Review – Prostate Cancer

Smoking and Prostate Cancer: A Systematic Review

By: Cosimo De Nunzioa , Gerald L. Andrioleb, Ian M. Thompson Jrc and Stephen J. Freedlandd

EU Focus, Volume 1 Issue 1, November 2015, Pages 28-38

Published online: 13 November 2015

Keywords: Prostate, Prostate cancer, Smoking, Outcome, Treatment

Abstract Full Text Full Text PDF (461 KB) Patient Summary



Cigarette smoking is the leading cause of death from cancer, although the relationship between smoking and prostate cancer (PCa) is controversial.


To evaluate the available evidence of the role of cigarette smoking and PCa development and progression and to discuss possible clinical implications for PCa management.

Evidence acquisition

A PubMed search for relevant articles published between 2004 and September 2014 was performed by combining the following PICO (patient population, intervention, comparison, outcome) terms: male, smoking, prostate, prostate cancer, prevention, diagnosis, treatment, and prognosis. Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines were followed.

Evidence synthesis

The association between cigarette smoking and PCa incidence is controversial, particularly in recent series. Current cigarette smoking is associated with an increased risk of PCa death, and the number of cigarettes smoked per day had a dose–response association with PCa mortality. Smokers present a higher risk of biochemical or distant failure after PCa treatment. Several biological mechanisms behind these associations have been proposed, although the molecular mechanisms remain unclear. Further research is required to better understand the role of smoking on PCa development and progression and, particularly, to evaluate the possible effect of smoking cessation on PCa management.


Data from the peer-reviewed literature suggested an association of smoking and aggressive PCa. Although the pathophysiology underlying this association remains unclear, smokers presented higher PCa mortality and worse outcome after treatment. Smoking-cessation counseling should be implemented for patients with PCa, although its effect on PCa progression should be investigated.

Patient summary

We looked at the association between smoking and prostate cancer (PCa). Smokers have a higher risk of PCa mortality and worse outcomes after treatment. Smoking cessation should be encouraged in men with or at risk of having PCa.

Take Home Message

Smoking is associated with worse prostate cancer (PCa) outcome and higher PCa mortality. Smoking cessation should be encouraged for PCa patients.

Keywords: Prostate, Prostate cancer, Smoking, Outcome, Treatment.

1. Introduction

Prostate cancer (PCa) is the leading cause of nonskin cancer among men worldwide and, after lung, is the second most common cause of death from cancer in men in the United States [1] and [2]. PCa is considered a chronic disease with early initiation and slow progression; it develops through early and late precancerous histologic modifications [3]. The only established risk factors associated with PCa are age, race, and family history, although large geographic variations in PCa risk suggest that lifestyle and environmental factors may also contribute to its etiology [3]. It has been hypothesized that the increased prevalence of metabolic syndrome resulting from lifestyle changes associated with a Western lifestyle (including physical inactivity and higher intakes of refined carbohydrates and excess calories) may explain, in part, the fact that once Asians migrate to the United States, their risk of PCa approaches that of white Americans within one or two generations [4], [5], and [6]. There is little evidence for any association between alcohol and prostate cancer [7]. Paradoxically, several studies have reported an inverse association between diabetes mellitus and prostate cancer risk [8] and [9].

Cigarette use is the leading cause of death from cancer, but the relationship between smoking and PCa remains controversial; some studies indicate no association, whereas others suggest an elevated risk among smokers [10]. A recent meta-analysis found a modest but statistically significant association between cigarette smoking and PCa death; a dose-response relationship was also found. Conversely, the association between cigarette smoking and PCa incidence was mixed [11]. Smoking may also have a significant effect on treatment outcome of cancers for which smoking is not related [12]. As such, there has been growing interest in the field as to whether patients with a history of smoking present with worse disease, have worse response to treatment, or have other confounding factors that could explain inferior outcomes [12].

The possibility of modifying environmental factors, including smoking, have been proposed as a new frontier in the prevention and management of several cancers including PCa [13]. In this review we evaluate contemporary evidence regarding smoking as a causative factor in PCa development and as a significant variable in disease outcome. We also discuss the potential clinical implications of this evidence and suggest directions for future research.

2. Evidence acquisition

A search of the National Center for Biotechnology Information PubMed database for relevant articles published between 2004 and September 2014 was performed by combining the following PICO (patient population, intervention, comparison, outcome) terms: male, smoking, prostate, prostate cancer, prevention, diagnosis, treatment, and prognosis. Only articles published in the English language were selected. In addition, sources in the reference sections of the identified publications were also added to the list. Evidence was not limited to human data; data from animal studies were also included in the review. Each article title and abstract was reviewed for relevance and appropriateness with regard to the relationship between cigarette smoking and PCa. Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines were followed to ensure transparent and complete reporting of this systematic review (Fig. 1). Details of the selected references are summarized in Table 1 and Table 2.


