment. The data for this study were obtained from the Surveillance, Epidemiology, and End Results (SEER) database, which covers approximately 34.6% of cancer registries in the United States and systematically records cancer incidence and survival data. In our study, we selected data from 5,087 elderly patients with urothelial carcinoma of the bladder registered between 2010 and 2015, based on which we developed a dependable Nomogram model aimed at assessing the risk of early death in patients, with a view to choosing the best clinical decision-making. We present this article in accordance with the TRIPOD reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-225/rc).

Methods

Data sources

This study was retrospectively analyzed based on the SEER database, and study data were collected via SEER*Stat software (version 8.4.4) from 17 registries in SEER Research Plus [2000–2021] collected in November 2023.These data cover survival, clinicopathologic characteristics, and demographic information for BLCA patients. Due to the lack of certain clinical variables in the SEER database, this study did not include information on patient comorbidities such as hypertension, diabetes mellitus and immunotherapy, which affected the comprehensiveness of the study to some extent, and we will collect patient information more comprehensively to ensure the reliability of the data in future studies. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Inclusion and exclusion criteria

In this study patients older than 60 years old were defined as elderly patient. Elderly patients diagnosed with BLCA (C67.0–C67.9) and pathologic type of transitional cell carcinoma, not otherwise specified (NOS), in 2010–2015 were screened according to International Classification of Diseases of Oncology, Third Edition (ICD-O-3) criteria. Initially, 23,192 patients were screened and, after exclusion, 5,087 eligible patients were finally included. Exclusion criteria included (I) identified by death certificate or autopsy; (II) involved several primary malignancies; (III) had Tis, T0, or an unknown stage of disease; (IV) had incomplete follow-up; (V) had anonymous variable information; readers can refer to Figure 1 for detailed screening process. Characteristics collected in this study included months of survival, age at diagnosis, gender, year of diagnosis, marital status, race, grade, tumor-node-metastasis (TNM) staging [American Joint Committee on Cancer (AJCC) 7th edition], tumor size, bone metastasis, brain metastasis, liver metastasis, lung metastasis, and treatment (including surgery, radiotherapy, and chemotherapy).

Figure 1 Flowchart of data selection of the elderly patients with bladder urothelial carcinoma. T, tumor.

Statistical analysis

The aim of this study was to investigate the association between early death and clinicopathologic, survival, and demographic characteristics of patients with bladder urothelial carcinoma. For this purpose, clinical characteristics, survival data and demographic information of the patients were systematically collected and organized into a baseline (Table 1) for visual presentation. In this study, the data of all patients were randomly divided into training and validation sets in a ratio of 6:4 using the seed package in the R software, which ensured the reproducibility of the data division. Pearson chi-square test was used to compare the balance of the baseline characteristics between the two groups, and the specific comparison results are shown in the baseline (Table 2). In terms of methodology, in this study, we used univariate and multivariate logistic regression analyses to analyze the training cohort data in order to identify the risk factors for early death in patients with bladder urothelial carcinoma. Based on these characteristics, we constructed a Nomogram model to predict the risk of early death. The performance of the model was assessed using receiver operating characteristic (ROC) curves and area under the curve (AUC), while the clinical application value of the model was quantified by decision curve analysis (DCA). During data analysis, we used R software (version 4.4.2) to complete the relevant calculations. The level of statistical significance set in the study was P<0.05.

Results

Patient’s characteristics and early death rates

This study included 5,087 patients with BLCA between 2010 and 2015, of whom 1,163 (23%) experienced early death. The basic characterization of BLCA patients who died early showed that 64% of BLCA patients were male and 87% were White, with a balanced age distribution, and with the highest percentage of patients aged 85 years or older at 31%. In terms of tumor grade, Grade IV cancers had the highest percentage at 62%. In addition, 89% of BLCA patients who died early had undergone surgery, while 86% had not received radiotherapy and 78% had not received chemotherapy. The percentage of patients with tumors with a maximum diameter of more than 30 mm reached 89%, which was identified as a significant risk factor (15). More detailed clinical characterization is described in Table 1.

