|Year : 2020 | Volume
| Issue : 3 | Page : 123-130
Smoking behavior and survival outcomes in bladder cancer patients
Wei-Chung Chu, Chung-Hsin Chen
Department of Urology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
|Date of Submission||04-Dec-2019|
|Date of Decision||07-Feb-2020|
|Date of Acceptance||08-Mar-2020|
|Date of Web Publication||26-Jun-2020|
Department of Urology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei; No.1, Changde St., Zhongzheng Dist., Taipei City 10048
Source of Support: None, Conflict of Interest: None
Purpose: The purpose of this study was to compare the survival outcomes of bladder cancer patients with different smoking behaviors.
Materials and Methods: Between January 2011 and December 2014, a total of 565 bladder cancer patients were included from one institute retrospectively. Regarding smoking behavior, among these patients, 337 were nonsmokers, 52 were “quitters” (patients who had quit smoking ≥10 years ago), 54 were ex-smokers (patients who had quit smoking <10 years ago), and 117 were current smokers. We compared the clinicopathological characteristics and survival outcomes among these four groups.
Results: In this cohort, the 3-year overall survival (OS) (95% confidence interval [CI]) of the nonsmoker, quitter, ex-smoker, and current smoker groups were 75.6% (95% CI: 72.9%–78.3%), 67.4% (95% CI: 59.8%–75%), 84.1% (95% CI: 78.9%–89.3%), and 83.2% (95% CI: 79.3%–87.1%), respectively. Nonsmoker patients included a higher number of females, and quitters were older than the patients in the other groups. Larger tumors in quitters and higher clinical stages in ex-smokers were observed more frequently than in the patients of the other groups. Compared with nonsmokers, quitters, and ex-smokers, current smokers had no impact on OS (P = 0.541, 0.406, and 0.175, respectively) nor on cancer-specific survival (CSS) (P = 0.631, 0.388, and 0.193, respectively). Higher diagnostic age, being underweight, larger tumor sizes, and higher clinical stages were independent factors predicting OS.
Conclusion: Smoking behavior seemed to not directly contribute to the deterioration of overall or CSS duration in patients with bladder cancer.
Keywords: Bladder urothelial carcinoma, smoking, survival
|How to cite this article:|
Chu WC, Chen CH. Smoking behavior and survival outcomes in bladder cancer patients. Urol Sci 2020;31:123-30
| Introduction|| |
Bladder cancer is the fourth most common cancer in men in the United States, with an estimated 61,700 new cases (7% of all newly diagnosed cancer cases) annually in the United States in 2019. Bladder cancer is the tenth most common cancer in Taiwanese men, with an estimated 1,510 new cases in 2015, representing a considerable burden to the country's health and economy.
Tobacco contains more than 60 carcinogens, causes at least 18 types of cancer, and is the second leading risk factor for death., Tobacco exposure is also the major risk factor for bladder cancer. Tobacco exposure increases the risk of bladder cancer two- to fourfold., Continuous smoking is associated with higher disease recurrence, and mortality rates., However, some studies have revealed that smoking does not affect disease-free interval and the adverse event-free survival rate in patients with bladder cancer.
The smoking rate in Taiwanese male adults is approximately 40%. However, only a few articles have been published on smoking behavior and survival outcomes of bladder cancer in Taiwan. Therefore, we attempted to determine whether smoking behavior affects the overall survival (OS) and cancer-specific survival (CSS) of patients with bladder cancer. In our study, smoking behavior seemed to not directly contribute to the deterioration of OS or CSS duration in patients with bladder cancer. Furthermore, patients who stopped smoking for 10 years or more (“quitters”) had noninferior OS and CSS rates compared with nonsmokers.
| Materials and Methods|| |
Between January 2011 and December 2014, a total of 570 patients who were newly diagnosed with bladder cancer were included from the National Taiwan University Hospital. Patients diagnosed with squamous cell carcinoma (n = 1), adenocarcinoma (n = 2), or other minor pathological types (n = 2 for both fibrosarcoma and small cell carcinoma) were excluded. Only patients (n = 565) with bladder urothelial carcinoma were enrolled in the final cohort. This study was approved by the Research Ethics Committee of National Taiwan University Hospital (approval no. 201305059RINC) and the patient informed consent was exempted from the committee.
