Erectile Dysfunction After External Beam Radiotherapy for Prostate Cancer

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1 european urology 55 (2009) available at journal homepage: Sexual Medicine Erectile Dysfunction After External Beam Radiotherapy for Prostate Cancer Michael Pinkawa *, Bernd Gagel, Marc D. Piroth, Karin Fischedick, Branka Asadpour, Mareike Kehl, Jens Klotz, Michael J. Eble Department of Radiation Oncology, RWTH Aachen University, Pauwelsstrasse 30, Aachen, Germany Article info Article history: Accepted March 12, 2008 Published online ahead of print on March 24, 2008 Keywords: Erectile dysfunction Prostate cancer Quality of life Three-dimensional conformal radiotherapy Abstract Background: There is a lack of prospective studies focusing on the sexual quality of life of prostate cancer patients after conformal radiotherapy (RT). Objective: To evaluate the incidence, progression, and predictive factors for erectile dysfunction (ED). Design, Setting and Participants: Patients who responded to the sexual domain of the Expanded Prostate Cancer Index Composite (EPIC) questionnaire before and more than 1 yr after RT and never received an antiandrogen treatment were included (n = 123). Intervention: RT dose was Gy. Eleven patients used a phosphodiesterase-5 (PDE-5) inhibitor. Measurements: Patients responded to the EPIC questionnaire before (time A), at the last day (B), a median time of 2 mo after (C), and 16 mo after (D) RT. In a multivariate analysis, risk factors (patient age, prostate volume, planning target volume, use of PDE-5 inhibitor, comorbidities) were tested for their independent effects on ED before and after RT. Results and Limitations: Sexual function and bother scores had already decreased by the end of RT (median function and bother scores at times A/B/C/D: 41/30/32/24 and 75/50/50/50). Initial function scores correlated well with late function scores (r = 0.7; p < 0.001). The ability to have an erection was reported by 81%/72%/74%/60% (preserved erectile ability in 70% at time D), erections firm enough for sexual intercourse by 44%/33%/35%/27% (preserved erections sufficient for intercourse in 53% at time D) of patients. A higher patient age and diabetes were predictive of both a pre-existing ED and a post-rt acquired ED. Nightly erections before treatment proved prognostically favourable (at least weekly vs. < weekly hazard ratio of 5.9 for preserved erections sufficient for intercourse; p = 0.01). Higher rates of ED can be expected with longer follow-up. Conclusions: The incidence of ED progressively increases after RT. Patient age and diabetes are risk factors for both pre-treatment and RT-associated ED. Nightly erections before RT proved prognostically favourable. # 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Department of Radiation Oncology, RWTH Aachen University, Pauwelsstrasse 30, Aachen, Germany. Tel ; Fax: address: MPinkawa@ukaachen.de (M. Pinkawa) /$ see back matter # 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo

2 228 european urology 55 (2009) Introduction 2. Methods Erectile dysfunction (ED) after three-dimensional conformal radiotherapy (RT) for localized prostate cancer is a well-recognized occurrence. However, assessment of the magnitude of this problem is complicated by numerous factors. Various antiandrogen treatments of different durations have a significant impact on the patients sexual life [1,2]. Prostate cancer occurs in an elderly population in whom other medical morbidity is common. As a consequence of disease or the associated treatment, a deterioration of sexual activity may result. Patients with comorbidities can be expected to react differently following a treatment. Failure to define and record potency before RT or other treatments and limitations of retrospective data collection lead to uncertainty as to the real impact RT has on sexual function. Most studies dealing with ED lack a definition of potency or impotence [3,4]. The European Association of Urology guidelines define impotence as the persistent inability to attain and maintain an erection sufficient to permit satisfactory sexual performance [5]. Studies of ED should involve a more extensive evaluation of the patients sexuality. By administering a quality-of-life questionnaire, symptoms are described from an unbiased patient perspective. Patients subjectively assess their problems as more severe compared to the assessments obtained by physicians [6]. Only 43% of subjects who verbally reported being fully potent were found to have a normal erectile function according to the International Index of Erectile Function (IIEF) questionnaire [7]. Quality-of-life issues