Identification of prognostic factors associated with early death

This study used a randomized group design, with the training cohort containing 3,052 patients and the validation cohort containing 2,035 patients. The basic characteristics of the patients in the two cohorts were highly similar: the percentage of male patients was the same (both 69%), the percentage of white patients reached 88%, and married patients predominated in the marital status (54% in the training cohort and 56% in the validation cohort). T2 stage was the most common type of staging (44% in the training cohort and 41% in the validation cohort). The two cohorts had a high degree of similarity in treatment modalities, with insignificant differences in the percentage of surgery, radiotherapy and chemotherapy received. Statistical analysis verified that there was no significant difference between the two cohorts in the distribution of all characteristics (P>0.05), as detailed in Table 2.

The univariate logistic regression analysis’ results showed that age, marital status, T stage, M stage, surgery, radiation, chemotherapy, brain metastasis, liver metastasis, and tumor size were significantly associated with early death in Table 3. Based on these significant risk factors identified in the univariate logistic regression analysis, we performed a multivariate logistic regression analysis. The results showed that early death in elderly patients with urothelial carcinoma of the bladder was independently predicted by the following factors: age, marital status, T-stage, M-stage, surgery, radiation, chemotherapy, brain metastasis, tumor size (P<0.05), as shown in Table 3.

Construction and assessment of the nomogram

In order to predict the probability of early death in elderly patients with urothelial carcinoma of the bladder, this study constructed a prediction model based on the results of multivariate logistic regression analysis in the SEER cohort. The model used Nomogram charts to quantitatively score each independent risk factor, and the probability of early death of patients was estimated by total score. The probability range of the prediction model was set between 0.01 and 0.95, and a vertical scale set below the chart was used to visualize the likelihood of early death.

The results of the model evaluation showed that brain metastasis was the most significant predictor of early death, while marital status and radiotherapy status had relatively low predictive value (Figure 2). The mechanism of brain metastasis from BLCA is not clearly established and accounts for only 1–3% of BLCAs. However its incidence is increasing because while platinum-based chemotherapy regimens improve extracranial disease in BLCA patients and prolong their overall survival (OS), they are at higher risk of developing brain metastases late in life. This may be due to poor penetration of chemotherapeutic agents through the blood-brain barrier and the central nervous system becoming a refuge for residual tumor (16,17). Brain metastasis will be the focus of our attention. The predictive performance of the Nomogram model was assessed by ROC curves, and the results showed that the AUC of the training and validation cohorts were 0.7938 and 0.8107, respectively, which indicated that the model had good prediction performance and reliability (Figure 3A,3B). And the calibration curve analysis showed that the predicted probabilities showed good agreement with the actual probabilities in both the training and validation cohorts (Figure 4A,4B). The results of DCA showed that the model demonstrated significant clinical application value in predicting early death, and excellent clinical net gains were obtained in both the training and validation cohorts (Figure 5).

Figure 2 Nomogram to forecast early death in elderly patients with bladder urothelial carcinoma. AJCC, American Joint Committee on Cancer; M, metastasis; SDW, separated, divorced, widowed; T, tumor.

Figure 3 ROC curves in training cohort (A) and validation cohort (B) for differentiating nomograms in predicting early death. The expression of the AUC is AUC (95% confidence interval). AUC, area under the curve; ROC, receiver operating characteristic.

Figure 4 Calibration curves for assessing the calibration of the nomogram in forecasting early death in the training cohort (A) and the validation cohort (B).

Figure 5 DCA was performed on nomograms to predict early death in the training cohort and validation cohort. DCA, decision curve analysis.

