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Review – Bladder Cancer

Smoking and Bladder Cancer: A Systematic Review of Risk and Outcomes

By: Michael Rinka , Joseph J. Crivellib , Shahrokh F. Shariatc, Felix K. Chuna, Edward M. Messingd and Mark S. Solowaye

EU Focus, Volume 1 Issue 1, November 2015, Pages 17-27

Published online: 13 November 2015

Keywords: Smoking, Urothelial carcinoma, Non–muscle-invasive bladder cancer, Muscle-invasive bladder cancer, Recurrence, Progression, Survival, Radical cystectomy, Transurethral resection, Intravesical therapy

Abstract Full Text Full Text PDF (421 KB) Patient Summary

Abstract

Context

Cigarette smoking is an established risk factor for urothelial carcinoma.

Objective

To elucidate the association between pretreatment smoking status, cumulative exposure, and time since smoking cessation and the development of and outcomes for urothelial carcinoma of the bladder (UCB) in patients treated with transurethral resection of the bladder (TURBT) or radical cystectomy (RC).

Evidence acquisition

A literature search was performed in September 2014 using the PubMed and Scopus databases limited to articles published in English since 1990. Eight contemporary studies on smoking and UBC development and 26 studies on smoking and UBC prognosis met the inclusion criteria.

Evidence synthesis

Current cigarette smoking increases the risk of UCB incidence by two to fourfold, while smoking cessation attenuates this risk. Smoking status, exposure, and cessation have an evident impact on disease recurrence for patients who undergo TURBT, with weaker associations between smoking and other endpoints for TURBT and RC patients.

Conclusion

Retrospective evidence suggests that smoking markedly increases UCB risk and may lead to unfavorable outcomes for patients who already have UCB; smoking cessation can attenuate these undesirable effects.

Patient summary

Current evidence proves that cigarette smoking is an established risk factor for the development of urothelial carcinoma of the bladder (UCB). There is a growing body of evidence that smoking negatively affects outcomes for UCB patients treated with transurethral resection and/or radical cystectomy, although not uniformly. Long-term smoking cessation seems to mitigate the detrimental effects of smoking in non–muscle-invasive and muscle-invasive bladder cancer.

Take Home Message

Cigarette smoking is a powerful established risk factor for the development of urothelial carcinoma of the bladder (UCB), increasing the risk two- to four-fold for current smokers and up to three-fold for former smokers. There is also a growing body of evidence that smoking negatively affects outcomes for UCB patients at different treatment points, although the evidence is not uniform. Long-term smoking cessation seems to mitigate the detrimental effects of smoking in nonmuscle-invasive and muscle-invasive bladder cancer.

Keywords: Smoking, Urothelial carcinoma, Non–muscle-invasive bladder cancer, Muscle-invasive bladder cancer, Recurrence, Progression, Survival, Radical cystectomy, Transurethral resection, Intravesical therapy.

1. Introduction

Urothelial carcinoma of the bladder (UCB) is the sixth most common cancer in both genders, with an estimated 72 570 new cases and 15 210 deaths in the USA in 2013 [1], representing a significant burden of morbidity and mortality. Approximately three-quarters of patients are initially diagnosed with non–muscle-invasive bladder cancer (NMIBC) and are thus eligible for bladder-preserving treatment including transurethral resection of the bladder (TURBT) with or without intravesical therapy [2]. By contrast, approximately 30% of patients have muscle-invasive or locally advanced UCB at diagnosis [3], and radical cystectomy (RC) with bilateral lymphadenectomy with or without perioperative systemic chemotherapy is the gold standard treatment for these patients [4].

Despite clear evidence that tobacco smoke contains over 60 carcinogens, causes at least 18 types of cancer, and is the second leading risk factor causing death, >30% of adults in the Western world are still current or former smokers [5], [6], and [7]. There is convincing evidence that cigarette smoking is the best-established and most important risk factor for the development of UCB [8] and [9]. The risk of UCB development is inversely associated with age at first exposure and cessation of cigarette smoking [9]. According to current smoking patterns, a global average of approximately 50% of young men and 10% of young women are smokers and only relatively few quit [10]. As these young smokers reach middle and old age, the effects of smoking will represent a future burden for all health care providers including urologists, as UCB is generally a disease of the elderly [11].