become more important as therapies become more widely used, are used for longer durations, and are used in patients with fewer symptoms [8]. Boththe assessment of specific functions and the actual associated subjective bother for the patient become possible. There is a lack of prospective studies focusing on the sexual quality of life of prostate cancer patients before and after a definitive conformal RT from the patients perspective. Theaimofthisstudywastoassessprospectively the incidence of ED and predictive factors in a patient population treated with the same RT technique and a homogeneous dose level. Patient age, comorbidities, prostate volume, planning target volume, pre-treatment sexual function, and treatment of ED have been considered Patients This study was based on consecutive patients who were treated due to ct1-3n0m0 prostatic carcinoma with conformal RT in the years Patients selected for this analysis had not received an antiandrogen treatment before or at any time after RT. A response to the sexual domain items in a validated questionnaire, the Expanded Prostate Cancer Index Composite (EPIC) [9], was required both before RT (time A) and more than 1 yr after RT (time D, median time of 16 mo, range months). A group of 123 patients met the inclusion criteria. Furthermore, 83 and 109 of the 123 patients responded at the last day (time B) and at a median time of 2 mo (time C, range 6 wk 6 mo) after RT. The sexual domain of the EPIC comprises 13 items concerning sexual function and sexual bother. The multi-item scale scores were transformed linearly to a scale, with higher scores representing better healthrelated quality of life. During the study period, 197 patients presented for a definitive RT of the prostate without neoadjuvant antiandrogen therapy. Within this group, 74 patients were excluded due to the following criteria: 5 patients received an antiandrogen treatment after RT, 45 patients did not consent to answer questions about the sexual domain before RT, and 24 patients did not respond at time D. Taking into account initially responding patients without antiandrogen treatment after RT, the response rate at time D was 84% (123 of 147 patients). The questionnaire was given to the patients personally by one of the physicians at times A, B, and C. The number of returned questionnaires was lowest at the end of RT (time B) because this point in time was limited to a single day (last radiotherapy fraction) and no second opportunity existed to make up for a missed questionnaire. Patients also presented in the department 2 mo after RT. Missed questionnaires in the acute phase (time C) and questionnaires more than 1 yr after RT (time D) were sent to the patients with a return envelope. All patients answered a question concerning any treatment of erectile dysfunction at time D. If a questionnaire was not returned within 4 wk, patients were contacted by telephone and urged to complete it Treatment RT treatment was based on a treatment planning computed tomography (CT) scan in supine position with a slice thickness of 5 mm. The same individual (M.P.) performed all prostate volume contouring. A prior study involving the same radiation oncologist demonstrated no statistically significant difference between transrectal ultrasound- and CT-defined prostate volumes [10]. Treatment plans were calculated using a fourfield box technique with 15MeV photons and a multileaf collimator. The planning target volume was required to be enclosed by the 90% isodose relative to the ICRU reference point [11], with a margin of 1.5 cm in the anterior/lateral and 1 cm in the craniocaudal and dorsal directions to the clinical target volume (prostate with or without seminal vesicles). The

3 european urology 55 (2009) Fig. 1 Significant correlation of sexual function scores before radiotherapy with sexual function scores more than 1 yr after radiotherapy (r = 0.7; p < 0.001). coefficient was used to test for correlations between sexual function scores before and after RT. Contingency table analysis with the chi-square test was performed to compare treatment groups with respect to categorical variables. In a univariate and forward stepwise multivariate analysis, different risk factors (patient age, prostate volume, planning target volume, use of phosphodiesterase type 5 (PDE-5) inhibitors, comorbidities with an incidence of at least 5%) concerning pre-treatment and post-rt acquired ED were tested for their significance. This specific analysis focused on ED as defined by very poor or no ability to have an erection, erections not firm enough for sexual intercourse, and the absence of erections while awakening in the morning or