UROLOGICAL ONCOLOGY Predictors of Secondary Bladder Cancer in Patients with Prostate Cancer Treated with Brachytherapy: A Single-institution Study of a Japanese Cohort Kiyoshi Takahara1, Makoto Sumitomo1, Masayuki Ito2, Fumitaka Ito2, Masashi Nishino1, Takuhisa Nukaya1, Masashi Takenaka1, Kenji Zennami1, Kosuke Fukaya1, Manabu Ichino1, Naohiko Fukami4, Hitomi Sasaki1, Mamoru Kusaka4, Shinya Hayashi2, Hiroshi Toyama3, Ryoichi Shiroki1 Purpose: The incidence of secondary bladder cancer after treatment for localized prostate cancer (PCa) remains unclear. In this study, PCa cases treated with brachytherapy (BT) were evaluated to assess the incidence of a sec- ond malignancy of bladder cancer in a Japanese cohort. Materials and Methods: Overall, 969 patients treated with BT at our hospital between July 2006 and January 2019 were included in the study cohort. The incidence and predictors of secondary bladder cancer were also assessed. Results: The incidence of secondary bladder cancer was 1.5% (n = 14). Of the seven factors (age, pretreatment PSA, Gleason score, cTNM stage, prostate volume, total activity, and combined external beam), prostate volume and total activity showed significant differences between the cohorts with and without secondary bladder cancer (P = .03 and P = .001, respectively). Upon comparison of the seven parameters for the 969 patients treated with BT, we found that only the total activity factor was affected by the incidence of secondary bladder cancer in the multivariate analysis (P = .007). Conclusion: The incidence of secondary bladder cancer was evaluated after BT for PCa. Total activity was asso- ciated with the incidence of secondary bladder cancer in Japanese patients who received BT. Keywords: brachytherapy; prostate cancer; secondary bladder cancer INTRODUCTION Prostate cancer (PCa) ranking is the second most fre-quent cancer and the fifth leading cause of cancer death in men(1). PCa has recently become a common type of cancer globally. However, owing to widespread PSA detection, PCa has often been discovered at a lo- calized stage(2,3). Many management strategies are avail- able for localized PCa, including active surveillance, radical prostatectomy (RP), robot-assisted radical pros- tatectomy, and radiation therapy. A systematic review showed that external beam radiation therapy (EBRT), brachytherapy (BT), and RP are effective monothera- pies for localized PCa; BT has a similar biochemical progression-free survival rate as RP in patients with a low to moderate risk of PCa(4). Multiple prospective studies have assessed patient-reported toxicity differ- ences among the three major definitive therapy options: RP, EBRT, and BT(5,6). With high survival rates asso- ciated with each of these therapies, men and their part- ners often make treatment decisions based on their un- derstanding of quality of life differences between each treatment modality(7). As mentioned above, BT is a valid treatment option 1Department of Urology, Fujita Health University School of Medicine, Toyoake, Aichi, Japan. 2Department of Radiation Oncology, Fujita Health University School of Medicine, Toyoake, Aichi, Japan. 3Department of Radiology, Fujita Health University School of Medicine, Toyoake, Aichi, Japan. 4Department of Urology, Okazaki Medical Center, Fujita Health University, Okazaki, Japan. *Correspondence to: Kiyoshi Takahara, M.D., Ph.D., Department of Urology, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi 470-1192, Japan. Tel: 81-562-93-2600, Fax: 81-562-93-4593, e-mail: takahara@fujita-hu.ac.jp. Received February 2021 & Accepted October 2021 for localized PCa. BT has been found to be a highly effective and safe treatment, providing a good alter- native to the surgical removal of the prostate, breast, and cervix, while reducing the risks of some long-term side effects(8). However, the long-term risk of secondary malignancy, especially the risk of bladder cancer, is a potential late effect of BT. This study aimed to evaluate localized PCa patients treated with BT at our hospital to assess the incidence and predictors of secondary bladder cancer in a Japa- nese cohort. MATERIALS AND METHODS Study Design In the current study, we retrospectively reviewed the clinicopathological data of 969 patients treated with BT at our hospital between July 2006 and January 2019. For all patients, serum PSA levels were checked; cTNM stage was assigned by computed tomography, magnetic resonance imaging, and whole-body bone scan. Pros- tate volume was assessed using transrectal ultrasound at the time of the prostate biopsy. The study design was approved by the ethics commit- Urology Journal/Vol 