UCB has the highest prevalence among all urinary tract malignancies because of moderate progression rates and long-term survival in many patients [8]; nevertheless, UCB screening is not performed, mainly because of the low overall incidence [12]. However, it is important to acknowledge that UCB is the most expensive cancer and has the highest lifetime treatment cost per patient among all cancers [13]. The necessity for long-term monitoring of UCB patients has steadily increased the health economic burden for decades. Together with long-term disease-related psychological effects, the economic burden of UCB surveillance and treatment underscores the urgent need for a better understanding of UCB risk factors and their impact on the natural history of the disease.

It has been suggested that smoking not only promotes carcinogenesis but is also associated with tumor behavior. However, the impact of smoking on the course of UCB disease and outcomes remains poorly understood and controversial. There is evidence from different smoking-related malignancies that continuing smoking after diagnosis negatively affects oncologic outcomes [14]. Previous studies investigating the effects of smoking on disease outcomes and prognosis face important methodological barriers, and it is important to realize that smoking is not just smoking [15]. To quantify cumulative cigarette smoking exposure, the medical convention has favored pack-years (average number of packs smoked per day multiplied by smoking duration in years). This measure assumes that duration and intensity (packs per day) have equivalent effects, but growing evidence suggests that this is not the case. In addition, long-term smoking cessation decreases the risk of cardiovascular and lung disease and the likelihood of developing various malignancies [16]. However, whether smoking cessation and time since cessation beneficially influence oncologic outcomes in UCB remains inconclusive.

Therefore, a better understanding of smoking-related biology in UCB development and the role of smoking in UCB prognosis may significantly influence clinical management strategies and thus health costs. In this systematic review we summarize evidence from the most recent articles regarding the effects of smoking and smoking cessation on UCB development and oncologic outcomes for patients with NMIBC and MIBC.

2. Evidence acquisition

2.1. Search strategy

J.J.C. conducted a literature search in September 2014 using the PubMed and Scopus databases. The following search was performed: (smok* OR tobacco OR cig* OR “smoking cessation”) AND (cancer OR carcinoma OR neoplas* OR tumor) AND (bladder OR urothelial OR “transitional cell”) AND (“risk factor” OR recur* OR progression OR survival OR death OR mortality OR prognos* OR outcome). Filters were applied to capture items published in English on or after January 1, 1990.

2.2. Study eligibility

Our procedure for including studies in this review is outlined in Figure 1, consistent with Preferred Reporting Items for Systematic Reviews and Meta-analyses [17]. M.R. and J.J.C. read all resulting abstracts and full-text articles in depth. All authors agreed that the articles selected for this review met the inclusion criteria dictated by the patient population, intervention/exposure, comparison, outcome, and study design (PICOS) approach. A record was considered relevant to this review if it assessed the following: adult men and women treated with surgery for UCB; significant smoking history or smoking exposure compared with lesser smoking history or smoking exposure or smoking cessation; and diagnosis of UCB and patient outcomes, including disease recurrence or progression and cancer-specific and any-cause mortality. We accepted all study designs except for case reports. Meeting abstracts, editorials, and commentaries on articles were not accepted, nor were review articles or meta-analyses.

gr1

Fig. 1

Outline of the search strategy and study inclusion process for this systematic review.

In an effort to provide the most recent data available, only studies published in 2011 or later were considered for associations between smoking and UCB risk (Fig. 1). In addition, we required that at least 100 patients were present in both the case and control groups.

We considered all items published in 1990 or later for associations between smoking and outcomes for UCB (Fig. 1). We divided studies into two groups according to the intervention performed (TURBT or RC). Cohorts for which both TURBT and RC outcomes were reported were excluded because these cohorts were deemed too heterogeneous for our analysis. We also required that the majority of the patients had urothelial carcinoma histology and that there were at least 10 patients in each smoking status or exposure group.

Studies reporting associations between smoking cessation and disease outcomes were also subjected to the aforementioned criteria. In addition, we required that the time period over which smoking cessation took place was clearly delineated and that the comparator group contained patients who were smoking at the time of diagnosis.

2.3. Data extraction

J.J.C. tabulated the data from all the studies included and M.R. reviewed the tables for accuracy. For studies reporting associations between smoking and UCB risk, we required that odds ratios (ORs) were available with 95% confidence intervals (CIs). When not available, ORs were calculated if the data permitted this. For associations between smoking and clinical outcomes, we recorded p values (or 95% CIs if p values were not provided), along with hazard ratios (HRs) or ORs if they were available. If both multivariate and univariate analyses were performed for the same smoking-endpoint association, we recorded the result of the multivariate analysis. Statistical significance was defined as p < 0.05.