night. The analysis of post-rt acquired ED involved only patients who affirmed having a specific function before RT (eg, only patients with sufficient erections for sexual intercourse before RT were included in the analysis of post-rt acquired loss of erections firm enough for sexual intercourse). All p- values reported are two-tailed; p < 0.05 is considered significant. total dose to the prostate in the reference point was Gy at Gy daily fractions. Patients were referred to the RT department by specialists in urology (31 different physicians). The respective urologists made the decision on possible treatment of ED Statistical analysis Statistical analysis was performed using the SPSS 14.0 (SPSS, Chicago, IL), software. The Wilcoxon s matched-pairs test was applied to determine longitudinal changes in sexual function and sexual bother scores. To analyse longitudinal changes for patients with different scores before treatment, the patient group was divided in three equal parts, excluding patients with initial scores of 0 points. The Pearson correlation 3. Results Baseline patient characteristics are presented in Table 1. Sexual function scores decreased progressively, with the lowest scores and highest incidence of erectile dysfunction at time D (Table 2). The greatest decline could already be observed at times B and C (phase of acute toxicity). A significant decline occurred in patients with both higher and lower initial scores. Sexual function scores before RT were strongly predictive of the sexual function scores at time D (Fig. 1). Sexual bother scores had already reached the lowest level in the acute phase. However, patients with low initial scores significantly improved their bother scores after treatment. Table 1 Baseline patient characteristics Patient age (yr); median (range) 71 (53 84) Planning target volume (cm 3 ); median (range) 333 ( ) Prostate volume (cm 3 ); median (range) 45 (14 151) PSA (ng/ml); median (range) 8 (1.2 51) 10 ng/ml; n (%) 81 (66) Biopsy Gleason score < 7; n (%) 86 (70) Clinical T-stage 2a; n (%) 111 (90) Low risk (PSA 10 ng/ml; Gleason score < 7; clinical T-stage 2a); n (%) 56 (45) Intermediate risk (PSA ng/ml or Gleason score = 7 or clinical T-stage 2b-c); n (%) 47 (38) High risk (two risk factors or PSA > 20 ng/ml or Gleason score > 7 or clinical T-stage >2c); n (%) 20 (16) Use of PDE-5 inhibitor; n (%) 2 (2) Comorbidities; n (%) 69 (56) Hypertension; n (%) 32 (26) Coronary heart disease; n (%) 30 (24) Diabetes; n (%) 14 (11) COPD; n (%) 12 (10) Stroke in past history; n (%) 6 (5) Haemorroids; n (%) 6 (5) PSA = prostate-specific antigen; PDE-5 = phosphodiesterase type 5; COPD = chronic obstructive pulmonary disease.

4 230 european urology 55 (2009) Table 2 Sexual function and sexual bother scores Time A Time B Time C Time D Significant differences compared to baseline (time A) Mean (quartiles) Mean (quartiles) Mean (quartiles) Mean (quartiles) Sexual function score sexual function scores before treatment (all patients); n = (26;41;53) 32 (18;30;50) 33 (15;32;50) 28 (8;24;47) B D ( p < 0.01) >0 35; n = (15;26;29) 21 (12;21;30) 21 (9;20;30) 15 (3;12;21) B ( p = 0.03); D ( p < 0.01) >35 50; n = (38;44;50) 31 (21;32;50) 31 (21;32;41) 27 (12;24;42) B D ( p < 0.01) >50 100; n = (57;65;71) 49 (35;51;65) 57 (47;55;73) 51 (41;53;62) B D ( p < 0.01) Sexual bother score sexual bother scores before treatment; n = (all patients) 62 (25;75;100) 50 (25;44;82) 52 (13;50;94) 52 (25;50;88) B D ( p < 0.01) >0 55; n = (13;25;44) 31 (13;25;44) 32 (13;22;53) 41 (19;31;69) D ( p = 0.02) >55 95; n = (63;81;89) 62 (36;66;81) 63 (38;63;89) 62 (38;69;88) B D ( p < 0.01) >95 100; n = (100;100;100) 70 (28;88;100) 79 (56;100;100) 72 (50;84;100) B D ( p < 0.01) The incidence of ED and other sexual problems (according to the answers to 9 selected of 13 available questions) at the various times is shown in Table 3. The majority of patients had some erectile function at each time of response; a lower percentage reported nightly erections, and the lowest percentage reported erections firm enough for sexual intercourse. A PDE-5 inhibitor was used by only two patients before the beginning of RT. Nine additional patients started treatment with a PDE-5 inhibitor (sildenafil, tadalafil, or vardenafil) 3 to 6 mo after the end of RT, resulting in 11 (9%) total patients at time D; nine patients were able to have an erection, and a single patient in this group had erections firm enough for sexual intercourse at time D. Patients with a pretreatment erectile ability (n = 96; at least poor ability) were able to retain this ability in 70% of cases (58% without PDE-5 inhibitor) at time D. Patients with preexisting erections