Association between Smoking and Overall and Specific Mortality in Patients with Bladder Cancer: A Population-based Study

INTRODUCTION

There are projected to be about 83,730 newly diagnosed bladder cancer patients in 2021 in the United States [1]. Bladder cancer was ranked sixth among all cancers in terms of incidence [1]. In addition, the number of bladder cancer-specific deaths was approximately 17,200, which ranked tenth among all types of cancer [1]. In Taiwan, bladder cancer is the ninth most common cancer, with approximately 1,600 new cases every year [2]. Cigarette smoking exposure is a major risk factor for bladder cancer; increasing the risk for bladder cancer by two- to fourfold [3, 4]. A recent study found that about 50% of young men and 10% of young women were smokers, and relatively few quit [5]. In Taiwan, although the government has implemented the 2009 Tobacco Hazards Prevention Act, tax increases, and warnings on tobacco packages, the smoking prevalence remains at 23.4% in men and 2.4% in women [2]. Thus, smoking is a considerable burden to Taiwan’s health and economy.

Approximately 75% of patients with bladder cancer are with diagnosed with non-muscle-invasive bladder cancer (NMIBC) and are then treated with transurethral resection of bladder tumor (TURBT) followed by intravesical therapy [6]. In contrast, muscle-invasive bladder cancer (MIBC), which accounts for approximately 25% of newly diagnosed bladder cancers, is usually treated with radical cystectomy (RC) or trimodal therapy with maximal transurethral resection of the bladder tumor followed by concurrent chemoradiotherapy [6]. Continuous smoking is an independent predictor of disease recurrence in patients with either NMIBC and MIBC [3, 7, 8]. Several studies have reported a high mortality rate in patients who underwent RC [8, 9]. However, conclusive evidence of an association between smoking and mortality in NMIBC is lacking [7, 10].

Smoking can significantly impact the clinical man-agement bladder cancer. Therefore, we used the Taiwan’s National Health Insurance Research Database to conduct a propensity score-matched study with a long-term follow-up period. We compared the risk for overall and specific mortalities associated with bladder cancer patients who had a history of smoking with matched cohorts using this nationwide database.

MATERIALS AND METHODS

Definitions of study subjects

Patients with bladder cancer between 2000 and 2017 were selected from the TCR using the International Classification of Diseases for Oncology, 3rd edition (ICD-O-3): C67. Smoking information was included in the TCR from 2011; thus, patients who were diagnosed with bladder cancer before 2011 were excluded. In addition, patients with incomplete information in the TCR were excluded from this study. A flowchart summarizing the selection of study subjects is presented in Fig. 1.

Fig. 1

Flow chart.

RESULTS

This study involved 9,456 patients who had bladder cancer after matching. The never-smoke and the ever-smoke groups each included 4,728 patients. The baseline characteristics of the never- and ever-smoke groups are shown in Table 1. The mean age of patients was 67.8 years. In addition, most of them were male (96.9%). Moreover, patients who were ever smokers showed a higher incidence of drinking wine and consuming betel nut than those who were never smokers (14.45% and 17.51%, respectively; P < 0.0001). More patients who were ever smokers were at the last clinical cancer stages (2, 3, 4; MIBC) compared to those who were never smokers (32.99% vs. 29.72%; P = 0.0006). Overall and specific mortality rates were significantly higher in patients who were ever smokers than in those who were never smokers (overall, 27.37% vs. 24.05%; P = 0.0002; specific, 13.9% vs. 12.25%; P = 0.0173).

Table 2 displays the finding that smoking is an independent risk factor for the overall and specific mortalities in patients with bladder cancer. The overall mortality rate in the patients who were ever smokers was 1.15-fold (95% confidence interval [CI], 1.06–1.26, P = 0.0014) adjusted HR compared with that of those who were never smokers. In addition, the specific mortality rate of the patients who were ever smokers was 1.16-fold (95% CI, 1.03–1.30, P = 0.0176) adjusted HR compared with those who were never smokers. The result was compatible with the Kaplan–Meier plotted the trend of overall and specific mortality between never smokers and ever smokers, as shown in Fig. 2. The overall and specific mortality rates were significantly higher in the patients who were ever smokers than in those who were never smokers (log-rank test, P = 0.0001 and P = 0.0083, respectively) during the follow-up period.

