Epidemiology and Etiology of Bladder Cancer

Epidemiology


Bladder cancer is the most common malignancy of the urinary tract and second only to the prostate in the entire genitourinary system. The most updated available global estimate, based on registry data collected through the year 2012, found approximately 430,000 new diagnoses worldwide, making it the 9th most common malignancy overall (6th in men and 17th in women) while being the 13th leading cause of cancer mortality (Figure 1).1 A more recent estimate available for the United States population based on Surveillance, Epidemiology, and End Results (SEER) data estimates the annual incidence will be 81,000 for the year 2018 corresponding to the 4th and 11th most common cancer among men and women, respectively.2 In the decade between 2006 and 2015 the annual incidence of bladder cancer per 100,000 persons has declined by 1.3% annually, however, the mortality rate has remained nearly unchanged.3 By comparison, the mortality rates of the other top malignancies, lung, colon, and prostate, have declined by 2.6%, 2.4%, and 2.9% over the same period of time, respectively.

figure-1a-epidemiology-bladder-cancer@2x.jpgfigure-1b-epidemiology-bladder-cancer@2x.jpg
Figure 1.  Age-standardized rates (ASR) of incidence (gold) and mortality (blue) from the World Health Organization International Agency for Research on Cancer GLOBOCAN 2012 dataset. (A) Worldwide ASR for the top 20 cancers, divided by sex. Bladder cancer incidence is the 6th most common among men and 17th among women. (B) Bladder cancer ASR incidence and mortality by WHO reporting region. More developed regions have 2-3 times higher incidence than less developed regions.


The gender disparity in bladder cancer risk is readily evident considering men represent slightly more than 75% of new diagnoses each year.2 Perhaps the most obvious explanation for this difference is the inequality in exposure to bladder carcinogens, namely tobacco smoke. This topic has undergone close examination but higher rates of smoking and tobacco use among males fails to entirely account for the increased bladder cancer risk.4,5 Sex hormones may play a key role in the development and progression of bladder cancer, with increased androgen receptor expression noted in lower stage/grade tumors while higher stage disease is associated with increased expression of the estrogen receptor β isoform (Figure 2).6-9 This may point to an explanation for the poorer stage-adjusted cancer-specific mortality in women compared to men (HR 1.17-4.47) in spite of a male to female incidence ratio of 4 to 1.10-14


figure-2-epidemiology-bladder-cancer@2x.jpg
 
Internationally, gender differences in bladder cancer mirrors the trends seen in the US population but incidences vary widely from region to region. For instance, the lowest age-standardized rates (ASR) in men are seen in Africa (Uganda ASR = 2.6 per 100,000) while the highest are found in North America (ASR = 19.5 per 100,000) and Europe (ASR = 17.7 per 100,000), including Spain with its ASR of 36.7 per 100,000 men.1 In an analysis of the WHO cancer databases, Antoni et al. made several notable observations regarding worldwide bladder cancer incidence and mortality.15 The ASR of more developed regions is approximately 3-times higher than the developing world and is likely explained by the high prevalence of cigarette smoking among the former population during the preceding three to four decades. Case-in-point, nearly 2 in 3 Spanish adult males actively smoked in the late 1970s, and while smoking rates have certainly declined among the developed world, it will take many more years to see the attendant decline in the disease burden of bladder cancer.15-17 Egypt – and the Northern African region as a whole – are worth highlighting given the abnormally high incidence when compared to the continent overall (ASR = 19.0, 15.1, and 6.3 per 100,000, respectively).15 Endemic parasitic infection with Schistoma haematobium has traditionally been associated with the increased prevalence of disease among the Egyptian population, especially squamous cell carcinoma (SCC) which accounted for up to 81% of all bladder cancers diagnosed before the turn of the century.18 More recently, bilharzial infection rates have fallen and SCC now accounts for less than 30% of bladder cancer pathology, but the overall incidence is holding steady due to smoking rates among the male population that has increased to over 50%.18,19

Racial disparity among the US population is skewed towards a 2-fold higher incidence of bladder cancer among Caucasian men, however, tumor stage and grade are higher at the presentation in African American men.20 Several researchers have noted worse disease-specific outcomes for African Americans and hypothesize that this is probably due to socioeconomic factors and poor access to healthcare, but a recent evaluation of a Florida cancer registry actually found significantly better overall survival among blacks (HR=0.35, p=0.045) when controlling for patient and disease factors.21-25

