Introduction. Methods. Original Article: Clinical Investigation

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1 International Journal of Urology (218) 25, doi: /iju.1353 Original Article: Clinical Investigation Impact of age on quality of life in patients with localized prostate cancer treated with high-dose rate brachytherapy combined with external beam radiotherapy Kazuro Kikkawa, 1 Akinori Iba, 1 Yasuo Kohjimoto, 1 Yasutaka Noda, 2 Tetsuo Sonomura 2 and Isao Hara 1 1 Department of Urology, and 2 Department of Radiology, Wakayama Medical University, Wakayama, Japan Abbreviations & Acronyms ADT = androgen deprivation therapy ANOVA = analysis of variance BP = body pain EBRT = external beam radiotherapy ED = erectile dysfunction EPIC = Expanded Prostate Cancer Index Composite GH = general health HDRBT = high-dose rate brachytherapy IIEF-5 = International Index of Erectile Function-5 IQR = interquartile range MCS = mental component summary MH = mental health NCCN = National Comprehensive Cancer Network PCS = physical component summary PDE5i = phosphodiesterase type-5 inhibitor PF = physical function PSA = prostate-specific antigen QOL = quality of life RE = role emotional RP = role physical SF-8 = Medical Outcome Study 8-Items Short Form Health Survey SF = social functioning VT = vitality Correspondence: Kazuro Kikkawa M.D., Ph.D., Department of Urology, Wakayama Medical University, Kimiidera, Wakayama , Japan. kzro@wakayama-med.ac.jp Received 2 June 217; accepted 22 December 217. Online publication 4 February 218 Objectives: To evaluate age-related quality of life changes in patients with localized prostate cancer treated by high-dose rate brachytherapy combined with external beam radiation therapy. Methods: A total of 172 patients with clinically localized prostate cancer were categorized to age groups <75 years and 75 years. Changes in their quality of life were evaluated using the Japanese version of Medical Outcome Study 8-Items Short Form Health Survey, Expanded Prostate Cancer Index Composite and International Index of Erectile Function-5 at baseline, and followed up to 24 months after treatment. Results: There were no significant differences in Medical Outcome Study 8-Items Short Form Health Survey scores, and urinary and bowel scores of the Expanded Prostate Cancer Index Composite for older men after treatment. International Index of Erectile Function-5 summary scores were significantly decreased in both groups. Although sexual function and sexual bother scores were decreased in patients aged <75 years, these scores were maintained in patients aged 75 years. Conclusions: Quality of life of prostate cancer patients undergoing high-dose rate brachytherapy combined with external beam radiation therapy does not seem to be significantly affected by age. Key words: external beam radiotherapy, high-dose rate brachytherapy, prostate cancer, quality of life. Introduction Recently, the number of patients with prostate cancer has been increasing in Japan because of the aging of society and the prevalence of PSA testing. Treatments for prostate cancer patients are increasingly being evaluated by QOL issues, as well as life extension. Patients with prostate cancer report negative physical and psychological health effects after treatment. 1,2 The varied symptoms might be associated with the type of therapy received. Therefore, QOL after treatment is important for patients with prostate cancer to select treatment options that might affect their life after treatment. Although QOL studies regarding surgery, EBRT and low-dose rate brachytherapy have been extensively carried out, there have been few QOL studies regarding HDRBT combined with EBRT. 3 5 Patient age is also important to the treatment decision. Because of fears for QOL changes after treatment, older patients might tend to avoid curative local therapy. 6,7 However, the age impact on QOL outcomes after HDRBT combined with EBRT are not well discussed. The present study aimed to evaluate QOL after treatment in Japanese patients with clinically localized prostate cancer who had undergone HDRBT + EBRT. Additionally, to optimize the selection of treatment for older patients with prostate cancer, we assessed QOL on the basis of patient age. Methods Between June 27 and December 214, 174 patients with clinically localized prostate cancer (T1NM T3aNM) underwent HDRBT + EBRT at Wakayama Medical University Hospital, Wakayama, Japan. Clinical stage was assessed by digital rectal examination, computed The Japanese Urological Association