Fig. 2

Kaplan-Meier plot of overall mortality among never smokers and ever smokers.

Table 2 also summarizes the risk factors for the overall and specific mortality rates of patients with bladder cancer. There was a significantly higher overall mortality rate in patients with bladder cancer with an underweight BMI {< 18.5; adjusted HR (95% CI): 1.65 (1.46–1.87); P < 0.0001}, a higher CCI {1–2 or ≥3; adjusted HR (95% CI): 1.14 (1.01–1.29), 1.28 (1.04–1.59); P = 0.0315 and 0.023}, and MIBC {adjusted HR (95% CI): 3.40 (3.09–3.73); P < 0.0001}. In addition, there was a significantly higher cancer-specific mortality rate in bladder cancer patients with an underweight BMI {< 18.5; adjusted HR (95% CI): 1.54 (1.29–1.84); P < 0.0001}, and MIBC {adjusted HR (95% CI): 6.71 (5.82–7.74); P < 0.0001}.

Table 3 shows the risk factors for the overall and specific mortalities associated with ever-smoke bladder cancer patients. Compared with never-smoke male patients, ever-smoke male patients exhibited a 1.16-fold and 1.17-fold adjusted HRs of overall and specific mortality rates (P = 0.0007 and 0.0145, respectively). Ever-smoke bladder cancer patients also had an increased overall and specific mortality rates by 1.31-fold and 1.55-fold adjusted HRs compared with non-smoking bladder cancer patients among those with a CCI≥3 (P = 0.0119 and 0.0092, respectively). Moreover, ever-smoke NMIBC patients exhibited a 1.21-fold and a 1.47-fold adjusted HRs for the overall and specific mortality rates compared with those of never-smoke patients (P = 0.0038 and 0.0014, respectively). Furthermore, we followed up comorbidity risks for bladder cancer; results are listed in Appendix 2. Having DM resulted in a 1.27-fold and a 1.28-fold adjusted HRs in the overall and specific mortality of ever-smoke patients (P = 0.0046 and 0.0419, respectively). Having hypertension also resulted in a 1.19-fold adjusted HRs in the overall mortality of ever-smoke patients (P = 0.0105). Regardless of the subsequent treatment for patients with bladder cancer, smoking increased the risk for overall mortality, and significant differences exist in operation and chemotherapy. (1.10-fold and 1.25-fold in the overall mortality, respectively; P = 0.0387 and 0.0163).

DISCUSSION

Bladder cancer is a common cancer worldwide. Previous studies reported that cigarette smoking may lead to a large primary tumor size, a higher clinical stage, and a higher pathological grade upon initial diagnosis of bladder cancer [18, 19]. In addition, smoking also contributes to the development of bladder cancer [3, 4] and influences outcomes. Over the past few years, several reviews investigated the course of smoking-influenced bladder cancer [7–10]. However, most studies investigated the oncological outcomes in patients receiving TURBT operations NMIBC or RC in MIBC. They only reported that cigarette smoking exposure increased the risk of disease recurrence. Conclusive evidence to support the relationship of smoking and the overall or cancer-specific mortality remains lacking. In the present study, the ever-smoke patients had higher clinical stages at initial diagnosis of bladder cancer (P = 0.0006) and had significantly worse overall and specific mortality rates (P = 0.002 and 0.017, respectively) compared with never-smoke patients. Subgroup analyses of NMIBC and MIBC revealed that the patients who were ever smokers had significantly increased overall and specific mortality rates (P = 0.0039 and 0.0015, respectively) in NMIBC. Although patients with MIBC who were ever smokers had a similar outcome that increased by 1.12-fold in terms of overall mortality and by 1.07-fold in terms of cancer-specific mortality, the difference was not significant (P = 0.0553 and 0.3669, respectively). As shown in Appendix 3, the patients who were ever smokers receiving TURBT in NMIBC had worse overall and cancer-specific mortality rates compared with patients who were never smokers (P = 0.0069 and 0.0026, respectively). Cigarette smoking exerted no significant influence on any treatment in MIBC. In general, bladder cancer is a complex and heterogeneous disease. Subset analyses of particular clinical stages with different treatment modalities are currently lacking. Therefore, several study-related and general limitations should be addressed in future research.