Etiology



Risk Factors

The urothelium is exposed to the outside environment, not unlike the skin or the lung epithelium, making it susceptible to damage from environmental toxins. Once filtered by the kidney and concentrated in the urine, these toxins remain in continuous contact with the urothelium of the bladder until expelled during urination. The result is DNA damage caused by several carcinogenic compounds (aromatic amines, polycyclic aromatic hydrocarbons, etc.) which leads to accumulation of oncogenic mutations over the course of decades and explains why bladder cancer carries one of the highest mutational burdens of all cancers.26,27

The most strongly attributable risk factor for bladder cancer is cigarette smoking, which causes approximate 50% of cases annually across both sexes.28 Since the overall rate of smoking in the US has dropped in the past several decades, one would expect to see a commensurate decline in the incidence of bladder cancer, but this has not been the case. Instead, it appears that the strength of association between bladder cancer and smoking has increased, likely due to the enrichment of carcinogenic agents found in cigarette tobacco over time – specifically nitrates, which become metabolized into carcinogenic N-nitrosamines.28,29

E-cigarettes are a popular “safe” alternative to cigarette smoking, but the vaporized liquid, comprised of nicotine and flavoring, contains several carcinogenic compounds found in tobacco smoke, such as polycyclic aromatic hydrocarbons, phenols, nitrosamines, and aldehydes, among others.30 It is too early to make a causal link between e-cigarettes and bladder cancer, however, studies have discovered, while less than cigarette smokers, levels of carcinogenic metabolites in the urine of e-cigarette smokers are significantly higher than non-smoking controls.31,32 Furthermore, pre-clinical work with mouse models demonstrated DNA damage induced by nitrosamines from e-cigarettes in the murine lungs, heart, and bladder.33

Other environmental toxins, aside from tobacco smoke, that are known to cause bladder cancer are often found in industrial settings where workers are subjected to repeated daily exposure. In a contemporary analysis of bladder cancer risk from occupational exposures, workers in tobacco, dye, rubber, printing, leather, and hairdressing industries as well as chimney sweeps, firefighters, aluminum workers, and oil workers were at highest risk for bladder cancer secondary to environmental presence of aromatic amines and polycyclic aromatic hydrocarbons (Table).26,34-37 The inorganic form of arsenic found both naturally and as a contaminant in the environment, has been strongly linked to urothelial malignancy, especially when the concentration in drinking water is over 150-300 µg/L.38,39

table-1-epidemiology-bladder-cancer@2x.jpg

Innumerable dietary risk factors have been associated with cancer risk in general and even a few with particular emphasis on bladder cancer.40 Meat consumption at the population level appears to be positively correlated with bladder cancer risk for both red meat and processed meats, but the quality of evidence is generally poor.41,42 Likewise, artificial sweeteners are a frequent suspect for dietary carcinogenesis while lacking any clear link to cancer of the urinary tract, only conflicting results from case-control studies.43-45

The most commonly cited hereditary links to bladder cancer are not tumor suppressor or proto-oncogene mutations, but rather related to the manner in which an individual metabolizes the carcinogens from the environment, especially in the form of cigarette smoke. Two isoforms of the N-acetyltransferase enzyme (NAT1 and NAT2) that are responsible for inactivating the carcinogenic aromatic and heterocyclic amine compounds can be associated with an increased risk of developing bladder cancer when certain germline polymorphisms are present that correlate with “slow” enzyme activity.46,47 Enzymes in the glutathione S-transferase (GST) family also carry a detoxifying function, and bladder cancer risk is increased in the GSTM1-null genotype, however, the effect in this population is more pronounced among never smokers over former or current smokers through an as of yet unknown mechanism.48,49