3. Evidence synthesis

3.1. Bladder cancer risk

We estimate that several hundred case-control and cohort studies have been conducted to estimate the risk of UCB attributable to smoking. An analysis performed in 2011 of 467 528 men and women found that former and current smokers had two- and fourfold increases, respectively, in UCB risk relative to never smokers [18]. The population risk of bladder cancer attributable to smoking was approximately 50% for both men and women.

This review summarizes the impact of smoking on bladder cancer risk in studies published since 2011. Among the eight case-control studies selected (Table 1) [19], [20], [21], [22], [23], [24], [25], and [26], UCB risk was two- to fourfold higher for current smokers, and up to threefold higher for former smokers. Risk estimates were similar for men and women across studies. One study found that smoking was more strongly associated with the development of MIBC than with NMIBC [22]. While smoking cessation attenuates UCB risk, former smokers are still approximately twice as likely to develop the disease 20 yr after quitting [24].

Table 1

Selected studies reporting associations of smoking and risk of urothelial carcinoma of the bladder

StudyYearsCases (n)Controls (n)Mean or median age (years)Male (%)Smoking category*Estimate
Alguacil et al. (2011)1998-2001712611NR89EverOR=2.4
FormerOR=1.8
CurrentOR=3.7
Jiang et al. (2012)1987-199615867255678EverOR=2.2 (1.8-2.8)
FormerOR=1.7 (1.3-2.1)
CurrentOR=3.2 (2.5-4.1)
Zheng et al. (2012)2006-2010765165158100EverOR=2.0
FormerOR=1.2 (0.9-1.7)
CurrentOR=2.1 (1.7-2.6)
Ferreccio et al. (2013)2007-2010232640NR69EverOR=1.6 (1.1-2.2)
Erdurak et al. (2014)201117328268§; 65NREverOR=3.2
FormerOR=3.3 (1.8-5.8)
CurrentOR=3.0
Moura et al. (2014)1998-2011431226971NR55Ever (male)OR=3.0 (2.8-3.2)
Ever (female)OR=3.0 (2.6-3.4)
Welty et al. (2014)2000-200837876055NR48EverOR=2.8
FormerHR=2.0 (1.6-2.6)
CurrentHR=3.8 (2.7-5.4)
Wu et al. (2014)2002-20092616726167EverOR=2.3 (1.6-3.3)

* All risk estimates are relative to never smokers.

Calculated based on available raw data.

Refer to full text for smoking quantity and duration data.

§ Applies to cases only.

Applies to controls only.

NR=not reported; OR=odds ratio; HR=hazard ratio.

Overall, the most current risk estimates are consistent with those of Freedman et al [18] from 2011. Interestingly, changes in the composition of cigarette smoke that might be more likely to induce bladder carcinogenesis could explain the nearly unchanged incidence in UCB despite the decreased prevalence of smoking. Although the molecular mechanisms behind bladder carcinogenesis remain incompletely elucidated, several have been proposed [27], [28], and [29]. In addition, investigating specific genetic susceptibilities may help in understanding smoking-related risk profiles for individual patients [30].

It is important to note that case-control studies such as those reported here are limited by their retrospective nature and demographic and clinical differences often unaccounted for between case and control populations. However, they are often adequate for obtaining risk estimates, especially in light of the high cost of performing a prospective cohort study.

3.2. Bladder cancer outcomes

3.2.1. Transurethral resection of the bladder

For patients treated with TURBT, smoking status and cumulative lifetime smoking exposure seem to influence disease prognosis (Table 2). The majority of studies (10 of 16) found that active/current cigarette smoking, as well as high lifetime exposure, significantly increase the risk of disease recurrence [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], and [46]. There is only moderate evidence that smoking increases the risk of disease progression in NMIBC (4 of 11 studies) [33], [35], [37], [38], [39], [41], [42], [43], [45], [47], and [48]. In addition, there is also no conclusive evidence of an association between smoking and cancer-specific mortality or any-cause mortality in NMIBC [42], [43], and [45]. The evidence for these three endpoints, however, is obviously compromised by a lack of data and overall low mortality rates for patients with NMIBC. The same is true regarding the gender-specific effect of smoking on NMIBC outcomes [49]. The findings are contradictory across studies and thus no final conclusions can be drawn. In addition, findings regarding the influence of smoking cessation on outcomes in NMIBC are partly conflicting, but the evidence for a reduction in recurrence rates is strongest (Table 4, 4 of 6 studies) [33], [34], [37], [40], [42], and [43]. In addition, there is some evidence that smoking reduces the efficiency of intravesical chemotherapy and immunotherapy [31], [35], [36], [40], [44], [45], and [50]. This finding seems reasonable considering the immunomodulatory effects of tobacco smoke.

