Elsevier

European Urology

Volume 70, Issue 3, September 2016, Pages 458-466
European Urology

Platinum Priority – Collaborative Review – Urothelial Cancer
Editorial by Mark P. Purdue and Debra T. Silverman on pp. 467–468 of this issue
The Role of Tobacco Smoke in Bladder and Kidney Carcinogenesis: A Comparison of Exposures and Meta-analysis of Incidence and Mortality Risks

https://doi.org/10.1016/j.eururo.2015.06.042Get rights and content

Abstract

Context

Tobacco smoke includes a mix of carcinogens implicated in the etiology of bladder cancer (BC) and renal cell cancer (RCC).

Objective

We reviewed the impact of tobacco exposure on BCC and RCC incidence and mortality, and whether smoking cessation decreases the risk.

Evidence acquisition

A systematic review of original articles in English was performed in August 2013. Meta-analysis of risks was performed using adjusted risk ratios where available. Publication bias was assessed using Begg and Egger tests.

Evidence synthesis

We identified 2683 papers, of which 107 fulfilled our inclusion criteria, of which 83 studies investigated BC and 24 investigated RCC. The pooled relative risk (RR) of BC incidence was 2.58 (95% confidence interval [CI] 2.37–2.80) for all smokers, 3.47 (3.07–3.91) for current smokers, and 2.04 (1.85–2.25) for former smokers. The corresponding pooled RR of BC disease-specific mortality (DSM) was 1.47 (1.24–1.75), 1.53 (1.12–2.09) and 1.44 (0.99–2.11). The pooled RR of RCC incidence was 1.31 (1.22–1.40) for all smokers, 1.36 (1.19–1.56) for current smokers, and 1.16 (1.08–1.25) for former smokers. The corresponding RCC DSM risk was 1.23 (1.08–1.40), 1.37 (1.19–1.59), and 1.02 (0.90–1.15).

Conclusions

We present an up-to-date review of tobacco smoking and BC and RCC incidence and mortality. Tobacco smoking significantly increases the risk of BC and RCC incidence. BC incidence and DSM risk are greatest in current smokers and lowest in former smokers, indicating that smoking cessation confers benefit. We found that secondhand smoke exposure is associated with a significant increase in BC risk.

Patient summary

Tobacco smoking affects the development and progression of bladder cancer and renal cell cancer. Smoking cessation reduces the risks of developing and dying from these common cancers. We quantify these risks using the most up-to-date results published in the literature.

Introduction

Tobacco smoke is the commonest human carcinogen. The World Health Organization estimates that in 2013 there were more than one billion smokers worldwide [1] and approximately six million people die each year from tobacco-related illnesses. These deaths include an estimated one million nonsmokers who obtained exposure indirectly from environmental tobacco smoke or secondhand smoking (SHS) [1]. The majority of smoking-related deaths occur because of cardiovascular and pulmonary diseases or malignancies. The risk of tobacco-related illnesses varies with the duration and intensity of smoking [2], the type of tobacco and mode of administration, and an individual's ability to detoxify carcinogens. Tobacco can be consumed in a variety of forms such as smoking cigarettes, cigars, pipes, and shisha (a molasses-tobacco hybrid compound), chewing, and inhalation as snuff, and can be used in isolation or in combination with illicit drugs such as opium and marijuana [3]. Tobacco can be prepared via flue (blonde) or air curing (black). The latter is considered to be more carcinogenic to the urinary tract owing to its higher concentration of nitrosamines, biphenyls, and arylamines [2], [4], [5]. With regard to carcinogen detoxification, variations in the activity of N-acetyl-transferase 2 (NAT2) and glutathione S-transferase mu μ1 (GSTM1) because of polymorphisms appear to affect cancer risk from smoking [6]. It is also evident that tobacco smoke can induce changes in the DNA damage response machinery, which can additively or synergistically impair the host response to carcinogens [7], [8].

Bladder cancer (BC) and renal cell cancer (RCC) are among the commonest smoking-related human malignancies. In 2013 there were an estimated 382 700 new cases of BC and 338 000 of RCC worldwide, with 143 000 and 150 300 resultant deaths, respectively [9], [10]. Both tumors are more common in males than females, reflecting the role of tobacco smoking, occupational carcinogen exposure, and lifestyle in their etiology. Tobacco smoke inhalation appears to be the commonest risk factor for BC, accounting for approximately 50% of BC cases [6] and 20–25% of RCC cases [11]. Further risk factors for RCC include obesity and hypertension. For both cancers, risk may be modified by genetic predisposition and interaction with further carcinogens [12], and altering smoking exposure may change the natural history of the disease. For example, smoking cessation may reduce BC recurrence rates [13], although conflicting data exist [14], [15]. Regardless of this contradiction, smoking-induced DNA damage (as detected in either blood or urine) reduces to normal levels after cessation [16].

Here we present a systematic review of the literature and meta-analysis of the associations between smoking and both BC and RCC. We analyze both incidence and mortality, and specifically combine risks for SHS and non–smoking-related tobacco exposures. Owing to the causal relationship between active smoking and BC, there has been strong reason to suspect that SHS (also known as environmental tobacco smoke or passive smoking) has a role in carcinogenesis. The strength of this association has been emphasized by evidence that urinary levels of carcinogens are greater in subjects exposed to SHS than those not subjected to this exposure [16].

Section snippets

Systematic review

We searched PubMed in August 2013 for all original articles in English using the string terms “tobacco”, “smoking” AND “bladder cancer”, and “tobacco”, “smoking” AND “kidney cancer”. Articles were included in the meta-analysis if they met the following inclusion criteria: (i) case-control, cohort, or nested case-control studies published as original articles in English investigating the relationship between smoking and the risk of BC or RCC in humans; (ii) incidence or disease-specific

Evidence synthesis

Our search identified 2683 reports (1237 BC, 225 RCC, 8 both, and 1213 unrelated cancers). All abstracts were read in full by one author (M.G.C.) before selection of 248 papers for extraction. From these full reports, we identified 107 articles (Supplementary Appendix 1) fulfilling our inclusion criteria for the meta-analysis (Supplementary Fig. 1). Outcomes for 39 933 BC cases and 47 015 controls, and for 17 245 RCC cases and 12 501 controls were included in the meta-analysis. Specifically, 102

Conclusions

We provide the largest meta-analysis to date on the relationship between tobacco smoking and BC and RCC incidence and mortality. Smoking involves a higher risk of cancer incidence and DSM, consistent with the literature. For BC, the incidence and DSM risk are greatest in current smokers and lowest in former smokers, indicating that cessation confers benefit. In 1988 smoking was responsible for 30–40% of BC and RCC cases [42]. Since then, some authors have suggested there has been an overall

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