Smoking effect on secondary bladder cancer after external beam radiotherapy for prostate cancer

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1 JJCO Japanese Journal of Clinical Oncology Japanese Journal of Clinical Oncology, 2016, 46(10) doi: /jjco/hyw098 Advance Access Publication Date: 18 July 2016 Original Article Original Article Smoking effect on secondary bladder cancer after external beam radiotherapy for prostate cancer Masaki Shiota 1, Akira Yokomizo 1, *, Ario Takeuchi 1, Junichi Inokuchi 1, Katsunori Tatsugami 1, Saiji Ohga 2, Tomonari Sasaki 2, Katsumasa Nakamura 2, Hiroshi Honda 2, and Masatoshi Eto 1 1 Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, and 2 Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan *For reprints and all correspondence: Akira Yokomizo, Department of Urology, Graduate School of Medical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka , Japan. yokoa@uro.med.kyushu-u.ac.jp Received 14 April 2016; Accepted 24 June 2016 Abstract Objective: Although it is well known that radiotherapy for prostate cancer increases comorbid rate of secondary bladder cancer, the effect of aging and smoking with radiotherapy on incidence rate of secondary bladder cancer remains unknown. Then, this study investigated the combinational effect of external beam radiotherapy for prostate cancer and aging or smoking on comorbid rate of secondary bladder cancer. Methods: This study included 754 Japanese patients with prostate cancer treated with radiotherapy (n = 319) and radical prostatectomy (n = 435) from 2000 through The relationship between therapeutic modality for prostate cancer as well as age or smoking status and comorbid rate of secondary bladder cancer was examined. Results: During the median follow-up period of 4.3 and 3.1 years, secondary bladder cancer occurred in 11 (3.4%) and 5 (1.1%) of patients with prostate cancer treated with external beam radiotherapy and radical prostatectomy, respectively. The 5-year bladder cancer-free survival rate was 97.3% in the external beam radiotherapy group and 99.4% in the radical prostatectomy group. Age (hazard ratio = 1.15, P = 0.027) and ever smoking (hazard ratio = 5.65, P = 0.011) were significant predictive factors of secondary bladder cancer incidence in the external beam radiotherapy cohort, but not in the radical prostatectomy cohort. Inversely, among men with ever smoking, but not among older men, external beam radiotherapy (hazard ratio = 9.64, P = ) was a significant risk factor of secondary bladder cancer. Conclusions: Taken together, these findings suggest that smoking history might be one of criteria to choose radical prostatectomy than external beam radiotherapy for prostate cancer, and that age would not be a criterion for therapeutic selection in terms of secondary bladder cancer. Key words: bladder cancer, prostate cancer, radical prostatectomy, radiotherapy, secondary cancer Introduction Prostate cancer is one of the most common cancers among men of developed countries. In USA, it is estimated that ~ men will develop prostate cancer and ~ men will die from prostate cancer in 2015 (1). In Japan, the incidence rate of prostate cancer has been increasing due to various reasons, including the growing prevalence of a Western-style diet and lifestyle and an increase in the aging population as well as prostate-specific antigen (PSA) screening (2). The Author Published by Oxford University Press. All rights reserved. For permissions, please journals.permissions@oup.com 952

2 Jpn J Clin Oncol, 2016, Vol. 46, No Several therapeutic modalities for prostate cancer are available and have been applied to patients according to various clinicopathological parameters and physicians or patients favor. Standard treatment options for localized prostate cancer include radical prostatectomy (RP) by open RP, laparoscopic RP or robot-assisted laparoscopic RP; prostate radiotherapy by external beam radiotherapy (EBRT) and/or brachytherapy; active surveillance; cryotherapy; and androgen deprivation therapy (ADT). Among these therapeutic modalities, physicians and patients can choose the best single option or combination. Due to longer life expectancy in patients with localized prostate cancer, late-phase adverse events are more meaningful and significant. Among late-phase adverse events, secondary cancer could be the most harmful or lethal event because of its aggressive characteristics and limited therapeutic options. In particular, the comorbid rate of secondary bladder cancer (BC) is increased after radiotherapy for prostate cancer (3 10). We recently reported that the incidence of secondary BC increased after radiotherapy, especially EBRT compared with marginally RP and significantly ADT (11). Common risk factors for BC incidence such as aging (12), gender (13) and smoking history (14), in addition to several uncommon risk factors including genetic factors, occupational exposures, water arsenic, Schistosoma haematobium infection and some