Table 2

Selected studies reporting associations of smoking and outcomes of patients with urothelial carcinoma of the bladder treated with transurethral resection of the bladder

Outcomes
Study and patient characteristicsDisease recurrenceDisease progressionCancer-specific mortalityAny-cause mortality
StudyYearsSample size
(n)
Mean or median age (years)Pathological stage
(%)
Pathological grade
(%)
Additional intervention (%)Mean or median follow-up (months)Smoking
status
Smoking exposureSmoking statusSmoking exposureSmoking statusSmoking exposureSmoking statusSmoking exposure
Allard et al. (1995)1990-199236865.1Ta 78.8;
T1 21.2
G1 34.2;
G2 53.8;
G3 12.0
Re-TUR NR;
BCG 17.4;
Chemo 2.2
23.7HR=1.28 (0.82-1.98);*
HR=1.45 (0.94-2.24)
-------
Cheng et al. (1999)1987-19928372T1 100LG 33.7;
HG 66.3
Re-TUR NR;
BCG 13.3;
Chemo 19.3;
Radiation 1.2
64.8--p=0.22-----
Fleshner et al. (1999)1985-199528661.2Ta 52.4;
Tis 16.8;
T1 30.8
G1 33.6;
G2 31.1;
G3 35.3
Re-TUR 100;
BCG 22.7;
Chemo NR
57.3HR=0.99, p=0.89;§
HR=1.40,p=0.03
-------
Chen et al. (2007)1997-200526567Ta 62.4;
T1 37.6
LG 72.5;
HG 27.5
Re-TUR NR;
BCG 18.9;
Chemo 57.7
38HR=2.2,p=0.03;
HR=1.4, p=0.35;**
HR=2.2,p=0.01††
HR=1.01, p=0.98;‡‡
HR=1.5, p=0.27;§§
HR=2.1,p=0.02∥∥
p=0.43;
p=0.29;
p=0.02††
-----
Gee et al. (2009)1991-20034367NRNRRe-TUR NR;
BCG 100;
Chemo NR
NRHR=3.20, p=0.05;¶¶
HR=0.27,p=0.03
-------
Gangawar et al. (2010)2006-200813557.1NRG1 50.4;
G2/G3 49.6
Re-TUR NR;
BCG 54.8;
Chemo 0.0
14HR=1.86,p=0.02¶¶-HR=1.96, p=0.39¶¶-----
Hwang et al. (2011)2000-201025167Ta 63.7;
T1 36.3
PUNLMP 5.6;
LG 62.5;
HG 31.9
Re-TUR NR;
BCG 50.1;
Chemo 14.3
34HR=1.63,p=0.02¶¶-p=0.21¶¶-----
Lammers et al. (2011)1998-200471866.5Ta 78.7;
T1 21.3
G1 42.1;
G2 47.0;
G3 10.9;
Re-TUR NR;
BCG NR;
Chemo 100
30HR=1.47,p=0.048¶¶
p=0.30;***
p=0.25;†††
p=0.06‡‡‡
------
Sfakianos et al. (2011)1994-200862376Ta 35.2;
Tis 30.3;
T1 34.5
LG 9.6;
HG 90.4
Re-TUR 100;
BCG 100;
Chemo NR
80.9HR=1.05, p=0.68;¶¶
HR=1.05, p=0.65;*
HR=1.04, p=0.81
-HR=1.02, p=0.93;¶¶
HR=1.00, p=0.99;*
HR=1.16, p=0.61
-HR=1.14, p=0.49;¶¶
HR=1.20, p=0.34;*
HR=1.03, p=0.91
-HR=1.15, p=0.61;¶¶
HR=1.14, p=0.63;*
HR=1.27, p=0.49
-
Ajili et al. (2012)2000-200711263.9Ta 60.7;
T1 39.3
G1 39.3;
G2 43.8;
G3 17.0
Re-TUR NR;
BCG 100;
Chemo NR
NRHR=0.49, p=0.06¶¶-------
Rink et al. (2012)1987-200739067Ta 67.9;
Tis 1.5;
T1 30.5
G1 36.9;
G2 28.7;
G3 34.4
Re-TUR NR;
BCG 15.4;
Chemo 3.3
66p=0.5;*
p=0.4;
p=0.7
p=0.02;§§§
p<0.001;∥∥∥
HR=2.08,p=0.006;¶¶¶
HR=4.31,p<0.001****
p=0.7;*
p=0.2;
p=0.2
p<0.001;§§§
p<0.001;∥∥∥
p=0.003††††
--p>0.05*
p>0.05;
-
Segal et al. (2012)1995-200527872.8T1 100HG 100Re-TUR NR;
BCG 35.6;
Chemo NR
36--HR=1.15, p=0.51¶¶-----
Rink et al. (2013)1987-2007204367Ta 61.0;
T1 39.0
G1 23.6;
G2 33.8;
G3 42.6
Re-TUR NR;
BCG 16.1;
Chemo 3.8
49HR=1.12 (0.94-1.34);*
HR=1.22 (1.01-1.48)
HR=0.43 (0.30-0.60);‡‡‡‡
HR=0.91 (0.77-1.07);§§§§
HR=0.35 (0.26-0.47)∥∥∥∥
HR=1.29 (0.79-2.09);*
HR=2.09 (1.29-3.39)
HR=0.12 (0.03-0.44);‡‡‡‡
HR=0.43 (0.29-0.63);§§§§
HR=0.05 (0.01-0.19)∥∥∥∥
--HR=1.10 (0.86-1.41);*
HR=1.12 (0.85-1.47)
HR=0.81 (0.51-1.27);‡‡‡‡
HR=0.67 (0.52-0.85);§§§§
HR=0.54 (0.37-0.80)∥∥∥∥
Serretta et al. (2013)2002-200339568Ta 36.5;
T1 63.5
G1 35.9;
G2 64.1
Re-TUR NR;
BCG NR;
Chemo 100
48HR=1.60,p=0.04¶¶-------
Grotenhuis et al. (2014)1995-201296364Ta 70.0;
Tis 3.8
T1 26.2
LG 61.8;
HG 38.2
Re-TUR NR;
BCG 22.0
Chemo 33.0
44HR=1.06, p=0.68;¶¶
p=0.47
p=0.62***;
p=0.61†††
HR=1.85, p=0.25;¶¶
p=0.54
p=0.95***;
p=0.15†††
----
Kashif Khan et al. (2014)2008-20126459.9NRNRRe-TUR NR;
BCG 100;
Chemo NR
28.4NS-OR=4.02,p=0.04¶¶-----
Rausch et al. (2014)1996-200619268.3Ta 76.3;
T1 23.7
G1 43.5;
G2 50.0;
G3 6.5
Re-TUR NR;
BCG NR;
Chemo NR
80OR=1.40, p=0.11¶¶-OR=0.51, p=0.20¶¶-----
Wyszynski et al. (2014)1994-2001726NRTa/T1 93.7;
Tis 6.3
LG 73.1;
HG 25.9
Re-TUR NR;
BCG NR;
Chemo NR
67.2HR=1.61,p=0.003;*
HR=1.51,p=0.02
-------