Discussion

Despite significant advances in surgical techniques and systemic drug therapy for BLCA, significant challenges remain in its treatment (18). The incidence and mortality rates of bladder urothelial cancer increase significantly with age in many countries, and the senior patients’ population will continue to expand with the aging problem, which poses higher demands on clinical care (19,20). As a result, there is an increasing demand for treatment of elderly patients with BLCA. Similar to other tumors, elderly BLCA patients have a significantly higher risk of early death compared to younger patients, a phenomenon that has been validated in clinical prediction models for other tumors (21,22). However, there is a paucity of studies on early death in elderly patients with urothelial carcinoma of the bladder. To fill this research gap and provide clinicians with an early mortality risk prediction tool to optimize treatment options, we developed a prediction model (nomogram), specifically for elderly patients with urothelial carcinoma of the bladder.

Age is an important risk factor for urothelial cancer of the bladder (19,20). Studies have shown a significant increase in mortality from urologic tumors since 2000 in people around 85 years of age, which is consistent with the results of our prediction model (19). In addition, several studies have pointed out that the age at diagnosis of BLCA patients is strongly associated with OS and BLCA-specific survival. For example, BLCA-specific survival was significantly lower in patients aged >75 years compared with those aged ≤54 years (13). These results suggest that advanced age is strongly associated with a high prevalence of BLCA and differences in prognosis. Marital status is also an important predictor. Our study found that unmarried patients had a significantly higher risk of early death compared to married patients. There is a correlation between marital status and early death. Although there are fewer studies on the effect of marital status on the prognosis of BLCA, it has been shown that the survival rate of married men is generally higher than that of unmarried men, which may be related to factors such as treatment adherence, social resources, and social support (23). In the future, studies need to further explore the effect of marital status on BLCA prognosis from multiple dimensions such as health behavior, economic status, and marital quality. TNM staging provides a systematic assessment of the disease by describing the size, location, extent of invasion, and lymph node and distant metastases of the tumor (6). Studies have shown that higher T, N, and M stages are usually associated with poorer prognosis and are more likely to lead to early death in elderly patients, which is consistent with our findings.