2 QOL in prostate cancer with HDRBT tomography scan, bone scan and magnetic resonance imaging. All patients were classified according to NCCN practice guidelines. 8 The indications for HDRBT + EBRT without ADT in our institution were limited to patients with histological diagnosis of adenocarcinoma, pretreatment PSA <2 ng/ml, clinical stage T1c T3a and Gleason score 8. HDRBT of a single implant was applied after 5-Gy EBRT. Iridium-192 HDRBT was carried out by the transperineal approach, delivering a total dose of 18 Gy in two fractions within 24 h. To rule out the effect of ADT on QOL, no patients treated with ADT were included in the present study. Two patients diagnosed with biochemical recurrence during 24 months after HDRBT + EBRT were eliminated from this study because of initiation of ADT. Age at diagnosis was categorized into two subgroups (<75 years and 75 years) for assessment. We carried out a longitudinal survey in the form of a questionnaire, using the Japanese version of SF-8, EPIC and IIEF-5. The validation studies of the Japanese version of these questionnaires had already been confirmed. 9,1 The SF- 8 is a QOL assessment consisting of eight scales (PF, RP, BP, GH, VT, SF, RE and MH) and generates two summary measures, PCS and MCS. The disease-specific QOL was evaluated using the EPIC, a 5-item questionnaire relating to the urinary, bowel, sexual and hormonal domains for function and bother. Sexual function of the patients was evaluated under the component of erectile function, intercourse satisfaction, organism function, overall satisfaction and sexual desire with the IIEF-5. The questionnaires were mailed and no interviews were carried out. The forms of questionnaire were administered before and 3, 6, 12 and 24 months after treatment. QOL scores were indicated by mean scores with standard deviation. PCS and MCS were calculated by weighting each SF-8 item using the norm-based scoring method. Each domain score of EPIC was scaled from to 1, with higher scores representing better QOL status. Statistical analysis was carried out using the SPSS 14. (SPSS, Chicago, IL, USA) software. Patient characteristics and QOL scores at baseline for each age group were compared using the Wilcoxon signed rank test for continuous variables, and the v 2 -test for categorical variables. Comparative analysis of QOL scores between the two groups were tested by two-way ANOVA. The QOL scores at 3, 6, 12 and 24 months after treatment for each group were compared with the baseline scores, respectively, using the Dunnett s test. P-values <.5 were considered significant. Results A total of 172 men were treated with HDRBT + EBRT for localized prostate cancer and reported QOL data within 24 months. Patient characteristics are listed in Table 1. Of the patients, 8 men were aged <75 years, and 92 men were aged 75 years. The characteristics did not differ between the two age groups. All patients responded to questionnaires before treatment. The complete answer rate of questionnaires was 98% after 3 months, 93% after 6 months, 88% after 12 months and 81% at 24 months after treatment. Throughout the follow-up period, 126 of 172 patients (73%) completed the questionnaires. The baseline scores are listed in Table 2. At baseline, mean physical function, sexual summary scores, sexual function scores and IIEF-5 scores in the <75 years age group were higher than these scores in the 75 years age group. In contrast, the mean sexual bother scores in the <75 years age group were lower than the 75 years age group. There was no significant change in PF, RP, BP, GH, VT, SF, RE and MH scores assessed with SF-8 after treatment in each age group. Figure 1 shows the SF-8 scores for PCS and MCS. The difference between the two groups in longitudinal changes of PCS scores was statistically significant (P <.1; Fig. 1a), but there was no significant difference between the two groups in longitudinal changes of MCS Table 1 Patients characteristics Aged <75 years (n = 8) Aged 75 years (n = 92) P-value Median age at treatment, 69 (66 72) 78 (77 79) years (IQR) Median pretreatment 8.69 ( ) 8.86 ( ).88 PSA, ng/ml (IQR) Biopsy Gleason score, n (%) 6 27 (34) 28 (3) (46) 4 (44) (2) 24 (26) Clinical stage, n (%) T1 28 (35) 4 (44).286 T2 49 (61) 49 (53) T3 3 (4) 3 (3) NCCN clinical risk, n (%) Low 18 (23) 16 (17).316 Intermediate 42 (52) 48 (52) High 2 (25) 28 (31) Table 2 Quality of life scores at baseline according to age group Quality of life domain Aged <75 years Aged 75 years P-value SF-8 Physical component scores <.1 Mental component scores EPIC Urinary summary Urinary function Urinary bother Urinary incontinence Urinary irritative/obstructive Bowel summary Bowel function Bowel bother Sexual summary Sexual function <.1 Sexual bother IIEF <.1 Data presented as mean SD. 218 The Japanese Urological Association 367