* Former vs. never smokers.

Current vs. never smokers.

Current vs. former vs. never smokers.

§ Quitters vs. former smokers.

Current vs. former smokers.

Never smokers vs. quitters.

** Former smokers vs. quitters.

†† Current smokers vs. quitters.

‡‡ 20-39 vs. 1-19 pack-years.

§§ 40-59 vs. 1-19 pack-years.

∥∥ ≥60 vs. 1-19 pack-years.

¶¶ Smokers vs. non-smokers.

*** Number of cigarettes per day.

††† Number of years of smoking.

‡‡‡ Number of pack-years.

§§§ ≥20 vs. <20 cigarettes per day.

∥∥∥ ≥20 vs. <20 years of smoking.

¶¶¶ Moderate vs. light short-term smokers.

**** Heavy long-term (>20 cigarettes per day for >20 years) vs. light short-term (≤20 cigarettes per day for ≤20 years) smokers.

†††† Heavy long-term vs. moderate (>20 cigarettes per day for ≤20 years or ≤20 cigarettes per day for >20 years) vs. light short-term smokers.

‡‡‡‡ Heavy short-term (>20 cigarettes per day for ≤20 years) vs. heavy long-term smokers.

§§§§ Light long-term (≤20 cigarettes per day for >20 years) vs. heavy long-term smokers.

∥∥∥∥ Light short-term vs. heavy long-term smokers.

G1=grade 1; G2=grade 2; G3=grade 3; re-TUR=repeat transurethral resection of the bladder; NR=not reported; BCG=bacillus Calmette-Guérin; chemo=adjuvant chemotherapy; HR=hazard ratio; LG=low-grade; HG=high-grade; PUNLMP=papillary urothelial neoplasm of low malignant potential; NS=non-significant.

Bold: statistically significant relationship.

