Cigarette smoke contains known bladder carcinogens—such as ß-naphthylamine, polycyclic aromatic hydrocarbons, and other aromatic amines—that are excreted renally, allowing a direct effect on bladder and other urinary tract tissues.1

Across populations, rates of bladder cancer and associated mortality are higher in both current and former smokers than in never-smokers; in addition, it is well recognized that cigarette smoking is the major risk factor for urothelial bladder cancer.1,2

Connecting the Dots between Smoking and Bladder Cancer

Two recent studies give further insight into the association between smoking and bladder cancer. One of these studies suggests that smokers are more likely to have advanced disease at diagnosis, while the other finds that a polymorphism in the x-ray repair cross-complementing group 1 (XRCC1) gene may play a role in protecting smokers from developing the disease.3,4

Related: Smoking Plus Biomarker Panel IDs Bladder Cancer Prognosis

More than 72,000 Americans will be diagnosed with bladder cancer this year. The disease occurs more often and results in more deaths among men than women, a difference partially attributed to higher rates of smoking among men.5 However, past trends show that as the number male smokers decreases and the number of female smokers increases, bladder cancer rates between the sexes have followed a similar pattern. Today, men and women smoke at similar rates in the United States, and it is no coincidence that a 2011 NIH/AARP study concluded that smoking is implicated in about half of all bladder cancer cases in both men and women.1,6

A meta-analysis of epidemiologic studies published in 2000 estimated that current smokers had a three-fold higher risk for developing bladder cancer compared with never-smokers.7 Since then, a number of studies in the United States have examined the magnitude of smoking-related risk for bladder cancer. In general, these studies concur that the risk for current—and some former—smokers is anywhere from 2.5 to more than 5 times higher than that of never-smokers (Table 1).6,8-10

Table 1: Risk for Bladder Cancer Associated With Current Cigarette Smoking*

Study Study design Risk (95% CI)
NIH-AARP6
Prospective cohort, nationwide
Men: n=281,394
Women: n=186,134
Men: HR=3.89 (3.46-4.37)
Women: HR=4.65 (3.73-5.79)
Baris 200910 Case-control study, New England
N=1,170 cases
N=1,413 controls
OR=5.2 (4.0-6.6)
Alberg 20078 Two-part prospective cohort, Maryland N=45,749 (in 1963)
N=48,172 (in 1975)
1963: RR=2.7 (1.6-4.7)
1975: RR=2.6 (1.7-3.9)
Iowa Women’s Study9 Prospective cohort, women, Iowa
N=37,459
RR=3.58 (1.86-6.88)
*Versus never smokers as reference.
Abbreviations: HR, hazard ratio; OR, odds ratio; RR, relative risk.

An interesting trend has also emerged, suggesting that bladder cancer risk from smoking has increased from the early 1990s through 2004, possibly due to the higher concentrations of carcinogens in cigarette smoke since the 1990s.2,10 

Does Smoking Duration and Intensity Affect Risk?      

Three in four bladder cancers are non–muscle invasive. Ninety percent of bladder cancers are transitional cell carcinomas; the remainder is comprised of squamous cell carcinoma or adenocarcinomas.11 Smoking increases risk for all subtypes of bladder cancer, but the risk overall is influenced by duration and intensity of smoking;  as a result, individuals with the longest smoking history or greatest intensity are at significantly higher risk for developing high-grade noninvasive and invasive disease than for developing low-grade noninvasive disease.9,10,12

Women are at higher risk for high-grade noninvasive and invasive disease compared with men with similar smoking histories and intensity.12 Smoking cessation reduces, but appears not to eliminate, the excess risk associated with tobacco use.8 While the risk for former smokers becomes substantially decreased over time, it appears not to return to the level of never-smokers. A recent prospective cohort study found bladder cancer risk remains elevated for more than 32 years after quitting, even among former moderate smokers. This risk reduction is much slower than that observed for lung cancer or cardiovascular disease in former smokers.7,9,11-13

A study published this summer in the International Journal of Cancer further elucidates the association between smoking and bladder cancer. In this hospital-based, case-comparison study, data from 1,067 patients with bladder cancer (616 former smokers, 227 current smokers, 224 never-smokers) were analyzed to determine if bladder cancer in smokers had unique clinical characteristics.3 In fact, at diagnosis, current smokers on average were 4 years younger and had larger (~17%) and higher (~16%) T-stage tumors compared with never-smokers (Table 2).3 In addition, muscle-invasive disease occurred significantly (P=0.002) more often in current (23%) and former smokers (24%) than never-smokers (12%).3