Patients' clinical demographics, such as gender, diagnostic age, body mass index (BMI), comorbidities, clinical stage, and pathological stage, were obtained from medical records. BMIs were grouped according to the BMI grouping definition provided by the Taiwan Health Promotion Administration. Tumor grades and stages were categorized according to the World Health Organization/International Society of Urological Pathology system (fourth edition) and the American Joint Committee on Cancer/Union for International Cancer Control system (eighth edition).
Information regarding smoking behavior, including smoking amount (defined as number per day), smoking years, and years of quitting smoking, were documented thoroughly. According to the aforementioned information, patients were further classified into four groups: (1) nonsmokers, who had never smoked, (2) ex-smokers, who had stopped smoking for <10 years before the diagnosis of bladder cancer, (3) quitters, who had permanently stopped smoking for ≥10 years before diagnosis, and (4) current smokers.
Patients' survival information, including death, cause of death, and date of death, was matched with the death registry database of the Bureau of Health Promotion, Department of Health, Executive Yuan, Taiwan. The final date for determining death was December 31, 2015. OS and CSS were defined as the interval between the date of bladder cancer diagnosis and death due to all causes or bladder cancer, respectively.
Statistical analysis was performed using SPSS version 12 (SPSS Inc., Chicago, IL, USA). The Kaplan–Meier method and log-rank test were used to analyze survival outcomes. The Kruskal–Wallis rank test was used to compare medians among the patient groups. All statistical tests were two-tailed, and P < 0.05 was considered statistically significant.
| Results|| |
In this bladder cancer cohort, there were 337 nonsmokers, 54 ex-smokers, 52 quitters, and 117 current smokers. Among the patient groups, nonsmokers included a higher number of females (P < 0.001). Quitters were older than the patients in the other groups (median age of 77, 70, 71, and 65 years for quitters, nonsmokers, ex-smokers, and current smokers, respectively, P < 0.001). Nonsmokers and quitters had a higher rate (23.7% and 17.3%, respectively) of chronic kidney disease (P < 0.05) than ex-smokers and current smokers. Quitters had a higher rate of chronic obstructive pulmonary disease (P < 0.001) than nonsmokers. All other variables were similar among the groups [Table 1].
The clinicopathological characteristics are shown in [Table 1].
Larger tumors were more often observed in quitters than in the patients of the other groups (median size: 45, 26, 26, and 31 mm for quitters, nonsmokers, ex-smokers, and current smokers, respectively, P = 0.047). Higher clinical stages were noted in ex-smokers than in nonsmokers (P = 0.017). No difference was observed in tumor grades among the groups.
A total of 113 (20%) patients in our cohort died during a median follow-up of 27.3 months. In the nonsmoker group, 21.07% of the patients died. Compared with the nonsmoker group, no significant differences in mortality rates were observed among the patients of the quitter group, ex-smoker group, or current smoker group (30.77%, 14.81%, and 14.53%, respectively). The 3-year OS (95% CI) of nonsmokers, quitters, ex-smokers, and current smokers was 75.6% (72.9%–78.3%), 67.4% (59.8%–75%), 84.1% (78.9%–89.3%), and 83.2% (79.3%–87.1%), respectively.
Based on the Cox proportional hazards model for OS, older diagnostic age, previous cerebrovascular accident event, chronic kidney disease history, underweight status (BMI <18.5 compared with 18.5 ≤BMI <24 as the standard, P < 0.001), larger tumor sizes, higher tumor grades, and higher clinical stages were predictors of poorer OS [Table 2]. Other univariate variables had no impact on the OS outcome.
|Table 2: Univariable and multivariable analyses of overall survival in bladder cancer patients|
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Variables that reached P < 0.1 in the univariate analysis were then assessed in a multivariable analysis using the Cox proportional hazards model. Smoking behavior of the quitter, ex-smoker, and current smoker groups had no impact on OS compared with that of the nonsmoker group (P = 0.541, 0.406, and 0.175, respectively). Older diagnostic age, underweight status, larger tumor sizes, and higher clinical stages were independent factors predicting OS. Stratification of the smoking amount was performed. The results are shown as model 2 and are not changed a lot [Table 2].