Table 4

Selected studies reporting associations of smoking cessation and outcomes of patients with urothelial carcinoma of the bladder treated with transurethral resection of the bladder or radical cystectomy

Selected studies and their smoking cessation categoriesOutcomes
InterventionStudy*Cessation groupComparator groupDisease RecurrenceDisease ProgressionCancer-specific mortalityOverall mortality
Transurethral resection of the bladderFleshner et al. (1999)1-10 yr before1 yr before to 3 mo afterHR=1.01, p=0.89---
1-10 yr beforeCurrent smokersHR=0.71,p=0.03---
Chen et al. (2007)>1 yr before1 yr before to 3 mo afterHR=1.4, p=0.35---
1 yr before to 3 mo afterCurrent smokersHR=0.5,p=0.01---
Lammers et al. (2011)≥15 yr before<15 yr beforep=0.34---
Rink et al. (2012)≥10 yr beforeCurrent smokersHR=0.40,p<0.001HR=0.51, p=0.11--
<10 yr beforeHR=1.44, p=0.05HR=1.26, p=0.48--
Rink et al. (2013)≥10 yr beforeCurrent smokersHR=0.66 (0.52-0.84)HR=0.42 (0.22-0.83)-HR=0.98 (0.72-1.34)
<10 yr beforeHR=1.30 (1.09-1.53)HR=0.99 (0.65-1.50)-HR=1.02 (0.79-1.30)
Grotenhuis et al. (2014)≥10 yr beforeCurrent smokersHR=1.22 (0.88-1.68)HR=1.40 (0.85-2.30)--
<10 yr beforeHR=1.38 (0.97-1.95)HR=1.68 (0.92-3.07)--
Radical cystectomyRink et al. (2013)≥10 yr beforeCurrent smokersHR=0.44 (0.31-0.62)-HR=0.42 (0.29-0.63)HR=0.69 (0.52-0.91)
<10 yr beforeHR=1.08 (0.88-1.33)-HR=1.09 (0.86-1.37)HR=1.05 (0.85-1.28)

* Refer to Table 2 and Table 3 for study and patient characteristics.

Smoking cessation time periods are relative to the time of diagnosis.

HR=hazard ratio.

Bold: statistically significant relationship.

Although the current evidence represents an improvement because of emerging interest in elucidating the associations between smoking and NMIBC outcomes, several study-related and general limitations need to be overcome in future research. In general, NMIBC is a complex and heterogeneous disease: while some patients experience early disease recurrence or even disease progression, others remain free of their disease for a long time if not forever [8]. However, subset analyses of particular NMIBC risk groups (eg, intermediate vs high risk, low-grade vs high-grade tumors) are currently lacking. Moreover, the impact of smoking according to different treatment modalities (eg, white light vs photodynamic diagnosis for TURBT guidance, repeat TURBT) remains unexamined to the best of our knowledge.

For risk stratification and patient counseling, two established models are frequently used, the risk tables of the European Organization for Research and Treatment of Cancer and Club Urologico Espanol de Tratamiento Oncologico (Spanish Urological Oncology Group) [2]. Recently published studies have challenged the accuracy and clinical utility of these models because of insufficient discrimination [51]. In fact, both models adjust for several established risk factors, but do not adjust for the impact of the best-established individually modifiable risk factor, which may improve outcome predictions.

Finally, UCB carcinogenesis is a complex process affected by several inherent genetic and biologic factors, as well as geographic, environmental, occupational, and social behavioral elements [52]. The majority of current studies only controlled for smoking as a sole risk factor, and studies adjusting for combinations of risk factors are warranted.

3.2.2. Radical cystectomy

There is some evidence that smoking impacts disease prognosis in UCB patients treated with RC (Table 3), although this effect was less apparent compared to patients treated with TURBT. Overall, two of eight studies found that cigarette smoking was an independent predictor of disease recurrence, cancer-specific mortality, or overall survival [53], [54], [55], [56], [57], [58], [59], and [60]. Again, current smoking status and escalating lifetime smoking exposure were inversely associated with outcomes in these studies.