Urologists must identify risk factors that can predict cancer progression, including cancer-specific and all-cause mortality rates, to help in patient counseling and to select further treatment [14, 15]. The present study identified risk factors for overall and cancer-specific mortalities associated with bladder cancer patients who were ever-smokers. They had a significantly higher overall and cancer-specific mortality rates, especially men, those with a CCI≥3, those with a DM comorbidity, and those with NMIBC. Factors for sex differences in bladder cancer incidence and survival, which was higher in men, were related to a few factors likely acting in combination, such as differences in access to health care, delayed diagnosis probably due to hematuria, or lower urinary tract symptoms being attributed to cystitis in women, occupational exposure, and smoking patterns [16, 17]. We identified several studies of sex-specific differential effects of smoking in patients with bladder cancer treated with TURBT or RC. In a cohort of 286 patients, Fleshner et al.[20] determined that continued smoking in men was associated with a diminished time to recurrence (HR: 1.40; 95% CI, 1.03–1.91) and diminished survival free of adverse events (P = 0.14). Rink et al. [8] reported that female smokers receiving RC for bladder cancer were more likely to experience disease recurrence (HR: 1.58, P < 0.001), cancer-specific mortality (HR: 1.67, P < 0.001), and any cause mortality (HR: 1.63, P < 0.001) compared with their male counterparts. These findings suggested that the effects of smoking on patient outcomes occurred more in one sex compared with the other [21]. In the present study, for the higher smoking prevalence rate of men in Taiwan (males: 23.4% and females: 2.4%) [2], we adjusted for confounding factors such as age and sex by using the multivariate analysis step-bystep to reduce these biases. As shown in Table 2, women with bladder cancer had higher overall and specific mortality rates than men, but there was no significant difference. However, ever-smoke men with bladder cancer showed significantly higher overall and specific mortality rates than their never-smoke counterparts, as shown in Table 3 (P = 0.0007 and 0.0145, respectively).

The CCI is a tool used for calculating comorbidities and therefore mortality risk. For bladder cancer, a higher CCI was associated with a higher mortality rate [22]. Ever-smoke patients had a significantly higher mortality rate. DM was also a risk factor for bladder cancer. It was associated with cancer incidence and poor prognosis [23–25]. In the present study, bladder cancer patients with DM who were ever-smokers had a multiplier effect, which significantly increased the overall and specific mortality rates.

Several large cohorts and case–control studies noted that smoking cessation enabled an immediate decrease in risk for bladder cancer [26]. Smoking cessation and the time since quitting favorably affected the risk for bladder cancer incidence and the prognosis [8, 27]. For many patients, a cancer diagnosis motivated them to successfully quit smoking. Patients with bladder cancer were often willing to quit smoking with the help of their physicians [28]. A survey of 601 urologists found that more than half of them never discussed smoking cessation with their patients, and almost one in four believed that cessation did not impact disease prognosis [29]. Appropriate patient education and physician meetings may increase the probability to quit smoking, improve outcomes, and enhance the quality of life [30]. Urologists must focus on smoking cessation and help patients stop smoking as soon as possible.

This study has several limitations. The retrospective nationwide database did not contain detailed smoking information, such as smoking duration, age of first exposure, number of cigarettes smoked, date of cessation, tobacco type, and whether smoking cessation occurred after diagnosis [27–32]. Tumor-related information was also lacking, including tumor histological data, different treatments in each stage, and recurrence condition. Further, some risk factors that are often associated with bladder cancer were unable to be included, such as environmental exposure, family history, and socioeconomic status [33, 34]. Due to the small proportion of women with bladder cancer [1] and the low population of female smoking in Taiwan [2], there were few female patients after matching in our study. Regarding women, the correlation between smoking and mortality will need to be investigated further in the future. Last, all patients were treated in the Taiwanese medical system, indicating a potential lack of generalizability, although some studies have confirmed the accuracy of the information in Taiwan’s National Health Insurance Research Database [35], and some topics which were discussed in our study have been published internationally, such as bladder cancer [36] and smoking [37].

In conclusion, smoking behavior directly contributes to the increased overall and cancer-specific mortality rates of patients with bladder cancer. It is also a risk factor along with other factors such as a male sex, a CCI≥3, a DM comorbidity, and NMIBC.