Fig. 1

Flow diagram of the search results.

Table 1

Characteristics of studies evaluating the association between smoking and prostate cancer published in the last 10 yr

StudyStudy name (or description); country, recruitment periodStudy design, outcomeLast FU (FUa, yr)Total no. men; cases bSmoking category*No. of cases*RR (95% CI)*
Visvanathan et al, 2004 [14]Campaign Against Cancer and Stroke (CLUE II); USA, 1989Nested CCS, incidence1996 (NR)10 178; 164 (324)Never-smoker
0.99 (0.63–1.36)
0.82 (0.39–1.71)
Hultdin et al, 2005 [15]Northern Sweden Health and Disease Cohort; Sweden, 1985–1999Nested CCS, incidenceNR (4.9)37 776; 254 (514)Never-smoker
1.08 (0.79–1.48)d
0.93 (0.61–1.41)d
Baglietto et al, 2006 [16]Melbourne Collaborative Cohort Study; Australia, 1990–1994Cohort, incidence2003 (10.3)16 872; 732Never-smoker
0.94 (0.81–1.07)d
0.73 (0.56–0.94)d
Giovannucci et al, 2007 [10]Health Professionals Follow–up Study; USA, 1986Cohort, incidence2002 (NR)47 750; 3544Never
Current/former (quit ≤10yr)
0.98 (0.89–1.07)
Cohort, mortality2002 (NR)47 750; 312Never-smoker
Current/former (quit ≤10yr)
1.41 (1.04–1.91)
Gonzalez et al, 2007 [17]Vitamins and Lifestyle (VITAL); USA, 2000–2002Cohort, incidence2004 (3.3)35 244; 832Never-smoker
0.92 (0.70–1.20)
0.94 (0.82–1.05)
Rohrmann et al, 2007 [18]Private census; Washington County, Maryland, USA, 1963Cohort, incidence1978 (NR)26 810; 147Never-smoker
1.16 (0.84–1.60)
1.00 (0.63–1.59)
Cohort, mortality2000 (NR)226 810; 240Never-smoker
0.97 (0.76–1.23)
0.93 (0.67–1.29)
USA, 1975Cohort, incidence1994 (NR)28 292; 351Never-smoker
1.01 (0.83–1.24)
0.98 (0.73–1.33)
Cohort, mortality2000 (NR)28 292; 184Never-smoker
1.13 (0.85–1.49)
1.25 (0.84–1.87)
Smit et al, 2007 [19]Puerto Rico Heart Health Program; Puerto Rico, 1965–1968Cohort, mortality2005 (NR)9777;167Never-smoker
1.16 (0.82–1.65)d
1.26 (0.82–1.94)d
Butler et al, 2009 [20]Singapore Chinese Health Study; Singapore, 1993–1998Cohort, incidence2006 (10.4)27 293; 250Never-smoker
0.95 (0.74–1.16)
0.88 (0.65–1.19)
Watters et al, 2009 [21]NIH–AARP; USA, 1995–1996Cohort, incidence2003 (NR)283 312; 16 640Never-smoker
11 128
0.89 (0.86–0.91)
0.85 (0.80–0.90)
Cohort, mortality2005 (NR)283 312; 394Never-smoker
1.13 (0.93–1.34)
1.69 (1.25–2.27)
Batty et al, 2011 [22]Whitehall I study; UK, 1967–1970Cohort, mortality2007 (NR)17 934; 551Never-smoker
1.03 (0.88–1.21)
1.14 (0.91–1.44)
Grundmark et al, 2011 [23]Uppsala Longitudinal Study of Adult Men (ULSAM); Sweden, 1970–1974Cohort, incidence2003 (26.5)2045; 208Never-smoker
0.67 (0.50–0.83)
0.60 (0.44–0.83)
Geybels et al, 2012 [24]Netherlands Cohort Study; Netherlands, 1986Cohort, incidence2003 (17.3)58 279;3451Never
1.01 (0.88–1.13)
0.98 (0.82–1.18)
Karlsen et al, 2012 [25]Danish Diet, Cancer and Health Study; Denmark, 1993–1997Cohort, incidence2000–2002 (NR)20 914; 129Nonsmoker
1.00 (0.70–1.43)
Karppi et al, 2012 [26]Kuopio Ischaemic Heart Disease Risk Factor; Finland, 1984–1989Cohort, incidence2008 (15)997; 68Nonsmoker
0.85 (0.76–0.95)d
Shafique et al, 2012 [27]Collaborative study; Scotland, 1970–1972Cohort, incidence2007 (28)6017; 318Never
1.08 (0.84–1.32)
0.93 (0.69–1.26)
Tseng, 2012 [28]Taiwan Insurance; Taiwan, 1995–1998Cohort, mortality2006 (NR)39 135; 105Nonsmoker
1.09 (0.82–1.46)
Bae et al, 2013 [29]Seoul Male Cancer Cohort Study; South Korea, 1991–1992Cohort, incidence2008 (NR)14 450; 87Never-smoker
0.65 (0.40–0.90)
0.70 (0.43–1.13)
Heikkila et al, 2013 [30]IPD-Work Consortium; Europe, 1985–2002Cohort, incidence2008 (12)116 056; 865Nonsmoker
0.70 (0.59–0.84)d
Koutros et al, 2013 [31]Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO); USA, 1993–2001Nested CCS, incidence2009 (3.4)28 243; 680 (824)Never-smoker
0.70 (0.58–0.84)d
0.50 (0.36–0.69)d
Lemogne et al, 2013 [32]GAZEL study; France, 1989Cohort, incidence2009 (15.2)8877; 412Never-smoker
0.86 (0.73–1.00)
Onitilo et al, 2013 [33]Marshfield Clinic; USA, 1995–2009Cohort, incidence2011 (NR)33 832; 3432Before DM onset
After DM onset