Table 3

Selected studies reporting associations of smoking and outcomes of patients with urothelial carcinoma of the bladder treated with radical cystectomy

Outcomes
Study and patient characteristicsDisease recurrenceCancer-specific mortalityAny-cause mortality
StudyYearsSample size
(n)
Mean or median age (years)Pathological stage
(%)
Pathological grade
(%)
Additional intervention
(%)
Mean or median follow-up (months)Smoking statusSmoking exposureSmoking statusSmoking exposureSmoking statusSmoking exposure
Thrasher et al. (1994)1969-199053164.5Ta 5.8;
Tis 4.3;
T1 31.3;
T2 40.1;
T3 7.0;
T4 11.5
G1/G2 12.4;
G3 42.2;
G4 45.4
Neoadj NR;
Adj NR
126--p=0.85*---
Boorjian et al. (2011)1980-2000150668T0-T1 30.0;
T2 37.7;
T3/T4 32.3
NRNeoadj/adj 11.0162HR=0.97, p=0.87*-----
Yafi et al. (2011)1998-2008228768T0-T2 50.7;
T3/T4 49.3
LG 10.1;
HG 89.9
Neoadj 3.4;
Adj 17.5
29.3 p =0.006*-HR=1.30, p=0.046*-HR=1.31, p=0.02*-
Boström et al. (2012)1986-200854666T0-T1 39.4;
T2 21.2;
T3 28.2;
T4 11.2
NRNeoadj NR;
Adj NR
50--HR=1.1, p=0.41-HR=1.3, p=0.10-
Lee et al. (2012)1989-200860262.2T0-T2 56.8;
T3/T4 43.2
G1/G2 15.6;
G3 84.4
Neoadj 0.0;
Adj NR
56.0HR=0.93, p=0.65;
HR=0.91, p=0.61§
HR=0.86, p=0.47HR=1.21, p=0.27;
HR=0.94, p=0.73§
HR=0.95, p=0.83HR=1.01; p=0.93-
Baumann et al. (2013)1990-200844267.0T0 7.9;
Ta 2.3;
Tis 15.4;
T1 8.1;
T2 18.8;
T3 31.7;
T4 15.8
NRNeoadj 8.8;
Adj 24.0
26.4HR=0.89, p=0.65*-----
Rink et al. (2013)2000-2008150666.4T0 5.2;
Ta 4.1;
Tis 11.2;
T1 11.3;
T2 26.6;
T3 30.5;
T4 11.2
None 5.2;
LG 1.9;
HG 92.9
Neoadj 0.0;
Adj 21.4
34.3HR=1.26 (0.96-1.66);
HR=1.47 (1.12-1.94)**
HR=1.54 (1.08-2.19);††
HR=1.70 (1.23-2.36);‡‡
HR=2.22 (1.62-3.02)§§
HR=1.22 (0.91-1.63);
HR=1.41 (1.04-1.90)**
HR=1.55
(1.04-2.32);††
HR=1.53 (1.04-2.24);‡‡
HR=2.07 (1.44-2.99)§§
HR=1.13 (0.89-1.44);
HR=1.25 (0.97-1.60)**
HR=1.23
(0.90-1.69);††
HR=1.36 (1.01-1.83);‡‡
HR=1.51 (1.13-2.01)§§
Kim et al. (2014)1990-201113965T0 17.3;
Tis 15.8;
T1 7.9;
T2 12.2;
T3 41.0;
T4 5.8
NRNeoadj 100;
Adj 0.0
46p=0.6∥∥p=0.11;¶¶
p=0.2***
p=0.9∥∥p=0.4;¶¶
p=0.4***

* Smokers vs. non-smokers.

Non-smokers vs. smokers.

Never vs. former smokers.

§ Never vs. current smokers.

Never smokers vs. ≥40 pack-years; also significant for never smokers vs. <10, <20, <30, and <40 pack-years.

Former vs. never smokers.

** Current vs. never smokers.

†† Heavy short-term (>20 cigarettes per day for ≤20 years) vs. light short-term (≤20 cigarettes per day for ≤20 years) smokers.

‡‡ Light long-term (≤20 cigarettes per day for >20 years) vs. light short-term smokers.

§§ Heavy long-term (>20 cigarettes per day for >20 years) vs. light short-term smokers.

∥∥ Current vs. former vs. never smokers.

¶¶ Number of packs per day.

*** Number of pack-years.

G1=grade 1; G2=grade 2; G3=grade 3; G4=grade 4; neoadj=neoadjuvant chemotherapy; NR=not reported; adj=adjuvant chemotherapy; HR=hazard ratio; LG=low grade; HG=high grade.

Bold: statistically significant relationship.

The highest level of evidence is obtained from prospective, randomized controlled studies, but the results reported here are from retrospective studies with all the inherent limitations that may limit the evidence base. Of particular importance for research on smoking is the fact that smoking status and exposure are mostly self-reported and are therefore subject to recall bias. Validated questionnaires to assess smoking in patients with cancer at different points during the disease course are still being developed [61]. In addition, if current smokers report themselves as former smokers, associations between smoking and outcomes would be biased toward the null, especially if such patients could not successfully quit smoking following diagnosis. Biochemical verification of smoking status may be a goal for future investigations.