Chronic inflammation contributes to bladder cancer formation through a process by which immune cells (neutrophils, monocytes, and macrophages) generate reactive oxygen species that induce DNA damage as well as stimulate cellular proliferation through cell-signaling pathways. 50 Urinary tract infections and urothelial irritants, such as calculi and indwelling catheters, are associated with increased risk of bladder cancer overall, as well as an increased proportion of squamous cell carcinoma.51,52 This is particularly evident among spinal cord injury patients and populations with endemic Schistosomiasis, and though the exact mechanism is unknown, urothelial to squamous metaplasia appears to precede the development of invasive carcinoma in these patients.50,53

Iatrogenic causes of bladder cancer include systemic agents (i.e. chemotherapy) and pelvic irradiation for other malignancies. The popular class of anti-diabetic medications known as thiazolidinediones (TZD), which includes the specific drugs pioglitazone and rosiglitazone, have been implicated in urothelial carcinoma carcinogenesis via activation of the peroxisome proliferator-activated receptors gamma (PPARγ). Large cohort studies have reported conflicting results regarding an increased incidence of bladder cancer that increases with duration of TZD therapy, especially pioglitazone, prompting the FDA to include a warning label regarding the increased risk and recommend ongoing re-evaluation of the data.54-58 Bladder cancer risk is also associated with systemic cyclophosphamide chemotherapy, due to either direct effect of toxic metabolites in the urine (acrolein and phosphoramide) or severe urothelial inflammation.59,60 Radiotherapy of the pelvis may lead to at least 30% increased risk, though this effect is seen only with the external beam but not brachytherapy.61

Prevention

Given the role of inflammation in carcinogenesis, it makes sense that inhibiting enzymes within the pro-inflammatory pathways (i.e. cyclooxygenase-2 [COX-2] or 3-hydroxy-3-mehylglutaryl-coenzyme A [HMGCoA] reductase) might be useful for disease prevention. Laboratory models of nonsteroidal anti-inflammatories (NSAIDs) have demonstrated promising results related to bladder cancer prevention, however, a randomized controlled trial of the COX-2 inhibitor celecoxib failed significantly reduce NMIBC recurrences in humans.62-64 Likewise, results from case-control studies suggest that HMGCoA reductase inhibitors do not offer a significant benefit.65,66

Smoking cessation, on the other hand, can help to erase some of the tobacco-associated bladder cancer risks, especially when the user quits prior to disease onset. The risk of developing bladder cancer in former smokers decreases with time since quitting but they still maintain a higher risk when compared to never smokers, though, this is approximately 50% less than that of current smokers.37,67-69 Smoking status remains important even after bladder cancer has developed, as former smokers who quit at least 1 year prior to bladder cancer diagnosis appear to have a lower recurrence risk when compared to more recent former smokers and current smokers, but some studies have only found a difference for patients who quit more than 10 years before.70,71

Cannabis may possess antineoplastic properties based on inhibition of tumor growth and pro-apoptotic effects seen in the laboratory, but supporting clinical data is currently lacking.72-74  A slightly higher incidence of bladder cancer was noted in non-smokers (neither tobacco nor cannabis) when compared to cannabis users (0.4% v. 0.3%, respectively) in one large cohort study, translating into a relative risk of 0.55 (p=0.048) on multivariate analysis, though only age, race, and BMI were used as co-variables.75 Conversely, a much smaller case-control study of Vietnam-era veterans found increased rates of habitual marijuana use among bladder cancer patients (88.5%) when compared to matched controls (69.2%), though tobacco use was equal among both groups.76

Proposed dietary factors offering a protective effect include increased fluid intake, fruits, vegetables, vitamin supplements (A, C, & D), selenium, and other antioxidants.67 Randomized controlled trials are lacking in this arena and systematic reviews of retrospective, case-control studies have yielded mixed results, so no definitive conclusions can be drawn at this time.40,77,78

Summary/Conclusions:

  • Bladder cancer is a leading malignancy worldwide but incidence is disproportionately higher among more developed nations, including the US.
  • The most important recognized risk factor is cigarette smoking, but despite declining rates of smoking, bladder cancer incidence has declined only slightly, owing to the long lead time and potentially increased carcinogenicity of modern tobacco products.
  • Men continue to have a 3-4 fold higher lifetime risk even though the gender gap for smoking has narrowed significantly, raising the possibility of a hormonal influence
  • Other environmental risks are largely related to occupational exposures to carcinogenic compounds (i.e. aromatic amines).
  • Lifestyle factors and chemoprevention may be able to reduce bladder cancer risk but currently available literature is inconclusive
  • Smoking cessation substantially lowers lifetime risk, though not reaching the same level as a never smoker.
Written by: Justin T. Matulay, MD, and Ashish Kamat, MD, MBBS
References:
  1. Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. 2013; http://globocan.iarc.fr. Accessed 8/8, 2018.
  2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7-30.
  3. Surveillance, Epidemiology, and End Results (SEER) Research Data (1973-2015). 2018; https://www.seer.cancer.gov. Accessed 8/10, 2018.
  4. Hemelt M, Yamamoto H, Cheng KK, Zeegers MPA. The effect of smoking on the male excess of bladder cancer: A meta-analysis and geographical analyses. International Journal of Cancer. 2009;124(2):412-419.
  5. Hartge P, Harvey EB, Linehan WM, et al. Unexplained Excess Risk of Bladder Cancer in Men. JNCI: Journal of the National Cancer Institute. 1990;82(20):1636-1640.
  6. Miyamoto H, Yao JL, Chaux A, et al. Expression of androgen and oestrogen receptors and its prognostic significance in urothelial neoplasm of the urinary bladder. BJU International. 2012;109(11):1716-1726.
  7. Tuygun C, Kankaya D, Imamoglu A, et al. Sex-specific hormone receptors in urothelial carcinomas of the human urinary bladder: A comparative analysis of clinicopathological features and survival outcomes according to receptor expression. Urologic Oncology: Seminars and Original Investigations. 2011;29(1):43-51.
  8. Shen SS, Smith CL, Hsieh J-T, et al. Expression of estrogen receptors-α and -β in bladder cancer cell lines and human bladder tumor tissue. Cancer. 2006;106(12):2610-2616.
  9. Boorjian S, Ugras S, Mongan NP, et al. Androgen receptor expression is inversely correlated with pathologic tumor stage in bladder cancer. Urology. 2004;64(2):383-388.
  10. Dobruch J, Daneshmand S, Fisch M, et al. Gender and Bladder Cancer: A Collaborative Review of Etiology, Biology, and Outcomes. Eur Urol. 2016;69(2):300-310.
  11. Messer JC, Shariat SF, Dinney CP, et al. Female gender is associated with a worse survival after radical cystectomy for urothelial carcinoma of the bladder: A competing risk analysis. Urology. 2014;83(4):863-867.
  12. Kluth LA, Rieken M, Xylinas E, et al. Gender-specific Differences in Clinicopathologic Outcomes Following Radical Cystectomy: An International Multi-institutional Study of More Than 8000 Patients. European Urology. 2014;66(5):913-919.
  13. Tilki D, Svatek RS, Novara G, et al. Stage pT0 at Radical Cystectomy Confers Improved Survival: An International Study of 4,430 Patients. The Journal of Urology. 2010;184(3):888-894.
  14. Tilki D, Reich O, Svatek RS, et al. Characteristics and Outcomes of Patients With Clinical Carcinoma In Situ Only Treated With Radical Cystectomy: An International Study of 243 Patients. The Journal of Urology. 2010;183(5):1757-1763.
  15. Antoni S, Ferlay J, Soerjomataram I, Znaor A, Jemal A, Bray F. Bladder Cancer Incidence and Mortality: A Global Overview and Recent Trends. Eur Urol. 2017;71(1):96-108.