0.92 (0.85–1.18)

0.83 (0.74–0.94)
Rohrmann et al, 2013 [34]European Prospective Investigation into Cancer and Nutrition (EPIC); Europe, 1992–2000Cohort, incidence2009 (11.9)145 112; 4623Never-smoker
0.93 (0.89–0.98)
0.90 (0.83–0.97)
Cohort, mortality2009 (11.9)145 112; 432Never-smoker
1.06 (0.87–1.24)
1.27 (0.98–1.65)
Sawada et al, 2013 [35]Japan Public Health Center-based Prospective Study (JPHC); Japan, 1990–NRCohort, incidence2010 (16)482 018; 913Never-smoker
Current (cumulative use)
0.80 (0.72–0.89)
0.79 (0.68–0.89)

* Data on cigarette smoking. For qualitative measures of use, data on current cigarette smoking (at baseline) are shown in this table.

a The mean or median of follow-up in years.

b The numbers in parentheses are the number of controls in nested CCSs.c Cumulative use during previous decade.

CI = confidence interval; CCS = case-control study; DM = diabetes mellitus; FU = follow-up; NR = not reported; RR = risk ratio.

Adapted from Islami et al [11].

Table 2

Characteristics of studies evaluating the association between smoking and prostate cancer treatment outcome

StudyStudy name (or description); country, recruitment periodStudy design, outcomeLast FU (FUa, yr)Total no.Smoking category*No. of cases*Main outcome
Roberts et al, 2003 [36]Johns Hopkins RRP series; USA, 1992–1999Retrospective CCS, RRP1999 (NR)1544Never-smoker
1.47 (0.84–2.56)
3.17 (1.13 – 8.85)
GS ≥7 or pT3 disease
Pickles et al, 2004 [37]Radiation Program, British Columbia Cancer Agency; Canada; 1994–1997Prospective, CCS, EBRT2003 (5)601Never-smoker
1.68 (1.11–2.56)
PSA relapse
Merrick et al, 2004 [38]USA, 1995–2000CCS, Brachytheraphy2000 (54.5)582Never-smoker
1.31 (NR)
2.69 (NR)
PSA relapse
Oefelein and Resnick, 2004 [39]USA, 1987–2003Retrospective CCS2003 (NR)222Never-smoker
2.7 (NR)
Castration-resistant PCa
Panatarotto et al, 2007 [12]Canada, 1990–1999Retrospective CCS, EBRT1999 (NR)434Never-smoker
HR: 2.90 (1.09–7.67)
HR 5.24 (1.75–15.72)
Distant failure
Gong et al, 2008 [40]Seattle, WA, USA, 1993–1996CCS, RRP, EBRT, ADT1996 (NR)752Never-smoker
Ever (quit >10 yr)
Ever (quit <10 yr)
0.45 (0.19–1.05)
1.48 (0.50– 4.37)
2.66 (1.01 – 3.99)
PCa–specific death
Kenfield et al, 2013 [41]The Health Professionals Follow–up Study; USA, 1986–2006Cohort Study, RRP, EBRT2008 (8.1)5366Never-smoker
1.11 (0.96 – 1.29)
1.61 (1.16– 2.22)
PSA relapse
Joshu et al, 2011 [42]Johns Hopkins RRP series; USA, 1993–2006Retrospective CCS2009 (7.3)1416Never-smoker
1.16 (0.78– 1.74)
2.31 (1.05– 5.10)
PCa recurrence
Dieperink et al, 2012 [43]Denmark, 2006–2008Retrospective CCS2008 (NR)317Never-smoker
7.8 (NR)
EPIC bowel overall bother
Oh et al, 2012 [44]Korea, 2004–2010Retrospective CCS2010 (NR)1165Nonsmoker
2.2 (1.04–3.83)
PSA relapse in BMI ≥25 kg/m2
Ngo et al, 2013 [45]Stanford, CA, USA, 1989–2005CCS, RRP2005 (NR)630Never-smoker

0.031 (0.015–0.048) Pack–yr
Cancer Volume
Moreira et al, 2014 [46]Shared Equal Access Regional Cancer Hospital (SEARCH); USA, 1995–2010Cohort, RRP20101670Never-smoker
2.67 (1.21–5.87)
Castration-resistant PCa

* Data on cigarette smoking. For qualitative measures of use, data on current cigarette smoking (at baseline) are shown in this table.

a The mean or median of follow-up in years.