The influence of smoking cessation on outcomes for UCB patients after RC remains undetermined (Table 4). We found only one study addressing this association, and it showed that quitting smoking reduced the risk of disease recurrence, cancer-specific mortality, and any-cause mortality [58]. Since there is some evidence that smoking influences the course of UCB, urologists should not only counsel patients regarding the detrimental effects of smoking but also assist in their smoking cessation attempts [62] and [63]. The association between smoking and UCB is not as well known as that for lung cancer [64]. For many patients, cancer diagnosis represents a teachable moment to motivate them to successfully quit smoking. UCB patients are often willing to quit smoking with the help of their physicians [65]. Appropriate patient education and brief physician meetings may increase compliance to ultimately cease smoking, improve outcomes, and enhance quality of life, as current smokers report increased fear of disease recurrence and psychological distress compared to nonsmokers [66]. However, too few patients are currently offered any intervention to aid in cessation by their urologists [64] and [67].

We also found contradictory evidence regarding a gender-specific effect of smoking in these patients. Interestingly, previous studies reported gender-specific differences in MIBC outcomes: women presented with more aggressive tumor biology and unfavorable sequelae [68]. Thus, this issue should be the subject of future investigations to clarify the effect of smoking on these variations.

As with NMIBC, research regarding the effects of smoking in MIBC needs to continue to improve our understanding and answer many questions. For example, the effects of smoking on UCB prognosis in conjunction with other demographic characteristics, such as race and ethnicity, other clinical risk factors, such as obesity [46], and multimodal therapies including neoadjuvant and adjuvant systemic chemotherapy require further investigation. Despite advances in surgical techniques and improvements in systemic chemotherapies, up to 50% of patients with MIBC experience disease recurrence within 5 yr after surgery, and the majority of these patients eventually die of UCB [69]. Similar to NMIBC, different decision-making tools have been developed to assist clinicians in patient counseling and estimation of multimodal treatment success in MIBC [70], [71], and [72], but are limited by imperfect discrimination. Combination with blood, tissue, and/or urine biomarkers improves these tools regarding outcome prognostication and patient selection for multimodal therapies [73]. A recently published study on MIBC patients treated with RC found that the combination of smoking information and tissue marker status achieved the highest level of discrimination and significantly improved outcome prediction [74].

4. Conclusions

Cigarette smoking is the best-established, individually modifiable risk factor for UCB development, although potential relationships with other inherent and environmental factors remain ambiguous. In addition, there is a growing body of evidence that smoking negatively affects UCB outcomes. According to the currently available literature, smoking status and cumulative lifetime smoking exposure at diagnosis and at different times during treatment seem to affect disease recurrence, progression, and survival. However, the evidence is quite heterogeneous, mainly because of the exclusively retrospective study designs. While studies have demonstrated that long-term smoking cessation reduces the risk of UCB carcinogenesis and improves prognosis, prospective evaluation of this relationship is lacking. Future research regarding the effects of smoking needs to continue to improve our understanding, and prospective studies need to address currently unanswered questions.


Author contributions: Michael Rink had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Rink, Crivelli.

Acquisition of data: Crivelli, Rink.

Analysis and interpretation of data: Rink, Crivelli.

Drafting of the manuscript: Rink, Crivelli.

Critical revision of the manuscript for important intellectual content: Rink, Crivelli, Shariat, Chun, Messing, Soloway.

Statistical analysis: Crivelli, Rink, Shariat.

Obtaining funding: None.

Administrative, technical, or material support: None.

Supervision: Rink, Crivelli.

Other (specify): None.

Financial disclosures: Michael Rink certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Michael Rink is a speaker for Pfizer Pharma. All the other authors have nothing to disclose.

Funding/Support and role of the sponsor: None.

Acknowledgments: Michael Rink is supported by a GEROK research grant from the University of Hamburg.

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Footnotes

a Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

b Department of Urology, Weill Cornell Medical College, New York Presbyterian Hospital, New York, NY, USA

c Department of Urology, Medical University Vienna, Vienna, Austria

d Department of Urology, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, NY, USA

e Department of Urology, Miller School of Medicine, University of Miami, Miami, FL, USA

Corresponding author. Department of Urology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. Tel. +49 40 741053442; Fax: +49 40 741042444.

These authors contributed equally to this review.

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