3 K KIKKAWA ET AL. (a) Physical Component Summary (a) Urinary Summary Score * P = P <.1 (b) Bowel Summary Score (b) Mental Component Summary * P = P =.524 (c) Sexual Summary Score * 34.6 * * * * 29. * 29. * 27.5 * Fig. 1 Longitudinal changes in the mean QOL scores in SF-8 according to age. (a) Physical component summary; (b) mental component summary. The solid line represents the scores of patients in the <75 years age group, and the dashed line represents the scores of patients in the 75 years age group. Asterisks (*) designate time-points at which scores were significantly different from those at pretreatment baseline (P <.5). These P-values were determined using two-way ANOVA for comparative analysis of scores between two groups. Error bars represent standard deviation. scores (Fig. 1b). In the <75 years age group, PCS was maintained until 12 months, but was decreased at 24 months. MCS was slightly increased at 6 months, and returned to a similar level at baseline after 12 months. In contrast, there were no significant changes in PCS and MCS throughout the follow-up period in the 75 years age group. In EPIC analysis, there was no significant difference between the two groups in longitudinal changes of urinary summary and bowel summary scores, and these scores had not changed throughout the follow-up period in each group (Fig. 2a,b). There was also no significant change in urinary function, urinary bother, bowel function and bowel bother scores assessed with EPIC after treatment in each age group. To the contrary, the difference between the two groups in longitudinal changes of sexual summary scores was statistically significant (P <.1; Fig. 2c). Both groups had a decline in sexual scores, and there were statistically significant differences after 3 months. There were significant P <.1 Fig. 2 Longitudinal changes in the mean QOL scores in EPIC according to age. (a) Urinary summary domain; (b) bowel summary domain; (c) sexual summary domain. The solid line represents the scores of patients in the <75 years age group, and the dashed line represents the scores of patients in the 75 years age group. Asterisks (*) designate time-points at which scores were significantly different from those at pretreatment baseline (P <.5). These P-values were determined using two-way ANOVA for comparative analysis of scores between the two groups. Error bars represent standard deviation. differences between the two groups in longitudinal changes of sexual function and sexual bother scores (P <.1 and P <.1, respectively; Fig. 3a,b). In patients aged <75 years, sexual function scores and sexual bother scores in the analysis of sexual domain of the EPIC had deteriorated. Sexual function scores were significantly decreased at 24 months, and sexual bother scores were significantly decreased after 12 months. In patients aged 75 years, sexual domain scores had been low before treatment. Although sexual summary scores were significantly decreased after treatment, there were no statistically significant changes in sexual function scores and sexual bother scores. In the present study, domains of hormone summary, function and bother were stable, because no patients had ADT The Japanese Urological Association

4 QOL in prostate cancer with HDRBT (a) 4 Sexual Function 14 P < P < * * 2.2 * (b) Sexual Bother P < * 69.4 Fig. 3 Longitudinal changes in the mean sexual domain scores in EPIC according to the age. (a) Sexual function domain; (b) sexual bother domain. The solid line represents the scores of patients in the <75 years age group, and the dashed line represents the scores of patients in the 75 years age group. Asterisks (*) designate time-points at which scores were significantly different from those at pretreatment baseline (P <.5). These P-values were determined using two-way ANOVA for comparative analysis of scores between the two groups. Error bars represent standard deviation. In IIEF-5 scores, the difference between the two groups in longitudinal changes of sexual summary scores was statistically significant (P <.1; Fig. 4). In patients aged <75 years, IIEF-5 scores were significantly decreased at 6 months. Then these scores improved at 12 months, but worsened further at 24 months. In patients aged 75 years, IIEF-5 scores also declined, and significantly decreased at 24 months. No patients were treated with PDE5i for ED during the 24 months after HDRBT + EBRT in the two groups. In addition, we evaluated patients without severe or moderate ED (IIEF-5 score 12) before treatment. 