There have been tremendous advances in disease management regarding BLCA in recent years. Below, we provide a comprehensive description of the treatment of BLCA. The mainstay of treatment for NMIBC is surgery, with transurethral resection of bladder tumor (TURBT) being the most common surgical procedure, which involves the removal of all visible bladder tumors down to the muscle layer (24). However, despite TURBT, these tumors usually recur and are at risk of progressing to MIBC. It has been shown that en bloc resection reduces postoperative complications and recurrence rates and facilitates postoperative pathologic staging compared with patients with NMIBC ≤3 cm (25). Depending on the degree of tumor invasion, an accurate pathological staging of the tumor can be performed, and NMIBC is usually classified into three stages: stage Ta, T1 and carcinoma in situ (CIS). Meanwhile, the European Association of Urology grouped the degree of risk of NMIBC based on the World Health Organization (WHO) 1973 grading method and the WHO 2004/2016 grading method: low risk, intermediate risk, high risk and very high risk (26). In patients with NMIBC, there is a need for adjuvant intravesical therapy after TURBT, including continuous bladder irrigation, chemotherapy, Bacillus Calmette Guerin (BCG) immunotherapy, and BCG combination chemotherapy. Patients with different levels of risk require different levels of adjuvant therapy to minimize postoperative complications and recurrence rates. For patients in the low-risk group, immediate postoperative single-titration chemotherapy significantly reduces the recurrence rate, and mitomycin C, epirubicin, and piribicin have all been shown to reduce the recurrence rate (27). BCG immunotherapy has tremendous benefits in preventing tumor recurrence. It has been noted that BCG after TURBT is superior to TURBT alone, TURBT combined with chemotherapy compared to mitomycin, with a 32% reduction in the risk of BCG recurrence (28,29). Also, BCG in combination with chemotherapy regimens reduces the risk of disease recurrence more than BCG alone (30). Radical cystectomy is the first option for patients who fail BCG treatment. However, the current use of some new drugs has opened up the possibility of preserving the bladder. It has been noted that systemic pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor, achieved a 40% complete remission rate in a BCG-naïve cohort of CIS patients (31), and a multicenter randomized controlled trial study demonstrated complete remission in up to 53.4% of BCG-naïve CIS patients (32), based on which a phase III randomized controlled clinical trial explored the potential for greater antitumor activity of BCG in combination with sasanlimab, the first treatment regimen to combine an immune checkpoint inhibitor with topical BCG (33). For high-risk NMIBC (including BCG-refractory, BCG-relapsed, BCG-unresponsive), lesions uncontrolled with TURBT and intravesical chemotherapy/immunotherapy alone and non-metastatic MIBC (T2-4a, N0-x, M0), radical cystectomy in combination with lymph node dissection remains the recommended standard of care (34). The scope of the procedure includes bladder and surrounding adipose tissue, distal ureter, and pelvic lymph node dissection, as well as removal of the prostate and seminal vesicles in male patients, and removal of the uterus, part of the anterior vaginal wall, and adnexa in female patients (35,36). Nowadays, robotic-assisted laparoscopic surgery is increasingly being used in BLCA surgery, and it can provide more benefits compared to open radical cystectomy. A systematic reviews and meta-analysis included eight randomized controlled trials reporting on a total of 1,024 participants and concluded that robotic-assisted laparoscopic surgery can provide patients with shorter hospital stays, avoiding thromboembolism, blood loss, and transfusions as much as possible, but no significant differences in health-related quality of life, progression-free survival, or OS were seen (37). Enhanced recovery after surgery (ERAS) is currently utilized in various surgical fields, and guidelines on ERAS applicable to patients with BLCA have been established (38). A meta-analysis noted that for patients undergoing radical cystectomy, ERAS performed perioperatively resulted in a shorter hospital stay, faster bowel recovery, as well as a lower incidence of associated complications such as impaired wound healing, fever, and thrombosis (39). However, even with radical cystectomy treatment, patients are still at high risk of recurrence and distant metastasis, with more than half dying within 5 years (40). Currently, several studies recommend cisplatin-based combination neoadjuvant chemotherapy to improve patients’ prognosis and achieve a survival benefit (41). Patients treated with neoadjuvant chemotherapy have a longer median OS (77 vs. 46 months, P=0.06), a higher 5-year survival rate (57% vs. 43%, P=0.06), and a significantly better proportion of patients with no residual disease than those who underwent cystectomy alone (38% vs. 15%, P<0.001) (42). If neoadjuvant chemotherapy is not administered preoperatively, adjuvant chemotherapy is given postoperatively to patients with pT3/4 and/or positive lymph nodes, depending on the pathologic findings. A systematic reviews and meta-analysis incorporating 10 randomized controlled trials demonstrated a benefit of cisplatin-based adjuvant chemotherapy on overall survival [hazard ratio (HR) =0.82, 95% confidence interval (CI): 0.70–0.96, P=0.02]. This represents an absolute improvement in survival of 6% at 5 years, from 50% to 56% (43). Local-regional recurrence (LRR) is a common adverse event in BLCA patients and is strongly associated with the development of distant metastases. When LRR occurs, the median survival of patients is only 9 months (44,45). Postoperative adjuvant immunotherapy has been approved for use in patients with MIBC who are at high risk of postoperative recurrence, and several studies have shown that the use of nivolumab and pabolizumab for postoperative adjuvant therapy is beneficial in improving median disease-free survival (46,47). For patients with BLCA who have developed distant metastases, enfortumab in combination with pembrolizumab is the new standard of care, and related therapeutic options include platinum-based chemotherapy, immunotherapy, monotherapy with antibody-drug couplings, fibroblast growth factor receptor (FGFR) inhibitors, and human epidermal growth factor receptor 2 (HER2)-targeted agents (34). The study shows that brain metastasis is an independent predictor of early death in elderly patients with urothelial carcinoma of the bladder and the single most influential variable. Although cases of BLCA metastasizing to the brain are rare, their prognosis is extremely poor. It has been noted that platinum-based chemotherapy regimens that improve extracranial disease also put BLCA patients at a higher risk of brain metastases. In turn, due to their lower incidence, they are usually treated only after the onset of symptoms (16). Currently, chemotherapy and whole brain radiotherapy are the main treatment for BLCA with brain metastases. A retrospective cohort study noted that patients with BLCA combined with brain metastases who underwent craniectomy, radiotherapy, chemotherapy, and who had good physical fitness had a better prognosis (14). In the future, genome sequencing data from primary tumors and metastatic samples, if available, may help to gain insights into the biology of BLCA with brain metastases to optimize therapeutic outcomes (16,48). The treatment of BLCA is leading to major breakthroughs that make it possible for patients to keep their bladder. In our study, immunotherapy was not used as an influencing factor for early death, which is a shortcoming of the study, and we will continue to optimize and improve our prediction model to make it more reasonable and scientific in future studies.