Regarding CSS, a total of 71 (12.7%) patients in our cohort died. In the nonsmoker group, 13.35% of the patients died due to bladder cancer. Compared with the nonsmoker group, differences in mortality rates remained statistically nonsignificant among the patients of the quitter, ex-smoker, and current smoker groups (19.23%, 11.11%, and 8.55%, respectively). The 3-year CSS (95% CI) of nonsmokers, quitters, ex-smokers, and current smokers was 83.4% (81%–85.8%), 81.5% (75.9%–87.1%), 87.4% (82.5%–92.3%), and 89.8% (86.7%–92.9%), respectively. Older diagnostic age, chronic kidney disease history, underweight status (BMI <18.5 compared with 18.5 ≤BMI <24 as the standard, P = 0.023), larger tumor sizes, higher tumor grades, and higher clinical stages remained prognostic of poorer CSS [Table 3]. Variables that reached P < 0.1 in the univariate analysis were also assessed in a multivariable analysis. Smoking behavior remained statistically nonsignificant for CSS (nonsmokers in comparison with P = 0.631, 0.388, and 0.193 for quitters, ex-smokers, and current smokers, respectively). Older diagnostic age, underweight status, larger tumor sizes, and higher clinical stages independently predicted the CSS outcome. Stratification of the smoking amount was also performed and shown as model 2. The results are also similar [Table 3].
|Table 3: Univariable and multivariable analyses of cancer-specific survival in bladder cancer patients|
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A large portion of the non-smokers in our study was female. To compare the factor of smoking behavior to patient survival without confounding factor of sex, we further performed an analysis excluding female patients. The results did not change a lot [Supplemental Table 1] and [Supplemental Table 2].
Comparing survival outcomes between nonsmokers and quitters
Differences in OS and CSS between nonsmokers and quitters (patients who had stopped smoking for ≥10 years) were also compared. Compared with the nonsmoker group, the quitter group showed a noninferior difference in the OS and CSS results (21.07% vs. 30.77% and 13.35% vs. 19.23%, P = 0.569 and 0.477, respectively). For the quitter group, older diagnostic age, diabetes mellitus, underweight status (BMI <18.5), higher clinical stages, and larger tumor sizes predicted poorer OS [Table 4]. Older diagnostic age, underweight status (BMI <18.5), higher clinical stages, and larger tumor sizes remained prognostic of poorer CSS outcomes in the quitter group [Table 5].
|Table 4: Univariable and multivariable analyses of overall survival in nonsmokers versus quitters|
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|Table 5: Univariable and multivariable analyses of cancer-specific survival in nonsmokers versus quitters|
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| Discussion|| |
In our study, nonsmokers comprised a higher number of females, and quitters were older than the patients in the other groups. At diagnosis, higher clinical stages were noted in ex-smokers than in nonsmokers. We found that smoking behavior did not directly contribute to the deterioration of OS or CSS duration in patients with bladder cancer.
Previous studies have reported that cigarette smoking may lead to larger primary tumor size, higher clinical stages,, and higher pathological grades, at the initial diagnosis of bladder cancer. Our study also found a similar result of significantly larger tumor sizes in quitters compared with nonsmokers (P = 0.01, 19 mm larger). Larger tumor sizes were also observed in current smokers compared with nonsmokers, although this did not reach statistical significance. In terms of clinical stages at initial diagnosis, we identified that ex-smokers had a higher stage than nonsmokers (P = 0.017). Quitters and current smokers also presented nonsignificant higher stages than nonsmokers. Therefore, smoking histories, including those for current smokers, ex-smokers, and quitters, were associated with high tumor stages. Nevertheless, our research did not demonstrate a greater proportion of high-graded cancer in those with a smoking history compared with nonsmokers. This discrepancy between our study and previous cohorts may be due to sample sizes and the higher proportion of high tumor stages. Another possibility includes differences in carcinogens between Taiwan and the rest of the world. Certain specific carcinogens, such as inorganic arsenic and aristolochic acid, are possibly responsible for bladder cancer among patients who do not smoke. Based on a previous report, aristolochic acid-induced urothelial cancer was associated with nonsmokers and resulted in similar tumor grades and stages compared with nonaristolochic acid-induced tumors.
