High risk of non-cancer mortality in bladder cancer patients: evidence from SEER-Medicaid

Purpose The objective of this study was to investigate non-cancer causes of death and associated risk factors after bladder cancer (BC) diagnosis. Methods Eligible BC patients were obtained from the SEER database. SEER*Stat software 8.3.9.2 was used to calculate the standardized mortality ratios (SMRs). The proportions of different non-cancer cause of death were calculated and analyzed in different follow-up periods. Multivariate competing risk model was used to analyze the risk factors for death of BC and non-cancer diseases. Results In total, 240,954 BC patients were included and 106,092 patients experienced death, with 37,205 (35.07%), 13,208 (12.45%) and 55,679 (52.48%) patients experienced BC, other cancer and non-cancer disease-related deaths, respectively. Overall SMR for BC patients who died from non-cancer diseases was 2.42 (95% CI [2.40–2.44]). Cardiovascular diseases were the most common non-cancer cause of death, followed by respiratory diseases, diabetes mellitus, and infectious diseases. Multivariate competing risk analysis identified the following high-risk factors for non-cancer mortality: age > 60 years, male, whites, in situ stage, pathological type of transitional cell carcinoma, not receiving treatment (including surgery, chemotherapy, or radiation), and widowed. Conclusions Cardiovascular diseases are the leading non-cancer cause of death in BC patients, followed by respiratory disease, diabetes mellitus and infectious diseases. Physicians should pay attention to the risk of death from these non-cancer diseases. Also, physicians should encourage patients to engage in more proactive self-surveillance and follow up. Supplementary Information The online version contains supplementary material available at 10.1007/s00432-023-04867-z.


Introduction
Bladder cancer (BC) is estimated to account for more than 500,000 new cases and 200,000 deaths per year worldwide. In the United States alone, there are more than 80,000 new cases and 17,000 deaths each year (Richters et al. 2020;Lenis et al. 2020;Siegel et al. 2019Siegel et al. , 2020. With the updating of various anti-cancer treatment strategies, cancer-related mortality has gradually decreased (Kochanek et al. 2019a;Robertson et al. 2018;Jalanko et al. 2020). As a result, non-cancer causes of death are of increasing concern as survival times increase. Studies have shown that non-cancer diseases such as heart disease are the leading cause of non-cancer mortality in cancer patients. In most cancer patients, the mortality rate from non-cancer diseases even exceeds that from primary cancer (Siegel et al. 2021;Abdel-Rahman 2017;Sturgeon et al. 2019).
With the increasing quest for longer survival and higher quality of life, deaths due to non-cancer diseases should be taken into account. Studying non-cancer causes of death allows us to more accurately evaluate the risk of death in patients with cancer. As a result, we can provide early intervention and management. The focus of this study was on standardized mortality ratios (SMRs) for non-cancer causes of death, and on high-risk factors that can contributed to experiencing non-cancer mortality in BC patients.

Data source
Patients information was obtained from the Surveillance, Epidemiology, and End Results (SEER) database, which includes approximately 28% of the general US population, and used the SEER*Stat software 8.3.9.2 to access the database: Incidence-SEER Research Plus Data, 18 Registries (excl AK), Nov 2020Sub (2000-2018 for SMRs.

Patients
We included patients who were pathologically diagnosed with BC between 2000 and 2017. Cases diagnosed by death certificate and autopsy were excluded. Cases with incomplete information were also excluded.

Standardized mortality ratio (SMR)
For patients with BC in the SEER database, we calculated the number of deaths under different variables. The focus of this study was on non-cancer mortality in patients with BC. We classify non-cancer diseases into the following six categories: infectious diseases, diabetes mellitus, cardiovascular diseases, respiratory diseases, digestive diseases, and other non-cancer diseases. Supplementary Table 1 shows the definitions of non-cancer causes of death and the ICD-10 codes for the diseases.
First, the SMRs were calculated for all causes of deaths (BC, other cancers, non-cancer diseases). We then calculated SMRs for non-cancer causes of death for BC patients at different follow-up period (< 1 year, 1-5 years, and > 5 years) after diagnosis, with the distribution of the population and the age (mean ± SD) by variables. SMR was defined as the observed-to-expected ratio; the observation population was defined as patients diagnosed with BC in the United States from 2000 to 2017, which was collected from the SEER database. The competing risk analysis using Fine-Gray model was performed to adjust for confounding effects of age, sex, race, summary stage, year of diagnosis, histologic type, treatment (surgery, chemotherapy, and radiation therapy), and marital status to evaluate risks for non-cancer diseases mortality and BC mortality, and to plot cumulative mortality curves.