medications, have been reported (15). Although EBRT would increase the risk of secondary BC, other common risk factors that may affect secondary BC after EBRT have not been well defined. Therefore, in this study, we investigated the effect of known BC-promoting factors including therapeutic modality (EBRT vs. RP) for prostate cancer, age, and smoking status on incidence rate of secondary BC. Patients and methods This study enrolled patients with prostate cancer treated by EBRT or RP at Kyushu University Hospital (Fukuoka, Japan) from 2000 to 2013, among whom smoking status data were available. Ever smoking was defined as former or current smoking experience while current smoking was defined as men with smoking habit at time of diagnosis as prostate cancer. This study was approved by the institutional review board. All patients were histopathologically diagnosed with adenocarcinoma of the prostate. Patients with <1-year follow-up after therapy were excluded. Secondary BC was defined as primary BC diagnosed after 1 year from prostate cancer diagnosis. Thus, cases with preceding BC, concurrent BC, and subsequent BC within 1 year from the diagnosis of prostate cancer as well as recurrent BC were excluded. Clinical staging was determined in accordance with the unified TNM criteria based on the results of a digital rectal examination, transrectal ultrasound, magnetic resonance imaging, computed tomography and bone scan (16). Most patients also underwent cystoscopy to determine tumor extension and to rule out comorbid BC. Patients in EBRT series were treated by EBRT with or without neoadjuvant/adjuvant ADT (more than 3 months) by surgical castration or medical castration using a luteinizing hormonereleasing hormone agonist (goserelin acetate or leuprorelin acetate) and/or an antiandrogen agent (bicalutamide, flutamide or chlormadinone acetate) (17,18). EBRT was performed with a median 72 Gy to the prostate only (n = 275, 86.4%) or the prostate and pelvis (n = 37, 11.6%) by conformal (n = 275, 86.2%) or intensitymodulated radiotherapy (n = 38, 11.9%). Patients in the RP series were treated by open RP (n = 185, 42.5%), laparoscopic RP (n = 67, 15.4%) or robot-assisted laparoscopic RP (n = 183, 42.1%) with or without ADT (19). The cases treated with adjuvant or salvage radiotherapy were excluded from RP series. Patients were followed up during or after treatment for prostate cancer at intervals of ~3 6 months with medical interview, urinalysis and blood test. If BC incidence was suspected, further examinations such as urine cytology and cystoscopy were performed. The time to development of secondary cancer was defined as the duration from starting date of EBRT or operation date to the date of pathological diagnosis of secondary cancer. All secondary BC were histologically confirmed. Pathological evaluation of BC was performed according to 2004 World Health Organization grading (20). All statistical analyses were performed using JMP9 software (SAS Institute, Cary, NC, USA). The secondary BC-free rates were determined using the Kaplan Meier method and the logrank statistic was used to compare survival duration across groups. Comparisons between groups were analyzed by Wilcoxon or Pearson tests. P values <0.05 were considered significant. Results This study enrolled a total of 754 patients, and the clinical and pathological characteristics are shown in Table 1. The median age of patients was 71 and 65 years and the median PSA at diagnosis was 11.0 and 7.8 ng/ml in the EBRT and RP groups, respectively. Advanced clinical T-stage in the EBRT group (ct3/4, 33.2%) was more frequent compared with the RP group (ct3/4, 1.4%). The Gleason scores of biopsy specimens from 91 (29.2%), 133 (42.6%) and 88 (28.2%) patients and 164 (36.4%), 201 (49.1%) and 62 (14.5%) patients were <7, =7 and >7 in those treated with EBRT and RP, respectively. Thus, compared with patients treated with RP, patients treated with EBRT were older and had worse characteristics, such as higher PSA values at diagnosis, higher Gleason scores and more progressive T-stage. During the median follow-up period of 4.3 years (interquartile range [IQR], ) in patients treated with radiotherapy, 11 men (3.4%) were diagnosed with secondary BC. Conversely, during the median follow-up period of 3.1 years (IQR, ) in patients treated with surgical treatment, 5 (1.1%) men were diagnosed with Table 1. Patient characteristics in both cohorts Variable EBRT (n = 319) RP (n = 435) P value Median age, years (IQR) 71 (67 76) 65 (60 69) < a Median PSA at diagnosis, 11.0 ( ) 7.8 ( ) < a ng/ml (IQR) NA 2 0 Clinical T-stage, n (%) ct1 130 (41.1%) 240 (60.4%) ct2 81 (25.6%) 166 (38.2%) ct3 94 (29.7%) 9 (1.4%) ct4 11 (3.5%) 0 (0%) < a NA 3 20 Biopsy Gleason score, n (%) <7 91 (29.2%) 164 (36.4%) (42.6%) 201 (49.1%) 8 88 (28.2%) 62 (14.5%) < a NA 7 8 NA, not available; EBRT, external beam radiotherapy; RP, radical prostatectomy; IQR, interquartile range; PSA, prostate-specific antigen. a Statistically significant.