  16. Regidor E, Gutiérrez-Fisac J, De los Santos Ichaso M, Fernández E. Trends in principal cancer risk factors in Spain. Annals of oncology. 2010;21(suppl_3):iii37-iii42.
  17. Regidor E, Gutierrez-Fisac JL, Calle ME, Navarro P, Domı́nguez V. Trends in Cigarette Smoking in Spain by Social Class. Preventive Medicine. 2001;33(4):241-248.
  18. Salem HK, Mahfouz S. Changing Patterns (Age, Incidence, and Pathologic Types) of Schistosoma-associated Bladder Cancer in Egypt in the Past Decade. Urology. 2012;79(2):379-383.
  19. Gouda I, Mokhtar N, Bilal D, El-Bolkainy T, El-Bolkainy NM. Bilharziasis and bladder cancer: a time trend analysis of 9843 patients. Journal of the Egyptian National Cancer Institute. 2007;19(2):158-162.
  20. Burger M, Catto JW, Dalbagni G, et al. Epidemiology and risk factors of urothelial bladder cancer. Eur Urol. 2013;63(2):234-241.
  21. Underwood W, 3rd, Dunn RL, Williams C, Lee CT. Gender and geographic influence on the racial disparity in bladder cancer mortality in the US. J Am Coll Surg. 2006;202(2):284-290.
  22. Mallin K, David KA, Carroll PR, Milowsky MI, Nanus DM. Transitional cell carcinoma of the bladder: racial and gender disparities in survival (1993 to 2002), stage and grade (1993 to 2007). J Urol. 2011;185(5):1631-1636.
  23. Scosyrev E, Noyes K, Feng C, Messing E. Sex and racial differences in bladder cancer presentation and mortality in the US. Cancer. 2009;115(1):68-74.
  24. Yee DS, Ishill NM, Lowrance WT, Herr HW, Elkin EB. Ethnic differences in bladder cancer survival. Urology. 2011;78(3):544-549.
  25. DeDeugd C, Miyake M, Palacios DA, Rosser CJ. The Influence of Race on Overall Survival in Patients with Newly Diagnosed Bladder Cancer. J Racial Ethn Health Disparities. 2015;2(1):124-131.
  26. Cumberbatch MG, Cox A, Teare D, Catto JW. Contemporary Occupational Carcinogen Exposure and Bladder Cancer: A Systematic Review and Meta-analysis. JAMA Oncol. 2015;1(9):1282-1290.
  27. Kandoth C, McLellan MD, Vandin F, et al. Mutational landscape and significance across 12 major cancer types. Nature. 2013;502(7471):333-339.
  28. Freedman ND, Silverman DT, Hollenbeck AR, Schatzkin A, Abnet CC. Association between smoking and risk of bladder cancer among men and women. Jama. 2011;306(7):737-745.
  29. Hoffmann D, Hoffmann I, El-Bayoumy K. The less harmful cigarette: a controversial issue. a tribute to Ernst L. Wynder. Chem Res Toxicol. 2001;14(7):767-790.
  30. Cheng T. Chemical evaluation of electronic cigarettes. Tob Control. 2014;23 Suppl 2:ii11-17.
  31. Fuller TW, Acharya AP, Meyyappan T, et al. Comparison of Bladder Carcinogens in the Urine of E-cigarette Users Versus Non E-cigarette Using Controls. Sci Rep. 2018;8(1):507.
  32. Hecht SS, Carmella SG, Kotandeniya D, et al. Evaluation of toxicant and carcinogen metabolites in the urine of e-cigarette users versus cigarette smokers. Nicotine Tob Res. 2015;17(6):704-709.
  33. Lee HW, Park SH, Weng MW, et al. E-cigarette smoke damages DNA and reduces repair activity in mouse lung, heart, and bladder as well as in human lung and bladder cells. Proc Natl Acad Sci U S A. 2018;115(7):E1560-E1569.
  34. Bosetti C, Boffetta P, La Vecchia C. Occupational exposures to polycyclic aromatic hydrocarbons, and respiratory and urinary tract cancers: a quantitative review to 2005. Ann Oncol. 2007;18(3):431-446.
  35. Letasiova S, Medve'ova A, Sovcikova A, et al. Bladder cancer, a review of the environmental risk factors. Environ Health. 2012;11 Suppl 1:S11.
  36. Rota M, Bosetti C, Boccia S, Boffetta P, La Vecchia C. Occupational exposures to polycyclic aromatic hydrocarbons and respiratory and urinary tract cancers: an updated systematic review and a meta-analysis to 2014. Arch Toxicol. 2014;88(8):1479-1490.