firm enough for sexual intercourse (n = 48) were able to retain this ability in 53% of cases (48% without PDE-5 inhibitor) more than 1 yr after RT. Chronic ED could be predicted very well shortly after RT. Patients with an erectile ability (at least poor ability) before RT and at time C were able to retain this ability in 80% of cases at time D; only 9% were able to regain it ( p < 0.01). Patients with erections firm enough for sexual intercourse both before RT and at time C were able to retain this function in 72% of cases at time D; only 9% regained this function ( p < 0.01). A multivariate analysis revealed the independent influence of patient age, prostate volume, and a history of diabetes or stroke on the incidence of pretreatment ED (Table 4). Patient age and diabetes were likewise found to be independent risk factors for post-rt acquired ED (Table 5). The use of PDE-5 inhibitors was associated with post-rt acquired ED, as defined by erections firm enough for sexual intercourse. No negative effect was found for patients with large prostates (even protective against a new big/moderate problem with lack of sexual function). Coronary heart disease was found to be protective against post-rt acquired ED only in univariate analysis (none of the 13 patients with Table 3 Incidence of erectile dysfunction/sexual problems Time A Time B Time C Time D Significant differences compared to baseline (time A) Very poor/no sexual desire 13% 19% 18% 28% D ( p < 0.01) Very poor/no ability to have an erection 19% 28% 26% 40% D ( p < 0.01) Very poor/no ability to reach orgasm 19% 31% 27% 35% D ( p < 0.01) No erections firm enough for sexual intercourse 56% 67% 65% 73% D ( p < 0.01) No nightly erections 35% 34% 43% 49% D ( p = 0.02) Big/moderate problem with the level of sexual desire 32% 50% 42% 39% C ( p = 0.01) Big/moderate problem with the ability to have an erection 33% 49% 46% 44% C ( p = 0.03) Big/moderate problem with the ability to reach orgasm 36% 50% 47% 46% Big/moderate problem with lack of sexual function overall 30% 47% 42% 45% C ( p = 0.01); D ( p = 0.02)

5 european urology 55 (2009) Table 4 Predictive factors for pretreatment erectile dysfunction in a univariate and multivariate analysis a Item Univariate analysis Multivariate analysis Risk factor Hazard ratio [95% CI] p-value Risk factor Hazard ratio [95% CI] p-value Very poor/no ability to have an erection No erections firm enough for sexual intercourse prostate volume (>median) 3.3 [ ] 0.01 prostate volume 3.9 [1.2 12] 0.01 (>median) diabetes 9.7 [2.8 33] <0.01 diabetes 8.4 [2.3 32] <0.01 stroke in past history 9.9 [1.7 57] 0.01 stroke in past history 8.6 [1.3 57] 0.02 patient age (>median) 2.8 [ ] 0.01 patient age (>median) 3.5 [ ] <0.01 diabetes 10.3 [1.3 83] 0.03 diabetes 9.8 [1.1 85] 0.04 No nightly erections diabetes 7.9 [2.0 30] <0.01 diabetes 7.9 [2.0 30] <0.01 Big/moderate problem with lack of sexual function overall CI = confidence interval. a The following variables were tested for each item: patient age, prostate volume, planning target volume, use of PDE-5 inhibitors, comorbidities with an incidence of at least 5% (hypertension, coronary heart disease, diabetes, chronic obstructive pulmonary disease, stroke in past history, haemorrhoids). Significant factors are presented. erections sufficient for sexual intercourse before treatment received a PDE-5 inhibitor). Patients who awakened in the morning or night with an erection at least once a week before the beginning of RT had significantly greater chances of preserving an erection firm enough for sexual intercourse (at least once a week vs. less than weekly preserved erections firm enough for intercourse in 67% vs. 33% more than a year after RT; p = 0.03). When added to the multivariate analysis, this factor (at least weekly nightly erections before treatment vs. less than once a week) proved to be an additional independent factor for the preservation of erections firm enough for sexual intercourse (hazard ratio = 5.9; 95% confidence interval = ; p = 0.01). Only a single patient reported having erections sufficient for intercourse without actually having sexual intercourse (no partner). This patient had lost this ability at time D. 4. Discussion According to the current literature, rates of ED vary from 6% to 84% after external beam RT [3]. This wide range can be explained by an often insufficient quality of studies. In most studies, the analysis is retrospective, the definition of ED is not clear, only one question about sexual function is asked, and nonvalid instruments are used [3]. A recently published study reporting results from a dose-escalation trial comparing 68 Gy to 78 Gy found