In our study, quitters are older than ex-smokers and current smokers. Owing to this reason, quitters may ask for medical help later than the other two groups, thus resulting in larger tumors at diagnosis. However, the condition does not cause poorer outcome according to our study. Similarly, ex-smokers are older than current smokers, and this may result in a higher tumor stage. This bias may be caused by the relatively small sample size or the differences of medical-seeking behavior.
To our knowledge, environmental factors are the most important risk factors for bladder cancer. Bladder cancer is caused by the exposure of the surface epithelium (urothelium) that lines the urinary tract to potential carcinogens that are excreted into the urine. This “field effect” hypothesis explains the multifocal feature of urothelial carcinomas of the urinary tract, of both the bladder and the upper urinary tract. Among the environmental factors, chemical carcinogens play an essential role. Diesel exhaust and hair dyes are both well-proven substances that may increase the risk of bladder cancer. Another well-identified chemical carcinogen is cigarette smoke. Approximately 50% of all bladder cancers are attributable to smoking, and smoking may result in more aggressive initial tumor presentations. Furthermore, Chen et al. showed that continued smoking increased the recurrence rate of nonmuscle-invasive bladder cancer and emphasized the importance of cigarette cessation. This research shows that cigarette smoke is a key factor for bladder cancer.
In our study, the nonsmoker group had a higher number of females. This may be due to the higher smoking prevalence rate of men in Taiwan (males: 23.4% and females: 2.4%). In the nonsmoker group, both genders were exposed to environmental factors other than tobacco, and thus, the proportion of both genders was identical. In Taiwan, women have a longer life expectancy than men (83.7 vs. 77.3 years of age). Compared with our study, other studies, have not presented a higher number of females in the nonsmoker group. Besides, the diagnostic age was older among quitters, who were patients who had stopped smoking for more than 10 years. To reduce these biases, we adjusted the confounding factors, such as age and gender, using multivariate analysis step by step.
For many cancers, smoking not only increases the risk of developing the disease but also causes poorer outcomes. In the field of urology, smoking decreases CSS of renal cell carcinoma patients relative risk (RR: 1.23, P = 0.01). For lung cancer, a large study that included 202,248 patients over 25 years in the United States reported conspicuous OS benefits over smokers by 14.6-fold in men and 17.8-fold in women. For cancers of the gastrointestinal tract, previous research has shown significant OS differences between nonsmokers and current smokers (hazard ratio: 1.29) in colorectal cancer patients. Compared with other cancers, our study showed that smoking resulted in more aggressive presentations at diagnosis but did not directly affect OS and CSS in bladder urothelial carcinoma.
There are several limitations in this study. First, the retrospective nature may make the accuracy of the data inferior to that of a prospective study. Our structured questionnaires may partially compensate for this shortcoming. Second, the low prevalence of smoking rates in female population limits the use of propensity-matched method. Third, the relatively small sample size cannot provide sufficient statistical power. Therefore, a nation-wide database can help resolve this limitation in the future. Fourth, our cohort does have some significant differences among demographics. We performed multivariable analysis attempting to adjust such difference. However, some results contrary to our knowledge such as tumor sizes and tumor stages still cannot be adjusted. Fifth, selection bias exists while we tried to enroll quitters, who are patients that stopped smoking for more than 10 years. This may result in having quitters older than the rest of the groups, and this may further influence clinicopathological outcomes at diagnosis. Sixth, the relatively short observation window limited the determination of survival outcomes. Seventh, the hospital-based cohort may impede the extension of the study conclusion to the general population. Eighth, our database does not contain the detailed information of occupation, which may also be a factor contributing to bladder cancer survival outcomes.
| Conclusion|| |
Smoking behavior did not directly contribute to the deterioration of OS or CSS duration in patients with bladder cancer. A large nation-wide cohort is still required to further investigate the outcomes of bladder cancer patients.
The authors acknowledge Point Blank Advertising Pvt. Ltd. (Mumbai, India) for medical writing assistance.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]