  37. 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.
  38. Meliker JR, Nriagu JO. Arsenic in drinking water and bladder cancer: review of epidemiological evidence. Trace Metals Other. 2007;9:551-584.
  39. Saint-Jacques N, Parker L, Brown P, Dummer TJ. Arsenic in drinking water and urinary tract cancers: a systematic review of 30 years of epidemiological evidence. Environ Health. 2014;13:44.
  40. Al-Zalabani AH, Stewart KF, Wesselius A, Schols AM, Zeegers MP. Modifiable risk factors for the prevention of bladder cancer: a systematic review of meta-analyses. Eur J Epidemiol. 2016;31(9):811-851.
  41. Crippa A, Larsson SC, Discacciati A, Wolk A, Orsini N. Red and processed meat consumption and risk of bladder cancer: a dose-response meta-analysis of epidemiological studies. Eur J Nutr. 2018;57(2):689-701.
  42. Li F, An S, Hou L, Chen P, Lei C, Tan W. Red and processed meat intake and risk of bladder cancer: a meta-analysis. Int J Clin Exp Med. 2014;7(8):2100-2110.
  43. Andreatta MM, Munoz SE, Lantieri MJ, Eynard AR, Navarro A. Artificial sweetener consumption and urinary tract tumors in Cordoba, Argentina. Prev Med. 2008;47(1):136-139.
  44. Moller-Jensen O, Knudsen JB, Sorensen BL, Clemmesen J. Artificial sweeteners and absence of bladder cancer risk in Copenhagen. Int J Cancer. 1983;32(5):577-582.
  45. Morrison AS, Buring JE. Artificial sweeteners and cancer of the lower urinary tract. N Engl J Med. 1980;302(10):537-541.
  46. Garcia-Closas M, Malats N, Silverman D, et al. NAT2 slow acetylation, GSTM1 null genotype, and risk of bladder cancer: results from the Spanish Bladder Cancer Study and meta-analyses. Lancet. 2005;366(9486):649-659.
  47. Moore LE, Baris DR, Figueroa JD, et al. GSTM1 null and NAT2 slow acetylation genotypes, smoking intensity and bladder cancer risk: results from the New England bladder cancer study and NAT2 meta-analysis. Carcinogenesis. 2011;32(2):182-189.
  48. Gu J, Wu X. Genetic susceptibility to bladder cancer risk and outcome. Per Med. 2011;8(3):365-374.
  49. Rothman N, Garcia-Closas M, Chatterjee N, et al. A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci. Nat Genet. 2010;42(11):978-984.
  50. Michaud DS. Chronic inflammation and bladder cancer. Urol Oncol. 2007;25(3):260-268.
  51. Vermeulen SH, Hanum N, Grotenhuis AJ, et al. Recurrent urinary tract infection and risk of bladder cancer in the Nijmegen bladder cancer study. Br J Cancer. 2015;112(3):594-600.
  52. Clouston D, Lawrentschuk N. Metaplastic conditions of the bladder. BJU Int. 2013;112 Suppl 2:27-31.
  53. Mostafa MH, Sheweita SA, O'Connor PJ. Relationship between schistosomiasis and bladder cancer. Clin Microbiol Rev. 1999;12(1):97-111.
  54. Lewis JD, Habel LA, Quesenberry CP, et al. Pioglitazone Use and Risk of Bladder Cancer and Other Common Cancers in Persons With Diabetes. JAMA. 2015;314(3):265-277.
  55. Tuccori M, Filion KB, Yin H, Yu OH, Platt RW, Azoulay L. Pioglitazone use and risk of bladder cancer: population based cohort study. BMJ. 2016;352:i1541.
  56. Tang H, Shi W, Fu S, et al. Pioglitazone and bladder cancer risk: a systematic review and meta-analysis. Cancer Med. 2018;7(4):1070-1080.
  57. Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366(9493):1279-1289.
  58. Erdmann E, Harding S, Lam H, Perez A. Ten-year observational follow-up of PROactive: a randomized cardiovascular outcomes trial evaluating pioglitazone in type 2 diabetes. Diabetes Obes Metab. 2016;18(3):266-273.
  59. Talar-Williams C, Hijazi YM, Walther MM, et al. Cyclophosphamide-induced cystitis and bladder cancer in patients with Wegener granulomatosis. Ann Intern Med. 1996;124(5):477-484.
  60. Travis LB, Curtis RE, Glimelius B, et al. Bladder and kidney cancer following cyclophosphamide therapy for non-Hodgkin's lymphoma. J Natl Cancer Inst. 1995;87(7):524-530.