ADT = androgen deprivation therapy; BMI = body mass index; CCS = case-control study; EBRT = external beam radiotherapy; EPIC = Expanded Prostate Index Composite Questionnaire; FU = follow-up; GS = Gleason score;

HR = hazard ratio; NR = not reported; PCa = prostate cancer; PSA = prostate-specific antigen; RRP = radical retropubic prostatectomy.

3. Evidence synthesis

3.1. The burden of smoking behavior

Native Americans were using tobacco products in the Americas prior to the arrival of Columbus, but widespread use of tobacco in cigarettes is more recent, occurring largely during the 20th century [47]. Concern among members of the scientific community that cigarette smoking caused disease grew with the publication of retrospective epidemiologic studies of lung cancer in the late 1940s and early 1950s. Currently, tobacco smoking is considered a major public health concern because it is responsible for high levels of mortality and morbidity worldwide. Smoking causes increased risk of mortality from lung cancer and aerodigestive, bladder, and several other cancers; it is also associated with an increased risk of cardiovascular disease, stroke, chronic respiratory disease, and a number of other medical conditions [48]. In the developed world, smoking was reported to be the risk factor with the largest attributable mortality and attributable disability-adjusted life years (DAYLS) by the World Health Organization: 12.2% of all DALYS were attributed to smoking. Most of the deaths attributable to smoking may be grouped into three broad categories: cancers, cardiovascular diseases, and respiratory diseases. Data from Canada showed that cancer accounted for 46.8% of smoking-attributable death, cardiovascular disease accounted for 27.6%, and respiratory diseases accounted for 22.3% [48].

Notwithstanding the related morbidity and mortality and all of the prevention campaigns and smoking-cessation counseling programs conducted in the last 50 yr, the number of daily smokers and total cigarettes consumed each year worldwide is increasing. There is a continuous increase in the number of men and women who smoke daily, increasing form 721 million (95% confidence interval [CI], 700 million–742 million) in 1980 to 967 million (95% CI, 944 million–989 million; p = 0.001) in 2012. Between 1980 and 2012, the number of cigarettes smoked worldwide increased from 4.96 trillion (95% CI, 4.78 trillion–5.16 trillion) to 6.25 trillion (95% CI, 6.07 trillion–6.44 trillion; p = 0.001). Estimated prevalence of daily smoking also varies according to different geographic area, from >50% in Western Europe and Asia (Russia, Armenia, Indonesia) to 27.5–34.7% in Central Europe (France, Spain, Germany); 16.5–19.7% in the United States, Canada, and Brazil; and <10% in sub-Saharan Africa (Niger, Nigeria, Ghana, Sudan) [49]. Possible differences in smoking behavior should be considered when comparing PCa data from different geographic areas.

3.2. Association between smoking and prostate cancer

3.2.1. Potential biological mechanisms

Some studies have shown possible mechanistic pathways linking smoking and PCa development and progression, but the evidence is limited and results are sometimes based on experimental or in vitro models only [11]. Constituents of cigarette smoke, such as polycyclic aromatic hydrocarbons (PAH), require metabolic activation, evasion or detoxification processes, and subsequent binding to DNA to exert their carcinogenetic action. Consequently, mutations or functional polymorphism in genes involved in PAH metabolism and detoxification may modify and influence the effect of smoking on PCa pathogenesis [50]. The glutathione-S-transferases (GSTs) comprise a class of enzymes that detoxify tobacco-related carcinogenesis including PAHs by conjugating glutathione to facilitate their removal. Of the seven mammalian GST classes characterized, those that have shown substrate specifically for PAH metabolites and that are expressed in the human prostate include GSTP and the GSTM. Human prostatic epithelium predominantly expresses the GSTP1 subtype, and loss of GSTP1 expression has been observed as one of the earliest events in prostate carcinogenesis [51]. In an exploratory case–control study evaluating 122 cases of PCa and 122 controls, among participants with the genotype GSTP1 Ile/Ile, smoking was associated with an increased risk of PCa with an adjusted odds ratio (OR) of 4.09 (95% CI, 1.25–13.35) compared with nonsmokers [51]. GSTM variants have also been shown to affect the association between smoking and PCa risk. In a family-based case–control design study (439 PCa cases and 479 brother controls), among white participants (90% of the study population), heavy smoking increased PCa risk nearly twofold in those with the GSTM1 null genotype (OR: 1.73; 95% CI, 0.99–3-05), but this increased risk was not observed in heavy smokers who carried the GSTM1 nondeleted allele (OR: 0.95%; 95% CI, 0.53–1.71) [50]. Mutation in the p53 gene, one of the most mutated tumor-suppressor genes in human neoplasms, or in the human cytochrome P450, which is involved in the metabolic pathways of several endogenous and exogenous compounds as steroids and environmental xenobiotics, may play a significant role in modifying PCa risk in smokers [52]. Increased hemeoxygenase 1 (HO-1) messenger RNA expression and upregulated HO-1 protein levels, induced by smoking, are also present in PCa cell lines [53]. HO-1 may have a role in tumor angiogenesis [54].