no significant sexual function differences between the dose levels. ED was defined as problems with achieving or maintaining Table 5 Predictive factors for post-radiotherapy acquired erectile dysfunction in a univariate and multivariate analysis a Item (n = patients in analysis) Risk factor Univariate analysis Hazard ratio [95% CI] Multivariate analysis p-value Risk factor Hazard ratio [95% CI] p-value Loss of the ability to have an erection (n = 96) Loss of erections firm enough for sexual intercourse (n = 48) Loss of nightly erections (n = 79) New big/moderate problem with lack of sexual function overall (n = 80) patient age (>median) 2.8 [ ] 0.03 patient age (>median) 3.7 [1.4 10] 0.01 diabetes 7.6 [0.8 76] 0.08 diabetes 9.8 [ ] 0.06 PDE-5 inhibitor 9.2 [1.0 84] 0.05 PDE-5 inhibitor 9.2 [1.0 84] 0.05 coronary heart disease 0.2 [0.1 1] 0.05 patient age (>median) 8.3 [2.5 28] <0.01 patient age (>median) 10 [2.6 39] <0.01 haemorrhoids 8.4 [0.8 85] 0.07 haemorrhoids 16 [ ] 0.04 prostate volume 0.3 [ ] 0.02 prostate volume (>median) 0.3 [ ] 0.02 (>median) CI = confidence interval; PDE-5 = phosphodiesterase type 5. a The following variables were tested for each item: patient age, prostate volume, planning target volume, use of PDE-5 inhibitors, comorbidities with an incidence of at least 5% (hypertension, coronary heart disease, diabetes, chronic obstructive pulmonary disease, stroke in past history, haemorrhoids). Significant factors are presented.

6 232 european urology 55 (2009) erections. After 1 yr, 73% preserved erectile function. After 2 yr, this percentage decreased to 64% [12]. These results are very comparable to the 70% of patients with preserved erectile ability in our study after a median follow-up period of 16 mo. Erections sufficient for sexual intercourse were not analyzed in the above-mentioned dose-escalation trial [12]. A comparable percentage of patients (14%) in that study used PDE-5 inhibitors as in ours (9%). As with other studies [12 14], this study supports a progressive decrease in sexual function with longer follow-up intervals due to chronic RT effects, patient age, and comorbidities. A stable level cannot be expected in a population of men with prostate cancer. The percentage of patients who would acquire an ED within 1.5 yr due to RT-independent reasons can be expected to be low. Thus, newly occurring ED can be ascribed to irradiation. In a retrospective study published by Roach et al [4], following a conformal RT with total doses between 65 and 87 Gy, 62% retained sexual function sufficient for intercourse after a median follow-up period of 21 mo (range 7 40 mo). This percentage is slightly higher than in our study (53% with preserved erections sufficient for intercourse). Patient age and comorbidities (diabetes or atherosclerosis causing a vasculogenic erectile dysfunction; stroke or diabetic neuropathy causing a neurogenic erectile dysfunction) are well-known risk factors for erectile dysfunction in the general population [15,16]. An association of ED with hypertension, the most common comorbidity in our patient population, has not been found. A high prevalence of ED was reported in patients with a benign prostatic syndrome [17], parallel to the adverse prognostic effect of prostate volume on the ability to have an erection in our study. As with benign prostatic syndrome, prostate volume is associated with greater lower urinary tract symptoms [18]. A recent report found both prostate volume and American Urological Association (AUA) symptom score to be predictive of ED [19]. However, only the AUA symptom score remained significant in the multivariate analysis. Patient age and sexual function are the most important prognostic factors for the return of potency after radical prostatectomy [20]. As shown in our study, these factors are of equally major importance after RT. The best predictor for preserving erections sufficient for sexual intercourse is the occurrence of spontaneous erections in the morning or night before treatment. Diabetic patients are not only predisposed for ED before RT, but additionally for post-rt acquired ED. Haemorrhoids proved to be predictive of post-rt loss of spontaneous nightly erections. The pathophysiological mechanism is not known. Both changes in blood flow or compression of the autonomous penile nerve supply by dilated blood vessels could be postulated as a hypothesis. The administration of a PDE-5 inhibitor was associated with a higher risk for erections not sufficient for sexual intercourse, simply because this patient group more frequently requires and demands treatment. An important result of this study is an early predictability of chronic