11 There were 24 patients without severe or moderate ED in the <75 years age group, and nine patients in the 75 years age group. The difference between the two groups in longitudinal changes of IIEF-5, sexual summary and sexual function scores in EPIC was statistically significant (P <.1, P =.4 and P <.1, respectively; Fig. 5a c), but there were no significant differences between the two groups in longitudinal Fig. 4 Longitudinal changes in the mean IIFE-5 scores according to age. The solid line represents the scores of patients in the <75 years age group, and the dashed line represents the scores of patients in the 75 years age group. Asterisks (*) designate time-points at which scores were significantly different from those at pretreatment baseline (P <.5). The P-value was determined using two-way ANOVA for comparative analysis of scores between the two groups. Error bars represent standard deviation. changes of sexual bother scores in EPIC (Fig. 5d). In these patients, both groups had significant decline in IIEF-5, sexual summary and sexual function scores in EPIC. IIEF-5 scores, sexual summary and sexual function scores in the EPIC in patients aged 75 years had deteriorated more than patients aged <75 years. Although sexual bother scores were significantly decreased at 24 months in the <75 years age group, there were no statistically significant changes in sexual bother scores in the 75 years age group. Discussion It has been reported that higher QOL scores after treatment are associated with younger age at treatment. 12,13 Pinkawa et al. studied the impact of age on QOL for patients treated with radiotherapy including EBRT and brachytherapy, and reported that urinary incontinence and sexual function with older age were worse. 14 In contrast, Hampson et al. reported that age does not predict a decrease in QOL scores after treatment including radical prostatectomy, radiation therapy and ADT for localized prostate cancer. 15 The present results show that age was not associated with changes in QOL scores other than sexual function, particularly urinary and bowel changes in EPIC after treatment with HDRBT + EBRT for localized prostate cancer. General QOL evaluated using the SF-8 was also maintained after treatment for the 75 years age group. Furthermore, the present data showed that older men had lower QOL scores for sexual function in EPIC and IIEF-5 both before and after treatment. Although men aged 75 years reported QOL decline in sexual summary scores in EPIC and IIEF-5 scores, there were no worsening sexual bother scores in EPIC. Additionally, in the analysis of patients without severe or moderate ED, although sexual function in patients aged 75 years deteriorated more than in patients aged <75 years, there were no statistically significant changes in sexual bother. This might indicate that they did 218 The Japanese Urological Association 369

5 K KIKKAWA ET AL. (a) IIEF P < * * 7.7 * 9. * 6.7 * (b) Sexual Summary Score in EPIC * 32.5 * 35. P = * 28.6 * (c) Sexual Function in EPIC * 38.9 P < * * (d) Sexual Bother in EPIC P = * Fig. 5 Longitudinal changes in the mean QOL scores in patients without severe or moderate ED according to age. (a) IIEF-5; (b) sexual summary domain in EPIC; (c) sexual function domain in EPIC; (d) sexual bother domain in EPIC. The solid line represents the scores of patients in the <75 years age group, and the dashed line represents the scores of patients in the 75 years age group. Asterisks (*) designate time-points at which scores were significantly different from those at pretreatment baseline (P <.5). These P-values were determined using two-way ANOVA for comparative analysis of scores between two groups. Error bars represent standard deviation. not expect the recovery of QOL more than younger patients, because of lower baseline QOL scores. These results suggest that the treatment option should be selected depending on baseline characteristics and QOL of patients rather than only their age. Incrocci reviewed the effectiveness of PDE5i to treat postradiation ED in prostate cancer patients. 