Tumor size was the last key characteristic in our study. The larger the tumor, the more invasive and the higher the TNM stage. A study has shown that a tumor diameter of ≥30 mm is significantly associated with the risk of postoperative recurrence (15). Therefore, we classified tumor size into ≥30 and <30 mm and validated ≥30 mm as an independent risk factor for early death.

Although this study developed a nomogram that accurately predicts the probability of early death in elderly patients with urothelial carcinoma of the bladder, several limitations remain. First, as a retrospective study, there may be intervention bias and confounding of variables. It often has recall bias, selection bias, and information bias, and some recorded data may be incorrect and we artificially excluded patients who lacked certain information. Second, the SEER database lacked some patient information, such as hypertension, diabetes, family history, and targeted therapy status. These common underlying diseases and familial hereditary diseases will affect the prognosis of patients with tumors. As well, with major advances in the treatment of BLCA, immunotherapy has dramatically improved the prognosis of patients. In addition, this study was only internally validated and lacked external validation. These limitations may mask the true treatment effect and the impact on patient prognosis, which may affect the reliability and generalizability of the results of this study. Nomogram is used as a visualization tool to transform a complex predictive model into an intuitive scoring system, with different components having different predictive values and scores. In future studies, we will focus on the improvement and external validation of the predictive model, including the addition of new important variables (e.g., hypertension, diabetes mellitus, family history, immunotherapy), the collection of local patient data for the validation of the predictive model, and the development of clinically convenient columnar plot scoring scales or apps, which will be beneficial for clinicians to better utilize the predictive model for a full understanding of the patient’s prognosis. For now, the prediction model has provided clinicians with a valuable decision support tool.

Conclusions

In this study, we constructed and validated a predictive model (Nomogram) to accurately predict the clinical prognosis of elderly patients with bladder urothelial carcinoma. Through multifactorial analysis, we systematically identified age, marital status, tumor stage, surgery, radiation, chemotherapy, brain metastasis, and tumor size as independent prognostic factors for the model. The model demonstrated excellent predictive performance in ROC curves, calibration analysis, and DCA assessment. However, it cannot be ignored that there are still some shortcomings in this study, including selection bias and information bias in the retrospective study, the lack of some important risk factors, and the lack of practical application of line graphs in clinical practice. In the future, we will focus on solving these problems: adding important risk factors, external validation, and the practical application of nomogram in clinical practice. We will continue to improve and optimize the predictive model to make it more reliable and generalizable. This predictive tool provides clinicians with an individualized prognostic assessment that can optimize the development of treatment regimens and improve patients’ clinical outcomes and quality of survival.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the TRIPOD reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-225/rc

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-225/prf

Funding: This study was supported by the Hainan Provincial Natural Science Foundation of China (No. 822RC842).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-225/coif). All authors report that this study was supported by the Hainan Provincial Natural Science Foundation of China (No. 822RC842). The authors have no other 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. This 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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