Statistical analysis
All analyses were performed using SEER*Stat software (version 8.3.9.2), R 4.1.1 (R foundation for Statistical Computing, Vienna, Austria), and Microsoft Excel 2019 (Microsoft, Redmond, WA). All statistical analyses were two-sided with a p value < 0.05 being considered statistically significant.

Baseline characteristics
Cumulatively, 240,954 eligible BC patients were obtained from the SEER database, of which 106,092 experienced mortality. Among all the causes of death in BC patients, only the proportion of non-cancer diseases increased with increasing follow-up time (Fig. 1) were white. The highest proportion of deaths was observed during the > 5 years follow-up period (41.58%), followed by 1-5 years (40.74%) after diagnosis. Table 1 shows the baseline characteristics of patients with BC who experienced non-cancer mortality: the number of deaths at different follow-up periods (< 1 year, 1-5 years, and > 5 years), and the mean ± SD age at diagnosis. Figure 1 shows the proportion of each cause of death in BC patients at different follow-up period. Figure 2A shows that SMR decreases with increasing follow-up time. At < 1 year follow-up period, the highest SMR was for BC, followed by other cancers, and then non-cancer diseases, while at 1-5 years follow-up period, the SMR for non-cancer diseases surpassed other cancers in second place. Figure 2B shows that SMR increases with increasing year of diagnosis, while BC consistently has the highest level of SMR. Figure 3A shows that the SMR for the six non-cancer diseases decreased with increasing follow-up time, with digestive diseases consistently having the highest SMR, followed by infectious diseases and diabetes mellitus, while cardiovascular diseases consistently having the lowest SMR. Figure 3B shows the proportion of the six non-cancer diseases at different follow-up periods, with cardiovascular diseases consistently having the highest proportion, followed by other non-cancer diseases and respiratory diseases.   Table 3).

Non-cancer causes of death at different follow-up period
The risk of death from non-cancer cause within 5 years after BC diagnosis was significantly higher than in the general population, especially for digestive diseases, infectious diseases, and diabetes mellitus (Table 3).

Non-cancer causes of death by different factors
Subgroup analysis of non-cancer causes of death by clinicopathological features at each follow-up period after BC diagnosis (Supplementary Tables 3-34). Some meaningful findings were as indicated below. higher risk of experiencing death from infectious diseases, and diabetes mellitus. Moreover, blacks were at higher risk of experiencing death from infectious diseases within 1 year after diagnosis, and other races had a significantly higher risk of death from diabetes mellitus within 1-5 years after diagnosis. Over 5 years after BC diagnosis, blacks were at higher risk than the general population for experiencing death from infectious disease and diabetes mellitus (Supplementary Tables 7-9).

Treatment
Treatment is divided into surgery (TURBT: transurethral resection of bladder tumor; PC: partial cystectomy; RC: radical cystectomy), chemotherapy, and radiation therapy. There were 2710 (4.87%) deaths in BC patients who did not receive surgical treatment, 49,655 (89.18%) deaths in patients treated with TURBT, 599 (1.08%) deaths in patients treated with PC, and 2715 (4.87%) deaths in patients treated with RC. The highest proportion of non-cancer deaths in BC patients without surgical treatment was observed 1-5 years after diagnosis (38.49%), and the highest proportion of deaths in patients who received surgical treatment all occurred 5 years after diagnosis.     Tables 21-24).

Marital status
The lowest risk of non-cancer mortality was observed in widowed patients, whereas separated, divorced, and unmarried patients all had a higher risk of non-cancer mortality.

Competing risk analysis
Multivariate competing risk models were used to assess prognostic factors for the development of BC-related death and non-cancer cause of death in BC patients (Table 4) and cumulative mortality (Supplementary Figs. 1 and 2). The risk of both mortalities increased significantly with increasing age, but patients of advanced age appeared to be more likely to experience non-cancer cause of death (