19 No. 3/ May-June 2022/ pp. 209-213. [DOI:10.22037/uj.v18i.6718] tee of our hospital (Approval number of Fujita Health University School of Medicine: HM18-089). The need for informed consent from all patients included in this study was waived because of the retrospective design. Treatment Classification The D’Amico Risk classification(9) was used to deter- mine the BT treatment. As a general rule, BT alone was performed for low-risk, combination of BT and EBRT for intermediate-risk, and trimodality treatment consist- ing of hormonal therapy, EBRT, and BT for high-risk PCa patients. Patient Selection Among the 969 localized PCa patients who received BT, 581 were treated with a 160 Gy permanent inter- stitial iodine-125 (I-125) implant alone by real-time intraoperative planning; 388 were treated with a 110 Gy permanent seed implantation, followed by a 45 Gy supplemental intensity-modulated radiation therapy to the prostate and seminal vesicles 2 months later. The current approach for BT dose calculation is based on the AAPM TG-43 dosimetry formalism, with recent ad- vances in acquiring single-source dose distributions (10). Follow-up Evaluations Follow-up evaluations were performed at 3- to 6-month intervals for 5 years and yearly thereafter. The clin- ical data of each patient were collected from medical records. Secondary bladder cancer was diagnosed by transurethral resection of the bladder. Pathological find- ings, including grade and pT stage, were also obtained. Statistical Analysis For statistical analysis, the comparison between two groups was performed using Mann-Whitney's U test, chi-square test, or Fisher’s exact test. The prognostic Secondary bladder cancer after BT-Takahara et al. Table 1. Patient characteristics. Table 2. Incidence of secondary bladder cancer and patient characteristics. Urological Oncology 210 Vol 19 No 3 May-June 2022 211 significance of certain factors was assessed using uni- variate and multivariate analyses. All data were analyz- ed using IBM SPSS Statistics version 23 (SPSS Japan Inc., Tokyo, Japan), and a p-value < 0.05, which was considered significant in all statistical analyses. RESULTS The clinical characteristics of 969 Japanese patients with localized PCa treated with BT included in this study are summarized in Table 1. The median age was 70 years; the median serum PSA level was 7.1. Regard- ing the cTNM stage and Gleason score, cT2N0M0 and Table 3. Patients’ characteristics with and without secondary bladder cancer. Table 4. Univariate and multivariate analyses of seven factors. Secondary bladder cancer after BT-Takahara et al. Urological Oncology 212 Gleason score < 6 were observed in 56.3% and 48.3% of patients, respectively. In the context of D’Amico risk classification, the low-risk group was most frequently observed in 40.1%. We then evaluated the incidence of secondary bladder cancer in 969 PCa patients treated with BT, which was observed in 14/969 (1.5%) patients. Upon histological grading, G2 was observed most frequently in 71.4% of cases; all cases of pT stage were under pT1 (Table 2). To investigate the effect on the incidence of second- ary bladder cancer, we focused on seven factors (age, pretreatment PSA, Gleason score, cTNM stage, prostate volume, total activity, and combined external beam) re- lated to PCa and BT in the 969 patients treated with BT. Prostate volume and total activity showed significant differences between cohorts with and without second- ary bladder cancer (P = .03 and P = .001, respectively) (Table 3). Among these seven factors, we evaluated which factor was associated with the incidence of secondary bladder cancer in 969 PCa patients treated with BT. Univariate analysis showed that prostate volume and total activity were independent factors for the incidence of secondary bladder cancer (P = .014 and .006, respectively). In the multivariate analysis, total activity was the only fac- tor directly associated with the incidence of secondary bladder cancer (P = .007) (Table 4). DISCUSSION The potential side effects and long-term toxicities of treatment for PCa are important considerations in se- lecting the best therapy for patients(11-14). A second primary cancer is generally considered to be radia- tion-induced if (i) it is diagnosed after a latency period (usually considered to be 5 years or more) following irradiation; (ii) it occurs within the radiation field (for prostate radiotherapy, this includes the rectum, bladder, anus, prostate, soft tissues, bones, or joints of the pelvis and pelvic lymphoma); (iii) it is a different histologi- cal type from the original cancer; and (iv) the second tumor was not