Table 2: Adjusted Predicted Means of Variables for Current Versus Never-Smokers With Bladder Cancer3

Smoking status Age at diagnosis (years) Grade T stage Tumor size (cm)
Never
69.7
(68.1-71.2)
2.16
(2.05-2.28)
1.56
(1.43-1.70)
2.84
(2.46-3.21)
Current 65.7
(64.2-67.2)*
2.31
(2.20-2.43)
1.81
(1.68-1.94)*
3.31
(2.95-3.68)*
*P<0.05

A second study, published last month in PLoS One, identified a single nucleotide polymorphism (SNP) in XRCC1 that appears to confer protection against bladder cancer in smokers.4 The gene is a crucial part of the base excision repair (BER) pathway, one of four major DNA repair mechanisms in humans. Because of this, SNPs in XRCC1 theoretically may influence the DNA repair function of the gene and BER pathway.4

This meta-analysis looked at studies with three relatively well-studied SNPs. The presence of the R399Q SNP in smokers (but not never-smokers) was associated with a significantly decreased risk for bladder cancer based on results of multiple studies.4 The R194W SNP and R280H SNP were associated with a significant increase in bladder cancer risk among Asian, but not other, populations, unrelated to smoking status.4 Their findings provide a rationale for further research on the influence of R399Q in smokers.

Summary

Although most bladder cancer is noninvasive, the disease is associated with high rates of recurrence despite therapy.1 Smoking is the major environmental risk factor for bladder cancer, responsible for about half of cases in both men and women. Smokers and former smokers are at higher risk than never-smokers, as evidenced in two recent studies that give more insight into the association between smoking and bladder cancer.

One study has clear clinical implications: smokers appear to be at greater risk for malignant disease and associated impacts on prognosis. They may require more aggressive treatment and follow-up regimens.3 The other identifies a SNP in the XRCC1 DNA repair gene that appears to protect smokers from developing bladder cancer. Further research may help establish the level of involvement for these genetic imperfections and how they may be used to improve prognosis and treatment among patients with bladder cancer and a history of smoking.


References

1. Burger M, Catto JWF, Dalbagni G, et al. Epidemiology and risk factors of urothelial bladder cancer. Eur Urol. 2013;63(2):234-241.

2. Alberg AJ, Hébert JR. Cigarette smoking and bladder cancer: a new twist in an old saga? J Natl Cancer Inst. 2010;102:1-2. Erratum.

3. Van Roekel EH, Cheng KK, James ND, et al. Smoking is associated with lower age, higher grade, higher stage, and larger size of malignant bladder tumors at diagnosis. Int J Cancer. 2013;133:446-455.

4. Li S, Peng Q, Chen Y, et al. DNA repair gene XRCC1 polymorphisms, smoking, and bladder cancer risk: a meta-analysis. PLoS One. 2013;8(9):e73448.

5. American Cancer Society. Cancer Facts & Figures 2013. Atlanta: American Cancer Society; 2013.

6. Freedman ND, Silverman DT, Hollenbeck AR, et al. Association between smoking and risk of bladder cancer among men and women. JAMA. 2011;306(7):737-745.

7. Zeegers MP, Tan FE, Dorant E, van Den Brandt PA. The impact of characteristics of cigarette smoking on urinary tract cancer risk: a meta-analysis of epidemiologic studies. Cancer. 2000;89(3):630-639.

8. Alberg AJ, Kouzis A, Genkinger JM, et al. A prospective cohort study of bladder cancer risk in relation to active cigarette smoking and household exposure to secondhand cigarette smoke. Am J Epidemiol. 2007;165(6):660-666.

9. Tripathi A, Folsom AR, Anderson KE. Risk factors for urinary bladder carcinoma in postmenopausal women. The Iowa Women’s Health Study. Cancer. 2002;95(11):2316-2323.

10. Baris D, Karagas MR, Verrill C, et al. A case–control study of smoking and bladder cancer risk: emergent patterns over time. J Natl Cancer Inst. 2009;101:1553-1561.

11. Sexton WJ, Wiegand LR, Correa JJ, et al. Bladder cancer: a review of non–muscle invasive disease. Cancer Contr. 2010;17(4):256-268.

12. Jiang X, Castelao JE, Yuan J-M, et al. Cigarette smoking and subtypes of bladder cancer. Int J Cancer. 2012;130(4):896-901.

13. Welty CJ, Wright JL, Hotaling JM, et al. Persistence of urothelial carcinoma of the bladder risk among former smokers: results from a contemporary, prospective cohort. Urol Oncol. 2013;Mar 15: doi: 10.1016/j.urolonc.2012.009.001. [epub ahead of print]