Discussion
Bladder cancer as one of the most common malignancies in urology, patients are often more concerned about BC-related mortality. However, due to continuous medical advances and developments, the overall survival of BC patients has been effectively improved (Richters et al. 2020;Lenis et al. 2020;Marrie et al. 2021), leading to the prominence of deaths from non-cancer diseases (Wang et al. 2022a).
Our study found that non-cancer causes of death from BC accounted for 52.48% of all deaths, with cardiovascular disease being the most common non-cancer cause of death, followed by respiratory disease, diabetes mellitus, and infectious diseases. Published studies showed that cardiovascular disease is one of the leading causes of non-cancer mortality (Du et al. 2021;Oh et al. 2020). Studies show that cancer patients are 2-6 times more likely to die from cardiovascular disease than the general population (Sturgeon et al. 2019). Studies have shown that chemotherapy and radiation therapy for cancer increase heart disease-specific mortality in patients (Yang et al. 2021;Dai et al. 2022;Guan et al. 2021). Meanwhile, other non-cancer diseases such as diabetes mellitus and nephrotic syndrome increase the cardiac burden by altering the body's metabolic status and hemodynamics. The risk of cardiovascular disease mortality in BC patients continues throughout the treatment and follow-up period. Therefore, we recommend more proactive self-observation and follow-up rather than reactive management only at the onset of clinical symptoms or complications, and that such self-observation and follow-up should continue from the start of oncologic treatment and for the rest of the life. The incidence of respiratory disease is higher among cancer patients (Li et al. 2020;Deckx et al. 2012). Among them, pulmonary infections caused by neutropenia are the most common. Published meta-analysis showed that the use of immune checkpoint inhibitors, compared to chemotherapy, significantly increased the incidence of pneumonia (Nishijima et al. 2017). Also, the incidence of chronic obstructive pulmonary disease was significantly higher in cancer patients (Song et al. 2022;. Also, the increase in smoking and air pollution has led to an increase in the incidence of pneumonia or chronic obstructive pulmonary disease in cancer patients. In cancer patients, it is very common for antitumor therapy (e.g., chemotherapy) to cause myelosuppression (Simonaggio et al. 2019). Neutropenia is an independent risk factor for sepsis (Kochanek et al. 2019b). Some studies have shown that cancer patients who have developed sepsis or bacteremia have an approximately 2.3 times higher risk of death than non-cancer patients (Abou Dagher et al. 2017). In addition, Liyanage et al. (2002) and Schreiber et al. (2011) showed that tumors can also cause an increased risk of infection in cancer patients through metastatic invasion and mechanical damage to the immune system.
The relationship between BC and diabetes mellitus should not be underestimated. Patients with a long history of impaired fasting glucose or diabetes mellitus are at significantly higher risk of BC due to diet, obesity and other factors (Choi et al. 2022;Lam et al. 2021;Gill et al. 2021). A metaanalysis suggests that diabetes mellitus has an increased risk of disease progression, recurrence and death in BC patients (Lu and Tao 2021). Meanwhile, our study showed a significantly higher SMR for diabetes mellitus -related deaths among BC patients, consistent with published studies. In addition, some studies have suggested that metformin use is associated with a better prognosis in non-muscle invasive BC (Wang et al. 2022b;Liu et al. 2022;Klose et al. 2021), but larger population studies are needed to confirm this.
Multivariate competing risk analysis showed that patients with BC are at significantly higher risk of experiencing death from non-cancer causes compared to the general population, with potential risk factors including: age > 60 years, male, whites, in situ stage, pathological type of transitional cell carcinoma, not receiving treatment (including surgery, chemotherapy, or radiation), and widowed. Therefore, for high-risk patients, we recommend aggressive treatment and follow-up. It is estimated that primary prevention of 30-40% of cancers can be achieved by modifying lifestyle and environmental risk factors known to be associated with cancer incidence. A healthy lifestyle, including reducing smoking, low BMI, being physically active, avoiding excessive alcohol consumption and maintaining a healthy nutrition are the best strategies to prevent and treat non-cancer diseases (Zhang et al. 2020).
Our study is limited by the inherent bias of the SEER database and the fact that this is a retrospective study without external validation. We reduce bias due to factors such as age, sex, and race by strictly controlling inclusion criteria and using SMR, while quantitatively assessing the impact of different factors on non-cancer mortality in BC patients through multivariate competing risk analysis. However, our inability to know whether patients had relevant noncancerous diseases before diagnosis and the lack of data on some high-risk factors, such as smoking, alcohol consumption, and lifestyle, led to certain shortcomings in our study. Therefore, future high-quality studies are needed to explore the major causes of non-cancer mortality in BC patients and the associated risk factors.

Conclusion
Non-cancer diseases accounted for the highest proportion of deaths during each follow-up period after BC diagnosis, with cardiovascular diseases being the most common causes. SMR for non-cancer causes of death decreased progressively with increasing follow-up time and was approximately 7.5 times higher within 1 year than 1-5 years after diagnosis. Additionally, the risk of non-cancer causes of death in BC patients is impacted by a number of factors that are inherently heterogeneous, such as age, gender, treatment modality (surgery, chemotherapy, and radiation therapy), and marital status. Therefore, physicians should pay attention to the risk of death from non-cancer diseases. Also, physicians should encourage patients to engage in more proactive self-surveillance and follow up.

Consent for publication Not applicable.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.