  61. Wallis CJ, Mahar AL, Choo R, et al. Second malignancies after radiotherapy for prostate cancer: systematic review and meta-analysis. BMJ. 2016;352:i851.
  62. Elwood PC, Gallagher AM, Duthie GG, Mur LA, Morgan G. Aspirin, salicylates, and cancer. Lancet. 2009;373(9671):1301-1309.
  63. Nicastro HL, Grubbs CJ, Margaret Juliana M, et al. Preventive effects of NSAIDs, NO-NSAIDs, and NSAIDs plus difluoromethylornithine in a chemically induced urinary bladder cancer model. Cancer Prev Res (Phila). 2014;7(2):246-254.
  64. Sabichi AL, Lee JJ, Grossman HB, et al. A randomized controlled trial of celecoxib to prevent recurrence of nonmuscle-invasive bladder cancer. Cancer Prev Res (Phila). 2011;4(10):1580-1589.
  65. Cholesterol Treatment Trialists C, Emberson JR, Kearney PM, et al. Lack of effect of lowering LDL cholesterol on cancer: meta-analysis of individual data from 175,000 people in 27 randomised trials of statin therapy. PLoS One. 2012;7(1):e29849.
  66. Crivelli JJ, Xylinas E, Kluth LA, et al. Effect of statin use on outcomes of non-muscle-invasive bladder cancer. BJU Int. 2013;112(2):E4-12.
  67. Kwan ML, Garren B, Nielsen ME, Tang L. Lifestyle and nutritional modifiable factors in the prevention and treatment of bladder cancer. Urol Oncol. 2018.
  68. van Osch FH, Jochems SH, van Schooten FJ, Bryan RT, Zeegers MP. Quantified relations between exposure to tobacco smoking and bladder cancer risk: a meta-analysis of 89 observational studies. Int J Epidemiol. 2016;45(3):857-870.
  69. 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(22):1553-1561.
  70. Rink M, Furberg H, Zabor EC, et al. Impact of smoking and smoking cessation on oncologic outcomes in primary non-muscle-invasive bladder cancer. Eur Urol. 2013;63(4):724-732.
  71. Simonis K, Shariat SF, Rink M, Urothelial Cancer Working Group of the Young Academic Urologists Working Party of the European Association of U. Smoking and smoking cessation effects on oncological outcomes in nonmuscle invasive bladder cancer. Curr Opin Urol. 2014;24(5):492-499.
  72. Orellana-Serradell O, Poblete CE, Sanchez C, et al. Proapoptotic effect of endocannabinoids in prostate cancer cells. Oncol Rep. 2015;33(4):1599-1608.
  73. Sreevalsan S, Joseph S, Jutooru I, Chadalapaka G, Safe SH. Induction of apoptosis by cannabinoids in prostate and colon cancer cells is phosphatase dependent. Anticancer Res. 2011;31(11):3799-3807.
  74. Gasperi V, Evangelista D, Oddi S, et al. Regulation of inflammation and proliferation of human bladder carcinoma cells by type-1 and type-2 cannabinoid receptors. Life Sci. 2015;138:41-51.
  75. Thomas AA, Wallner LP, Quinn VP, et al. Association between cannabis use and the risk of bladder cancer: results from the California Men's Health Study. Urology. 2015;85(2):388-392.
  76. Chacko JA, Heiner JG, Siu W, Macy M, Terris MK. Association between marijuana use and transitional cell carcinoma. Urology. 2006;67(1):100-104.
  77. Liu H, Wang XC, Hu GH, et al. Fruit and vegetable consumption and risk of bladder cancer: an updated meta-analysis of observational studies. Eur J Cancer Prev. 2015;24(6):508-516.
  78. 78. Xu C, Zeng XT, Liu TZ, et al. Fruits and vegetables intake and risk of bladder cancer: a PRISMA-compliant systematic review and dose-response meta-analysis of prospective cohort studies. Medicine (Baltimore). 2015;94(17):e759.
E-Newsletters

Newsletter subscription

Free Daily and Weekly newsletters offered by content of interest

The fields of GU Oncology and Urology are rapidly advancing. Sign up today for articles, videos, conference highlights and abstracts from peer-review publications by disease and condition delivered to your inbox and read on the go.

Subscribe