ED as soon as immediately after the end of RT. Thus, we could demonstrate that ED is not only a chronic effect, but to a large extent an acute effect of irradiation. Sexual function scores decreased most in the acute phase at the end of and shortly after RT. Sexual bother scores had already reached the lowest level in the acute phase. Improving bother scores for patients with initially low scores could be interpreted as some adaptation to the sexual problems. In view of the known efficacy of PDE-5 inhibitors for patients after RT [21 24], ED should be diagnosed early to ensure the best treatment efficacy. Erection rehabilitation or prophylaxis of erectile dysfunction using PDE-5 inhibitors as soon as a few weeks after radical prostatectomy is common to reach optimal erectile function [25]. Though corresponding studies after RT do not exist, a longer duration of ED could likewise be postulated to be detrimental after radical RT. A prophylactic application cannot be advised presently in view of the treatment cost and the lack of studies addressing this aspect. Though nerves are at risk during radical external beam RT as they are closely applied to the prostate posterolaterally, colour ultrasound studies suggest that in the majority of patients, the cause of post-rt ED is arterial, with reduced peak systolic velocity in the cavernous arteries in 60% of patients [26]. In a randomized, placebo-controlled study, 67% of the patients reported an improvement of erectile function with tadalafil (placebo: 20%), and 48% reported successful intercourse with tadalafil (placebo: 9%) [21]. Other studies could demonstrate the efficacy of sildenafil for treatment of ED after conformal RT [22 24]. Sexual counselling of patients, especially those with adequate erectile function, about RT effects and treatment options is a prerequisite. 5. Conclusions The incidence of ED progressively increases after RT. Patient age and, above all, diabetes mellitus are

7 european urology 55 (2009) independent risk factors for both pre-treatment and RT-associated ED. The presence of spontaneous erections in the morning or night before treatment independently predicted preserved erections sufficient for sexual intercourse more than 1 yr after RT. Chronic ED can be predicted very well shortly after RT, so that ED cannot only be regarded as a chronic effect of irradiation. As is common after radical prostatectomy, the initiation of early treatment could result in improved erectile function after radical RT. Author contributions: Michael Pinkawa 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: Pinkawa, Gagel, Piroth, Fischedick, Asadpour, Kehl, Klotz, Eble. Acquisition of data: Pinkawa, Gagel, Piroth, Fischedick, Asadpour, Kehl, Klotz. Analysis and interpretation of data: Pinkawa, Gagel, Piroth, Fischedick, Asadpour, Kehl, Klotz, Eble. Drafting of the manuscript: Pinkawa. Critical revision of the manuscript for important intellectual content: Gagel, Piroth, Fischedick, Asadpour, Kehl, Klotz, Eble. Statistical analysis: Pinkawa. Obtaining funding: Eble. Administrative, technical, or material support: Pinkawa, Fischedick. Supervision: Pinkawa, Eble. Other (specify): None. Financial disclosures: I certify 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: None. Appendix A. Questionnaire How did you rate each of the following during the last 4 wk? very poor to none/poor/fair/good/very good 1. Your level of sexual desire 2. Your ability to have an erection 3. Your ability to reach orgasm (climax) 4. How would you describe the usual quality of your erections during the last 4 wk? none at all/not firm enough for any sexual activity/firm enough for foreplay only/firm enough for intercourse 5. How would you describe the frequency of your erections during the last 4 wk? never had an erection when I wanted one/i had an erection less than half the time I wanted one/i had an erection about half the time I wanted one/i had an erection more than half the time I wanted one/i had an erection whenever I wanted one 6. How often have you awakened in the morning or night with an erection during the last 4 wk? never/less than once a week/about once a week/several times a week/daily 7. During the last 4 wk, how often did you have any sexual activity? not at all/less than once a wk/about once a wk/several times a wk/daily 8. During the last 4 wk, how often did you have sexual intercourse? not at all/less than once a wk/about once a wk/several times a wk/daily 9. Overall, how would you rate your ability to function sexually during the last 4 wk? very poor/poor/fair/good/very good How big a problem during the last 4 wk, if any, has each of the following been for