3 954 Smoking effect on secondary bladder cancer secondary BC. Accordingly, the 5-year BC-free survival rate was 97.3%, and 99.4% among patients treated with EBRT and RP, respectively. When age, ever smoking, current smoking and therapeutic modality were analyzed in incidence of secondary BC among both EBRT and RP cohorts, age (hazard ratio (HR) [95% confidence interval (CI)] = 1.17 [ ], P = 0.006) and ever smoking (HR [95% CI] = 3.11 [ ], P = 0.028) were significantly associated with increased risk of secondary BC, although EBRT (HR [95% CI] = 2.62 [ ], P = 0.064) marginally increased secondary BC risk (Table 2, Supplementary Fig. 1A). As well, former smoking was a significant risk factor of secondary BC compared with never smoking (HR [95% CI] = 4.22 [ ], P = ). However, current smoking (HR [95% CI] = 0.72 [ ], P = 0.65) was not associated with the incidence of secondary BC (Table 2, Supplementary Fig. 1B). The incidence of secondary BC were 5 (1.2%), 9 (4.0%) and 2 (1.6%) cases among 404 never smokers, 225 former smokers and 125 current smokers, respectively. When analyzed in the EBRT cohort, age (HR [95% CI] = 1.15 [ ], P = 0.027) and ever smoking (HR [95% CI] = 5.65 [ ], P = 0.011) were significant risk factors of secondary BC while current smoking (HR [95% CI] = 0.46 [ ], P = 0.12) was not (Table 2, Fig.1A and B). As well, former smoking was a significant risk factor of secondary BC compared with never smoking in the EBRT cohort (HR [95% CI] = 8.38 [ ], P = ). The incidence of secondary BC in the EBRT cohort were 2 (1.1%), 8 (8.8%) and 1 (1.9%) cases among 176 never smokers, 91 former smokers and 52 current smokers, respectively. On multivariate analysis using age and ever smoking as variables, both age (HR [95% CI] = 1.16 [ ], P = 0.016) and ever smoking (HR [95% CI] = 6.09 [ ], P = ) were significant risk factors of secondary BC when treated with EBRT. However, both ever smoking (HR [95% CI] = 0.93 [ ], P = 0.94) and current smoking (HR [95% CI] = 1.29 [ ], P = 0.82) did not affect the comorbid rate of secondary BC in the RP cohort whereas age did marginally affect the comorbid rate (HR [95% CI] = 1.18 [ ], P = 0.062; Table 2, Fig.1C and D). Finally, the impact of therapeutic modality on the risk of secondary BC among men with ever smoking was analyzed. The results showed that age (HR [95% CI] = 1.18 [ ], P = ) and EBRT (HR [95% CI] = 9.64 [ ], P = ) were significant risk factors of secondary BC among ever smokers (Table 3, Fig. 2A), though were not risk factors in never smokers (Table 3, Fig. 2B). However, when divided by age (younger, <70 vs. older, 70), therapeutic modality did not affect the incidence rate of secondary BC (Supplementary Fig. 1A and B). Comment Several studies using Surveillance, Epidemiology, and End Results (SEER) database and UCSF Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) database suggested that radiotherapy for prostate cancer can induce secondary BC (3 10). In contrast, several studies using smaller cohorts failed to show a significant increased risk of secondary BC (21 23). Consistent with these findings, the present study showed a marginal increased risk of secondary BC after EBRT for prostate cancer compared with RP, probably because of the small sample size. Boorjian et al. reported the impact of smoking on BC incidence among men with prostate cancer using the CaPSURE database (9), and showed increased risk of BC incidence with treatment with radiotherapy of ~2-fold compared with RP and smoking status also increased BC incidence risk ~2-fold. Furthermore, radiotherapy and presence of smoking in combination increased the incidence rate of BC ~4-fold. Similarly, this study showed the promoting effect on BC incidence by EBRT and smoking history, as well as a combinational effect of radiotherapy and smoking history. The consistent result in both studies from the USA and Japan as well as by a populationbased database and single institution