Exposure to carcinogenic substances found in cigarettes (eg, cadmium) has been proposed as an alternative mechanism for PCa carcinogenesis. Cadmium has been shown to indirectly induce prostate carcinogenesis through interaction with the androgen receptor. Ye et al [55] have reported that cadmium can activate the androgen receptor response in human PCa cell lines in the absence of androgen but in the presence of the androgen receptor. Cadmium also enhances androgen-mediated transcriptional activity in the prostate when applied in combination with the androgen [56].

Another possible mechanism linking smoking and aggressive PCa involves changes in the sex steroid pathway. Current smokers have higher concentrations of total testosterone, free testosterone, total estradiol, and free estradiol than former or never smokers [57]. Smoking may alter testosterone secretion from Leydig cells or may act as an aromatase inhibitor, reducing the conversion of testosterone to estradiol, thus increasing testosterone concentrations [57]. Data from the Third National Health and Nutrition Examination Survey (NHANES III) also showed that higher daily numbers of cigarettes smoked, pack-years smoked, and serum cotinine were all associated with greater concentrations of total and free estradiol. Smoking is associated with increased estrogen 2-hydroxylation in the liver, causing the formation of 2-hydroxy estrogens [18]. Although the exact role of androgens and estrogens in PCa development and progression is still unclear, it has been suggested from animal and experimental studies that testosterone may exert a differentiating effect on PCa and that elevated estrogen levels may promote testosterone-induced carcinogenesis and result in higher-volume and more aggressive PCa [4], [6], and [58].

Another possible mechanism relates to inflammation. Smoking induces inflammation in various tissues [59], and smokers have more inflammation within the prostate than nonsmokers [60]. Chronic prostatic inflammation as observed in smokers is associated with a milieu rich in proinflammatory cytokines, inflammatory mediators, and growth factors that may lead to an uncontrolled proliferative response with rapidly dividing cells that are more likely to undergo mutation, as observed in cancer [58].

Although not heretofore studied in the prostate, nicotine can also induce angiogenesis in some tissues, and smoking can inhibit a wide variety of immune reactions including response to vaccines. Both conditions may lead to faster cancer progression and worse prognosis for smokers [12].

Possible biological mechanisms linking smoking with PCa development are summarized in Figure 2.


Fig. 2

Biological hypothesis for prostate cancer development and smoking.

3.2.2. Clinical evidence

Despite the links between smoking and a variety of solid tumors as well as the multitude of potential biological pathways affected by smoking that are involved in PCa carcinogenesis, the association between cigarette smoking and PCa remains a matter of debate [61] (Table 1). Recently, two meta-analyses summarized the evidence regarding the association between cigarette smoking and PCa risk [11] and [61]. A meta-analysis of 24 prospective studies published in 2010, but including studies up to February 2007, found no significant association between current smoking and PCa incidence but showed a significant 11–22% increased risk depending on the exposure measurement method (daily amount of use, cumulative use) [11] and [61]. The data presented by Islami et al [11] showed a possible association between smoking and increased PCa incidence but only in studies completed in 1995 or earlier, whereas studies completed afterward showed a null or even inverse association. Cigarette smoking at baseline was inversely associated with incident PCa (risk ratio [RR]: 0.90; 95% CI, 0.85–0.96); however, results showed high heterogeneity (I2 = 68%; p < 0.001). In meta–regression analysis, the amount of cigarettes smoked per day was not significantly associated with PCa risk (p = 0.09). No significant, clear pattern of association was observed between smoking duration and PCa risk. Previous smoking showed no association (RR: 1.00; 95% CI, 0.95–1.06), but ever smoking showed an inverse association (RR: 0.94; 95% CI, 0.90–0.98) with incident PCa; however, heterogeneity in results for both groups was high (previous smoking: I2 = 61%; p < 0.001; ever smoking: I2 = 68%; p < 0.001). It is unlikely that the difference in pattern of association over time is related solely to differences in the quality of studies. Some earlier studies were large, well-conducted studies. One possible explanation, suggested by the authors, is that smoking may reduce the risk of indolent nonaggressive cancers, which predominate among cancers detected in more recent years, while promoting more aggressive cancers [11]. Alternatively, smoking has been linked with lower risk of screening and poor compliance with prostate biopsy [62]. A recent analysis of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study, in which men with a negative baseline biopsy and elevated prostate-specific antigen (PSA) were randomized to dutasteride or placebo and were required to under biopsy at 2 and 4 yr, found that smokers were less compliant [62]. On the 2-yr biopsy, smokers had more high-grade disease; when considering the whole REDUCE study and the fewer biopsies performed, this effect was lost. On a population level, perhaps smokers are less likely to be screened, resulting in the detection of fewer nonaggressive PCa screen-detected cancers and making smoking appear “protective” in more recent years.