evident at the time of radiotherapy(15,16). Rather than using this definition, we opted for a more inclusive strategy, as suggested by others(17). Several re- cent studies have reported the incidence of secondary bladder cancer among PCa treatments, including RP, EBRT, and BT. A previous study using the Surveil- lance, Epidemiology, and End Results database from 1973 to 2011 showed that the relative risk of develop- ing bladder cancer after 10 years was significantly high- er following BT than after EBRT or EBRT and BT(18). Another study showed that PCa patients treated with any radiation therapy were 1.70 times more likely to develop secondary bladder cancer compared with RP alone(19). However, Zelefsky et al. reported that the 10- year likelihood of bladder cancer that developed after treatment in the RP, BT, and EBRT cohorts was 1.4%, 1.0%, and 1.2%, respectively, with no significant dif- ferences(20). Collectively, these findings suggest that the prognostication of each PCa treatment for secondary bladder cancer should be conducted. Accordingly, in the current study, we focused on localized PCa patients treated with BT to investigate the incidence and predic- tors of secondary bladder cancer in a Japanese cohort. In this study, 969 Japanese patients who underwent BT for localized PCa treatment were evaluated. The in- cidence of secondary bladder cancer was observed in 14/969 (1.5%) patients. In the context of histological findings of secondary bladder cancer after BT treat- ment, G2 and G3 were observed in 85.7% of cases; pT stage in all cases was under pT1. Our histological results were consistent with a previous report that the majority of bladder cancers following BT were of high grade and low stage at diagnosis, most of which demon- strated luminal immunophenotype(21). To evaluate which factors influenced the incidence of secondary bladder cancer after BT therapy in Japanese patients with localized PCa, several analyses were per- formed with the seven factors (age, pretreatment PSA, Gleason score, cTNM stage, prostate volume, total ac- tivity, and combined external beam). Between cohorts with and without secondary bladder cancer, prostate volume and total activity showed significant differenc- es. Since the total activity was dependent on the pros- tate volume in order to deliver 160 Gy, except com- bining extra beam, our analysis between cohorts with and without secondary bladder cancer was acceptable. Interestingly, in the multivariate analysis, total activity was the only factor directly associated with the inci- dence of secondary bladder cancer. In this study, BT was not performed for PCa with a large prostate vol- ume; total activity was decreased when the extra beam was combined. Furthermore, only total activity remains an important factor for the incidence of secondary blad- der cancer. Moreover, the combination of BT and exter- nal beam therapy was not associated with the incidence of secondary bladder cancer in our Japanese cohort. In the current study, we reported that the incidence of secondary bladder cancer after BT for localized PCa patients was 1.5%, within a median follow-up of 81 months. Total activity was an important predictor of the incidence of secondary bladder cancer in Japanese pa- tients who received BT. This study has some limitations. First, this was a ret- rospective, single-institution study. In addition, since patient characteristics were not fully obtained, well-de- signed analyses were lacking. In particular, the popu- lation of patients who had a history of smoking should be selected, considering that tobacco smoking is the best-established risk factor for bladder cancer in both men and women(22). Further studies are needed to vali- date our assessment of the predictors of secondary blad- der cancer in patients with PCa and BT. CONCLUSIONS In conclusion, the incidence of secondary bladder can- cer after BT for localized PCa treatment was evaluat- ed. Total activity was the only significant independent predictive factor for the incidence of secondary bladder cancer in Japanese patients who received BT. CONFLICTS OF INTEREST The authors have no conflict of interest to declare re- garding this study. REFERENCES 1. Global Burden of Disease Cancer C, Fitzmaurice C, Allen C, et al. Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life- years for 32 Cancer Groups, 1990 to 2015: A Systematic Analysis for the Global Burden of Secondary bladder cancer after BT-Takahara et al. Vol 19 No 3 May-June 2022 213 Disease Study. JAMA Oncol. 2017;3:524-48. 2. Andriole GL, Crawford ED, Grubb RL, 3rd, et al. 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