Recent studies have suggested that active smokers are more likely to die of prostate cancer than are nonsmokers.3,9,12,13
The greater mortality among smokers could be explained in part by a greater incidence of aggressive disease in active smokers.3,12
Alternatively, smoking could be responsible for a suboptimal response to treatment. Two studies of patients with prostate cancer who underwent radiotherapy showed a worse outcome among smokers, even after adjustment for disease aggressiveness.4,5
However, the effects of smoking on outcomes in patients who underwent radical prostatectomy have not been evaluated. Therefore, we analyzed the risk of BCR between smokers and nonsmokers among subjects from the SEARCH cohort.
In the SEARCH database, we found the prevalence of active cigarette smoking at surgery to be nearly one third, greater than the approximately 25% prevalence in the general adult male population.14
In contrast, in a cohort of men undergoing radical prostatectomy at Johns Hopkins, the prevalence of smoking was 5%.15
It is likely the observed high prevalence of smoking in the present study, especially for a surgical cohort, was related to the high overall prevalence of smoking among Veterans Affairs patients.16
Moreover, the smokers were younger than the nonsmokers. This finding is supported by population-level studies that found the prevalence of smoking to decrease with age after the fourth decade of life.17
We also observed active smokers had a significantly lower BMI at surgery, and the prevalence of smoking was lower in obese men. Several studies showed smoking was associated with a lower weight and that smoking cessation can lead to weight gain.17,18
Nicotine’s physiologic effects result in appetite suppression, increased resting metabolic rates, and reduced calorie storage, which act synergistically to reduce body weight.18
In agreement with the observations from our surgical cohort, on the population level, smokers also tend to be younger and weigh less.14,18
In our study, smokers had a significantly greater pre-operative PSA level, greater percentage of positive biopsy cores, and greater prevalence of extracapsular extension and seminal vesicle invasion, suggesting that smoking might be associated with more advanced disease at diagnosis. Roberts et al15
found an association between cigarette smoking and extraprostatic tumor extension among younger men undergoing radical prostatectomy. Additionally, 2 recent meta-analyses of observational studies found smoking was not an important risk factor for prostate cancer incidence but that smokers with prostate cancer tended to have greater mortality from the disease.3,12
Although smokers seemed to have more advanced disease than nonsmokers at presentation in the present study, the risk of BCR among smokers was statistically similar to that of the nonsmokers. When adjusted for BMI only, smoking was associated with a greater risk of BCR. In addition, obese smokers had a greater risk of recurrence than did obese nonsmokers. However, smoking did not increase the risk of BCR among nonobese men. Thus, a suggestion was found that the combination of obesity and smoking could result in a particularly aggressive cancer. Whether this resulted from shared biologic causes or was a function of selection bias (ie, obese smokers might have been discouraged from undergoing surgery unless they had more aggressive disease) or some other reason is unknown, and more study is needed to confirm these findings and to explore the possible reasons.
After adjustment for patient characteristics, tumor grade, and tumor stage, the effect of smoking on BCR was essentially null. Two studies considered the association of smoking and outcomes in patients with prostate cancer treated with radiotherapy. The first study found that smokers had a slightly greater risk of BCR.4
In the second study, smoking was shown to be associated with a greater progression to metastatic disease.5
These findings suggest that smoking might play a role in cancer progression after radiotherapy but not surgery. One possible explanation for this disparity in outcomes between radical prostatectomy and radiotherapy might relate to smoking-induced tissue hypoxia.19
Given that radiotherapy requires oxygenated tissue to enact cell killing, it is possible that smoking results in intratumor hypoxia, which would, in theory, explain why smokers treated with radiotherapy have poorer outcomes than nonsmokers. In contrast, the effectiveness of surgery would be unrelated to tissue hypoxia, because surgery relies on complete malignancy excision, regardless of intratumor perfusion. Ultimately, if this dichotomy between outcomes after radiotherapy and surgery is confirmed in future studies, it would suggest that surgery might be the preferable oncologic treatment relative to radiotherapy for active smokers with localized prostate cancer, notwithstanding the potential surgical complications related to surgery in men with greater smoking-related comorbidities. Nevertheless, additional studies are required to establish the association between smoking and BCR after radical prostatectomy.
Given the data to link smoking with prostate cancer progression and death, it was noteworthy that several plausible biologic mechanisms could explain how smoking can accelerate the course of prostate cancer. For example, smoking has an antiestrogen effect that, in turn, might promote prostate cancer growth.20
In addition, smoking is associated with a myriad of genetic and epigenetic abnormalities, such as gene mutations, deletions, and DNA methylation. For instance, the polycyclic aromatic hydrocarbons present in tobacco smoke can induce mutations in the p53 gene, which could potentially lead to worse cancer progression.21
Smoking has also been demonstrated to affect the immune system by both promoting inflammation and suppressing the immune function such as reducing T-cell and natural killer cell activation.22
Both pathways (inflammation and decreased immune function) could facilitate tumor growth. Finally, confounder factors might play a role in the association between smoking and aggressive disease. For example, cigarette smoking has been associated with greater ethanol consumption, lower exercise rates, and an overall unhealthy lifestyle.23
Although, the epidemiologic association between lifestyle characteristics such as exercise and ethanol consumption with prostate cancer progression remains murky, it is likely that a combination of these biologic and behavioral factors is responsible for the association between smoking and aggressive prostate cancer.
The main limitation of our study was the retrospective nature of our cohort. In addition, cigarette smoking has generally been associated with comorbidities such as cardiovascular disease, which were not controlled in our analyses. These comorbidities might, in turn, influence the decision of whether a patient should undergo radical prostatectomy. For example, patients at greater surgical risk with less-aggressive disease could undergo other treatments (e.g., watchful waiting) and those with similar surgical risk and more aggressive disease could be assigned to surgery. This would result in more aggressive disease in the high comorbidity group (ie, smokers) relative to the low comorbidity group (ie, nonsmokers). However, except for slightly greater preoperative PSA levels in smokers, we did not find any other evidence of more aggressive disease among the smokers in the preoperative variables (ie, greater biopsy Gleason score or greater clinical stage) to support such a hypothesis. We did not analyze the cumulative and current amount of tobacco exposure, because these data were not available for most of the smokers. We also did not analyze other types of tobacco exposure (eg, cigars or chewing tobacco) or different forms of tobacco exposure, because the number of men in those categories was presumably low. Although earlier BCR has been shown to correlate with greater mortality24
and given cigarette smoking can increase the risk of death by noncancer-related causes, studies analyzing smoking history and long-term outcomes after radical prostatectomy such as mortality and metastasis are needed to further identify the independent effects of smoking on cancer progression. Finally, given our relatively modest follow-up (37 months), additional studies with larger sample sizes and longer follow-up are needed to confirm or refute these findings.