Regarding PCa mortality (as opposed to PCa incidence), the data were more clear. A significant 14% increased risk of PCa death associated with current smoking was reported in that meta-analysis [62]. The highest categories of smoking were associated with 24–30% increased risk [11] and [61]. Results of several prospective studies were published recently and included in a meta-analysis by Islami et al [11]. The recent meta-analysis observed a robust association between cigarette smoking and PCa death: It was observed in analyses of current, former, and ever use and in meta–regression models, suggesting a dose-response association, and persisting in subgroup analyses including when stratified by geography or study completion time [11]. Current cigarette smoking at baseline was associated with an increased risk of death from PCa (RR: 1.24; 95% CI, 1.18–1.31) with little heterogeneity in results (I2 = 1%; p = 0.45). In meta–regression models, the amount of cigarette smoking at baseline (cigarettes per day) showed a dose-response association with PCa death (p = 0.02; 20 cigarettes per day, RR: 1.20). The RR for the association between previous cigarette smoking at baseline and PCa mortality was 1.06 (95% CI, 1.00-1.13) with little heterogeneity (I2 = 0%; p = 0.62). The RR for the association between ever cigarette smoking and PCa mortality was 1.18 (95% CI, 1.11–1.24) but with moderate, statistically significant heterogeneity (I2 = 36%; p = 0.04).

Limitations of the available evidence should be considered. Only a few of the studies included in the two meta-analyses provided information about PCa screening in their study populations, probably because this information was not available from most cancer registers, which were the main sources of outcome measures [11] and [61]. The few papers that did provide this information suggest that the association between smoking and PCa death may be slightly stronger in those with no screening compared with those with PCa screening [11], [61], and [62]. It is also important to emphasize that most available data on the possible association of smoking and PCa incidence and mortality from observational studies are often geographically limited to a specific area or population with different smoking and lifestyle behavior and consequently should be considered exploratory and serve primarily to develop and implement future clinical trials.

3.3. Association between smoking and prostate cancer outcome after treatment

Several observational studies have shown that smoking is associated with worse outcome in patients with PCa treated with radiotherapy or medical or surgical treatment (Table 2). Roberts et al [36] provided evidence that in 352 men undergoing radical retropubic prostatectomy (RRP) for PCa, a dose-dependent relationship exists between cigarette smoking, on the one hand, and extraprostatic disease and Gleason sum ≥7, on the other. Risk was greatest for current smokers (OR: 3.85 [95% CI, 1.44–10.33] and 1.76 [95% CI, 0.66–4.72], respectively), although the association remained increased for former smokers (OR: 1.49 [95% CI, 0.92–2.42] and 0.72 [95% CI, 0.44–1.19], respectively) when compared with nonsmokers (OR: 1.66 [95% CI, 1.04–2.65] and 0.81 [95% CI, 0.5–1.30], respectively). A recent study confirmed this observation and showed a significant difference in PCa volume (2.54 vs 2.16 ml; p = 0.016) as well as high-grade cancer volume (0.58 vs 0.28 ml; p = 0.004) when comparing smokers and nonsmokers [45]. Smoking also heralded a greater risk of biochemical recurrence (hazard ratio [HR]: 1.27; 95% CI, 1.03–1.54; p = 0.02), the magnitude of which was approximately 1% per pack-year smoked [45].

Recent data from the Shared Equal Access Regional Cancer Hospital Cohort (SEARCH) database confirmed that active smoking was associated, after adjusting for preoperative features, with an increased risk of biochemical recurrence (HR: 1.25; p = 0.024), metastasis (HR: 2.64; p = 0.026), and overall mortality (HR: 2.14; p < 0.001). Similar results were noted after further adjustment for postoperative features, with the exception of BCR (HR: 1.10; p = 0.335), metastasis (HR: 2.51; p = 0.044), and death (HR: 2.03; p < 0.001) [46].

Data from the Health Professionals Follow-up Study also confirmed a direct relationship between the number of cigarettes smoked and inferior treatment outcome in PCa patients [41]. Current smokers of ≥40 pack-years, versus never-smokers, had an increased risk of PCa mortality (HR: 1.82; 95% CI, 1.03–3.20) and BCR (HR: 1.48: 95% CI, 0.88–2.48). Compared with current smokers, those who had quit smoking for ≥10 yr (HR: 0.60; 95% CI, 0.42–0.87) or who had quit for <10 yr but smoked <20 pack-years (HR: 0.64; 95% CI, 0.28–1.45) had PCa mortality risk similar to never smokers (HR: 0.61; 95% CI, 0.42–0.88).