16 Furthermore, Pugh et al. reported that PDE5i improved erections of patients treated with low-dose rate brachytherapy. 17 In contrast, the usefulness of PDE5i for prostate cancer patients after HDRBT was not reported previously. Although we suggested the use of PDE5i to patients in the present study, no patients hoped to be treated for ED with PDE5i during the 24 months after HDRBT + EBRT. Because PDE5i is not covered by public health insurance in Japan, the treatment cost with PDE5i is generally expensive. Most patients in the present study were also worried about adverse events with PDE5i. As Okihara et al. reported a low PDE5i medication rate in Japanese patients after low-dose rate brachytherapy, 18 male sexual function might not be important for a majority of Japanese patients treated with HDRBT. A future study is necessary to clarify whether administration of PDE5i can contribute to maintaining sexual function of patients after HDRBT. Several studies have reported the QOL outcome of HDRBT. 3 5 Egawa et al. reported the QOL outcome of HDRBT, and showed that general QOL scores using SF-36 were decreased during 1 month after treatment, and all recovered to the baseline level 12 months after treatment. 3 Joseph et al. reported a prospective study in which patients were treated with EBRT alone or HDRBT + EBRT. 5 The study showed no difference in QOL scores using the Functional Assessment of Cancer Therapy-Prostate between the two groups at 1 year after treatment. However, the impact of age on QOL outcomes after treatment with HDRBT + EBRT for localized prostate cancer has not been previously reported. Considering the results of the present study, physicians can potentially use these data to provide better information for patients about treatment selection, and to discuss the association of age and the type of treatment on QOL. In the present study, it was shown that age does not predict deterioration in QOL, other than sexual function, after treatment with HDRBT + EBRT. Additionally, older men had slight changes in QOL scores for sexual function both before and after treatment. Therefore, the treatment options for older men with localized prostate cancer should not be limited. The small number of patients and short follow-up period were limitations of the present study. In addition, not all patients completed the questionnaires up to 24 months after treatment. Another limitation of the present study was that is was carried out at a single institution. Because HDRBT doses and fractions vary among institutions, the results might differ when different radiation doses and fraction schedules are used. Physical activities commonly decline with age. Furthermore, older men often have urinary symptoms and sexual dysfunction. It was a limitation of the present results that we did not evaluate these changes during the follow-up period. Long-term follow-up data from multiple institutions will help physicians and better predict patients QOL after treatment The Japanese Urological Association

6 QOL in prostate cancer with HDRBT In conclusion, older patients are less likely to have a worse QOL outcome after treatment with HDRBT for localized prostate cancer. Patients QOL changes after treatment should be an important part of treatment selection. The results of this study can potentially help to avoid deferring a decision regarding treatment for older men. Conflict of interest None declared. References 1 Zenger M, Hinz A, Stolzenburg JU, Rabenalt R, Schwalenberg T, Schwartz R. Health-related quality of life of prostate cancer patients compared to general German population: age-specific results. Urol. Int. 29; 83: Diefenbach MA, Mohamed NE. Regret of treatment decision and its association with disease-specific quality of life following prostate cancer treatment. Cancer Invest. 27; 25: Egawa S, Shimura S, Irie A et al. Toxicity and health-related quality of life during and after high dose rate brachytherapy followed by external beam radiotherapy for prostate cancer. Jpn. J. Clin. Oncol. 