database suggested the robustness of the finding that smoking history increases the BC incidence in combination with radiotherapy. Furthermore, in addition to current smoking status indicated by Boorjian et al. (9), this study has shown that smoking history was also a risk factor of secondary BC after EBRT for prostate cancer. Previous studies in breast cancer and Hodgkin s lymphoma showed that smoking and radiotherapy in combination increased the risk of secondary lung cancer (24,25). Thus, smoking status may be helpful in choosing the therapeutic options for prostate cancer, indicating that smokers may be better to undergo RP instead of radiotherapy. However, age may not be informative in the selection between radiotherapy or RP in terms of secondary BC. Most cancer including BC can be induced by the accumulation of genetic mutations by various environmental stimuli. Both irradiation and cigarette smoking are known to cause genetic mutations by their genotoxic effects. Therefore, such genotoxic effects in the bladder may synergistically increase genetic aberrations, resulting in the increased incidence of BC. Smoking history affected the BC incidence, which may be accounted for by the hypothesis that tumorinitiated region by smoking can be promoted by irradiation, but not vice versa. This hypothesis can be supported by the promoting role of irradiation, as irradiation-induced BC has been reported to be associated with aggressive phenotype (26,27). In contrast, smoking Table 2. Associations between parameters and comorbidity with secondary BC according to therapeutic modality Variable EBRT + RP EBRT RP HR 95% CI P value HR 95% CI P value HR 95% CI P value Age (per unit) a a Ever smoking No Yes a a Current smoking No Yes Therapeutic modality RP 1 EBRT HR, hazard ratio; CI, confidence interval. a Statistically significant.

4 Jpn J Clin Oncol, 2016, Vol. 46, No Figure 1. Secondary bladder cancer (BC)-free survival rates in patients with prostate cancer according to smoking status. (A) and (B) Secondary BC-free survival rate in patients treated with EBRT stratified by ever smoking (A) and current smoking (B). (C) and (D) Secondary BC-free survival rate in patients treated with RP stratified by ever smoking (C) and current smoking (D). Table 3. Associations between clinicopathological parameters and comorbidity with secondary BC according to smoking history Variable Ever smoker Never smoker HR 95% CI P value HR 95% CI P value Age (per unit) a Current smoking No 1 Yes Therapeutic modality RP 1 1 EBRT a a Statistically significant. is a risk factor of BC incidence, but not related to recurrence, progression and motility (28,29). The present study had several limitations. For instance, the study design was retrospective, the sample size was relatively small, and the follow-up period was relatively short. In addition, this study lacks the information about the smoking year and smoking amount. Also, detection bias by symptoms such as gross-hematuria and bladder irritation, which are often caused by radiotherapy, may have affected the results. Selection bias of therapy for prostate cancer may also have affected the results. Conversely, this study included a cohort from the urological department from single institution, assuring high integrity of the data, in contrast to data from registry databases. Taken together, these findings revealed that cigarette smoking may increase comorbid risk with secondary BC in men with prostate cancer treated with EBRT, but not with RP, which suggests that smoking history might be one of criteria to choose RP than EBRT, whereas age would not be a criterion for therapeutic selection in terms of secondary BC. Supplementary data Supplementary data are available at org. Acknowledgements We would like to thank Dr Junji Kishimoto for consulting about statistical analyses and the Edanz Group Japan for editorial assistance.

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