A single experience from Asia does not support the association between smoking and a worse treatment outcome in patients treated with RRP, although the association was evident in obese patients [44]. However, this single negative outcome related to a retrospective study in a Korean population could also reflect different cultural and lifestyle backgrounds when compared with data from the United States. For men undergoing RRP for PCa, a history of smoking is associated with adverse pathologic features and a higher risk of biochemical failure. If confirmed in large cohort studies, smoking history could be considered an important risk factor in evaluating patients with PCa treated with RRP.

A similar scenario is evident for radiotherapy. Pantarotto et al [12] investigated 434 patients affected by PCa and treated by external beam radiotherapy (EBRT). A significantly (p = 0.007) higher proportion of current smokers (24.3%) had distant failure events when compared with nonsmokers (7.6%) or previous smokers (16.9%). Smoking was associated with a higher risk of developing metastatic disease in both current smokers (HR: 5.24; 95% CI, 1.75–15.72) and previous smokers (HR: 2.90; 95% CI, 1.09–7.67). However, it was unclear when or if the risk of distant failure was reduced after stopping smoking. Overall survival was also significantly worse for current smokers than nonsmokers (45.7% vs 25.8%; log-rank test: 0.03), but no significant differences were observed in PCa-specific mortality. Similar results were obtained by Pickles et al [37] who followed 601 men receiving EBRT and documented 28 PCa deaths; they reported a worse 5-yr biochemical outcome for smokers than for former smokers or nonsmokers (55%, 69%, and 73%, respectively; p = 0.01 and p = 0.0019), but no significant increase in PCa-specific deaths between smokers (10%) and nonsmokers or former smokers (3.7%; p = 0.08) was observed [37] and [40]. Merrick et al [38] evaluated the same association in patients treated by brachytherapy. Although no statistically significant difference was found in biochemical progression-free survival at 7 yr, a trend for poorer biochemical outcome was demonstrated in current smokers when compared with former smokers or nonsmokers (91.6%, 95.6%, and 96.2%, respectively; p = 0.126) [38].

A lower quality of life assessed through different standardized questionnaires such as the Short Form-12 (SF-12) and the Expanded Prostate Index Composite (EPIC-26) was observed in the follow-up (minimum 1 yr) of patients who smoked and who were treated by EBRT. Mean urinary incontinence score was lower (−9.6 points; p = 0.019) in smokers compared with nonsmokers. Furthermore, smoking reduced the mean bowel score (−9.2; p = 0.023) and the mean sexual score (−9.9; p = 0.0023). Current smokers had an increased risk of moderate to severe problems with the SF-12 vitality measure (OR: 2.9; p = 0.034), with the EPIC bowel overall bother measure (OR: 7.8; p = 0.003), and with the EPIC sexual overall bother measure (OR: 2.6; p = 0.0035) [43].

All of these studies, although limited to small retrospective series with short follow-up, supported the concept that current smokers treated with EBRT have worse tumor control than former smokers. One possible explanation is related to more aggressive cancer observed in current smokers and to reduced tissue oxygenation that is required for radiotherapy efficacy to kill tumor cells. Current smoking increases carboxyhemoglobin, which has been shown in experimental models to decrease tumor oxygenation and lead to increased radiation resistance [37].

Few studies evaluated the possible influence of smoking on PCa patients treated with medical therapy. Oefelein et al [39] followed 222 patients with advanced PCa treated with hormonal manipulation. Hormone-refractory PCa was observed in 133 patients, and death occurred in 77 cases. The median time to hormone-refractory PCa was significantly lower for smokers when compared with former smokers or nonsmokers (11 mo, 23 mo, and 35 mo, respectively; p = 0.00001). Median overall survival time on androgen-ablative therapy was 38 mo, 47 mo, and 60 mo in patients with current, former, or never tobacco smoking history, respectively. Recent data from the SEARCH database confirmed that active smoking was associated with an increased risk of castration-resistant PCa (HR: 2.62; p =: 0.21) in patients treated with radical prostatectomy [46].