21; 31: Lev EL, Eller LS, Gejerman G et al. Quality of life of men treated with brachytherapies for prostate cancer. Health Qual. Life Outcomes 24; 2: Joseph KJ, Alvi R, Skarsgard D et al. Analysis of health related quality of life (HRQoL) of patients with clinically localized prostate cancer, one year after treatment with external beam radiotherapy (EBRT) alone versus EBRT and high dose rate brachytherapy (HDRBT). Radiat. Oncol. 28; 3: 2. 6 Resnick MJ, Barocas DA, Morgans AK et al. Contemporary prevalence of pretreatment urinary, sexual, hormonal, and bowel dysfunction: defining the population at risk for harms of prostate cancer treatment. Cancer 214; 12: Bechis SK, Carroll PR, Cooperberg MR. Impact of age at diagnosis on prostate cancer treatment and survival. J. Clin. Oncol. 211; 29: Carroll PR, Parsons JK, Andriole G et al. NCCN guidelines insights: prostate cancer early detection, version J. Natl. Compr. Canc. Netw. 216; 14: Sugimoto M, Takegami M, Suzukamo Y, Fukuhara S, Kakehi Y. Healthrelated quality of life in Japanese men with localized prostate cancer: assessment with the SF-8. Int. J. Urol. 28; 15: Kakehi Y, Takegami M, Suzukamo Y, Vargas Souto CA. Health related quality of life in Japanese men with localized prostate cancer treated with current multiple modalities assessed by a newly developed Japanese version of the Expanded Prostate Cancer Index Composite. J. Urol. 27; 177: Rhoden EL, Teloken C, Sogari PR, Vargas Souto CA. The use of the simplified International Index of Erectile Function (IIEF-5) as a diagnostic tool to study the prevalence of erectile dysfunction. Int. J. Impot. Res. 22; 14: Sanda MG, Dunn RL, Michalski J et al. Quality of life and satisfaction with outcome among prostate-cancer survivors. N. Engl. J. Med. 28; 358: Huang GJ, Sadetsky N, Penson DF. Health related quality of life for men treated for localized prostate cancer with long-term follow up. J. Urol. 21; 183: Pinkawa M, Fischedick K, Gagel B et al. Impact of age and comorbidities on health-related quality of life for patients with prostate cancer: evaluation before a curative treatment. BMC Cancer 29; 9: Hampson LA, Cowan JE, Zhao S, Carroll PR, Cooperberg MR. Impact of age on quality-of-life outcomes after treatment for localized prostate cancer. Eur. Urol. 215; 68: Incrocci L. Radiotherapy for prostate cancer and sexual health. Transl. Androl. Urol. 215; 4: Pugh TJ, Mahmood U, Swanson DA et al. Sexual potency preservation and quality of life after prostate brachytherapy and low-dose tadalafil. Brachytherapy 215; 14: Okihara K, Yorozu A, Saito S et al. Assessment of sexual function in Japanese men with prostate cancer undergoing permanent brachytherapy without androgen deprivation therapy: analysis from the Japanese Prostate Cancer Outcome Study of Permanent Iodine-125 Seed Implantation database. Int. J. Urol. 217; 24: Editorial Comment Editorial Comment to Impact of age on quality of life in patients with localized prostate cancer treated with high-dose rate brachytherapy combined with external beam radiotherapy Kikkawa et al. assessed age-related quality of life changes for patients with localized prostate cancer treated by highdose rate brachytherapy (HDRBT) combined with external beam radiation therapy. 1 The data in this study show important evidence in terms of treatment choice for combining HDR based on patient age. From this study, as the authors stated, older patients were less likely to have a worse quality of life outcome after treatment with HDRBT for localized prostate cancer. I believe HDRBT combined treatment might be a potential option in determining curative treatment specifically in elderly men with localized prostate cancer. Surprisingly, in this study, no patients were treated with phosphodiesterase type-5 inhibitors in all the cohorts. As the authors stated in the Discussion, the proportion of phosphodiesterase type-5 inhibitors prescribed in men undergoing HDRBT in this study, as well as low-dose rate brachytherapy, 2 is so extremely low. Although sexual function itself is not currently a key factor for QOL after HDRBT and lowdose rate brachytherapy, I agree with the authors opinion that a future study is necessary to clarify whether administration of phosphodiesterase type-5 inhibitors can contribute to maintaining the sexual function of patients, and such a study is required focusing on future generations, specifically in the Japanese population. Koji Okihara M.D., Ph.D. Department of Urology, Kyoto Prefectural University of Medicine, Kyoto, Japan kokihara@koto.kpu-m.ac.jp DOI: /iju The Japanese Urological Association 371