3.4. Smoking as a target for prevention

Smoking is considered a major challenge to global public health. Smoking is associated with several major benign and malignant diseases and represents one of the most important modifiable risk factors for human health [63]. Considering the possible link between smoking and more aggressive PCa, including a suboptimal outcome after primary treatment, it has been hypothesized that smoking cessation by counseling or medical interventions could have a positive effect on PCa disease outcomes. Continued smoking after cancer diagnosis has been linked with several adverse outcomes for cancer patients, including treatment complications, reduced treatment efficacy or need for increased treatment dose, increased risk of secondary cancers, and diminished quality of life [63]. Unfortunately, about 10–60% of cancer patients smoke after diagnosis, with variation depending on cancer site and time since diagnosis [64]. Advising patients that smoke to quit smoking after a cancer diagnosis represents an important step in cancer management. A recent meta-analysis suggested that even 3 min of provider advice and counseling may increase the odds of tobacco abstinence by 30% [65]. Physician interventions may need to be combined with higher-intensity behavioral and pharmacologic interventions to increase long-term cessation among cancer patients [64]. Despite the demonstrated efficacy of provider interventions and counseling, only about 40% of cancer survivors report that a provider asked them about their smoking in the last year; although most oncology providers (60–80%) reported advising patients to quit smoking, only 15–30% reported providing interventions to assist their patients with smoking cessation. It has been argued recently that oncologists have an ethical responsibility to strongly advise their patients to quit smoking, and the American Society of Clinical Oncology has also urged all oncologists to integrate tobacco cessation and control into practice [66]. Whether or not smoking cessation after PCa diagnosis affects outcomes in PCa patients is unknown; however, it is reasonable to suggest that PCa patients should quit smoking to prevent or reverse smoking-related adverse events. This advice will at least improve heart health and reduce the risk of cardiovascular disease, the most common cause of male mortality, and could eventually reduce the risk of other concomitant cancers.

Another peculiar characteristic of smokers that could influence PCa prevention and management is that adherence to PSA testing may be negatively associated with tobacco smoking for various reasons, including lower socioeconomic status [11] and [67]. Smoking has been linked with lower risk of screening and poor compliance with prostate biopsy [11] and [62]. Rolison et al [67] recently observed that nonsmokers were 1.95 times more likely to have been screened for PCa than smokers. Furthermore, smokers were most likely to have been screened only once, whereas quitters and nonsmokers were most likely to have been screened at least three times. PSA testing in smokers could also be influenced by changes in PSA level. Data from a nationwide population-based sampling survey have shown an approximate 8–12% decrease in PSA among current and former smokers. Thus, men who have ever smoked are less likely to have an abnormal result on PSA screening and diagnostic biopsy, possibly resulting in fewer screen-detected PCas than those who have never smoked [68]. However, because PSA screening reduces PCa death by only approximately 21%, for screening to explain the 25% increased mortality of PCa in smokers reported by Islami et al [11] in their meta-analysis, screening must be nearly universal among nonsmokers and nearly completely absent among smokers. Furthermore, the patterns of association between smoking and PCa death before and after the PSA screening era were almost similar, refuting any major influence of PSA screening on this association [11]. As such, screening differences are unlikely to explain all of the excess PCa mortality among smokers, although they may contribute. Finally, PSA accuracy in smokers and nonsmokers has never been tested.

4. Conclusions

Smoking is a major public health problem and is the leading cause of death from cancer. Smoking is associated with several biological factors that may influence the development and progression of PCa. Although the exact molecular mechanisms linking smoking and prostate carcinogenesis remain incompletely understood, the cumulative evidence summarized in this report strongly suggests an association of smoking with higher PCa mortality and with worse outcomes after treatment. Whether smoking cessation after PCa diagnosis influences the natural history of PCa is unknown, but it is a reasonable step for physicians to recommend smoking cessation to PCa patients to improve their health. Knowledge of tobacco cessation and control actions should be considered for inclusion in the core curriculum of urologic oncology training. Although such an approach will undoubtedly improve overall health, it may also improve overall PCa outcomes.

Author contributions: Cosimo De Nunzio 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: De Nunzio, Thompson, Andriole, Freedland.

Acquisition of data: De Nunzio.

Analysis and interpretation of data: De Nunzio.

Drafting of the manuscript: De Nunzio.

Critical revision of the manuscript for important intellectual content: Thompson, Andriole, Freedland.

Statistical analysis: None.

Obtaining funding: None.

Administrative, technical, or material support: [last name or names—or None].

Supervision: Thompson, Andriole, Freedland.

Other (specify): None.

Financial disclosures: Cosimo De Nunzio 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: None.

Funding/Support and role of the sponsor: This work was supported by grants U01CA86402 and 5P30 CA0541474 (I.M.T.) and K24CA160653 (S.J.F.).


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a Department of Urology, Sant’Andrea Hospital, University “La Sapienza”, Rome, Italy

b Division of Urology, Barnes-Jewish Hospital, Washington University School of Medicine, St. Louis, MO, USA

c Department of Urology, The Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio TX, USA

d Section of Urology, Durham VA Medical Center and Division of Urology, Duke Prostate Cancer Centre, Departments of Surgery and Pathology, Duke School of Medicine, Durham, NC, USA

Corresponding author. Department of Urology, Sant’Andrea Hospital, “La Sapienza” University, Via di Grottarossa 1035 - 00189, Rome, Italy. Tel. +39 0633777716; Fax: +39 0633775059.

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