you? no problem/very small problem/ small problem/moderate problem/big problem 10. Your level of sexual desire 11. Your ability to have an erection 12. Your ability to reach orgasm (climax) 13. Overall, how big a problem has your sexual function or lack of sexual function been for you during the last 4 wk? no problem/very small problem/small problem/moderate problem/big problem References [1] Green HJ, Pakenham KI, Headley BC, et al. Quality of life compared during pharmacological treatments and clinical monitoring for non-localized prostate cancer: a randomized controlled trial. BJU Int 2004;93: [2] Valicenti RK, Winter K, Cox JD, et al. RTOG 94-06: is the addition of neoadjuvant hormonal therapy to dose-escalated 3D conformal radiation therapy for prostate cancer associated with treatment toxicity? Int J Radiat Oncol Biol Phys 2003;57: [3] Incrocci L, Slob AK, Levendag PC, et al. Sexual (dys)function after radiotherapy for prostate cancer: a review. Int J Radiat Oncol Biol Phys 2002;52: [4] Roach III M, Chinn DM, Holland J, Clarke M. A pilot study of sexual function and quality of life following 3d conformal radiotherapy for clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 1996;35: [5] Wespes E, Amar E, Hatzichristou D, et al. Guidelines on erectile dysfunction. Eur Urol 2002;41:1 5. [6] Davidson SE, Burns MP, Routledge JA, et al. Assessment of morbidity in carcinoma of the cervix: a comparison of the LENT SOMA scales and the Franco-Italian glossary. Radiother Oncol 2003;69: [7] Salonia A, Zanni G, Gallina A, et al. Baseline potency in candidates for bilateral nerve-sparing radical retropubic prostatectomy. Eur Urol 2006;50: [8] Moul JW, Anderson J, Penson DF, et al. Early prostate cancer: prevention, treatment modalities, and quality of life issues. Eur Urol 2003;44: [9] Wei JT, Dunn RL, Litwin MS, Sandler HM, Sanda MG. Development and validation of the expanded prostate cancer index composite (EPIC) for comprehensive assessment of health-related quality of life in men with prostate cancer. Urology 2000;56: [10] Pinkawa M, Gagel B, Piroth MD, et al. Changes of dose delivery distribution within the first month after permanent interstitial brachytherapy for prostate cancer. Strahlenther Onkol 2006;182:

8 234 european urology 55 (2009) [11] International Commission on Radiation Units and Measurements. ICRU Report 50: Prescribing, recording and reporting photon beam therapy. Bethesda, Maryland. International Commission on Radiation Units and Measurements [12] van der Wielen GJ, van Putten WL, Incrocci L, et al. Sexual function after three-dimensional conformal radiotherapy for prostate cancer: results from a dose-escalation trial. Int J Radiat Oncol Biol Phys 2007;68: [13] Turner SL, Adams K, Bull CA, et al. Sexual dysfunction after radical radiation therapy for prostate cancer: a prospective evaluation. Urology 1999;54: [14] Roach M, Winter K, Michaelski J, et al. Penile bulb dose and impotence after three-dimensional conformal radiotherapy for prostate cancer on RTOG 9406: findings from a prospective, multi-institutional, phase I/II doseescalation study. Int J Radiat Oncol Biol Phys 2004;60: [15] Wespes E, Amar E, Hatzichristou D, et al. EAU Guidelines on erectile dysfunction: an update. Eur Urol 2006;49: [16] Lue TF. Erectile dysfunction. N Engl J Med 2000;342: [17] Hoesl CE, Woll EM, Burkart M, Altwein JE. Erectile dysfunction (ED) is prevalent, bothersome and underdiagnosed in patients consulting urologists for benign prostatic syndrome (BPS). Eur Urol 2005;47: [18] Pinkawa M, Fischedick K, Asadpour B, et al. Toxicity profile with a large prostate volume after external beam radiotherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys 2008;70:83 9. [19] Antunes AA, Srougi M, Dall Oglio MF, et al. The role of BPH, lower urinary tract symptoms and PSA levels on erectile function of Brazilian men who undergo prostate cancer screening. J Sex Med 2008;5: [20] Dubbelman YD, Dohle GR, Schröder FH, et al. Sexual function before and after radical retropubic prostatectomy: A systematic review of prognostic indicators for a successful outcome. Eur Urol 2006;50: [21] Incrocci L, Slagter C, Slob AK, et al. A randomized, doubleblind, placebo-controlled, cross-over study to assess the efficacy of tadalafil (Cialis) in the treatment of erectile dysfunction following three-dimensional conformal external-beam radiotherapy for prostatic carcinoma. Int J Radiat Oncol Biol Phys 2006;66: [22] Zelefsky MJ, McKee AB, Lee H, Leibel SA. Efficacy of oral sildenafil in patients with erectile dysfunction after radiotherapy for carcinoma of the prostate. Urology 1999; 53: [23] Valicenti RK, Choi E, Chen C, et al. Sildenafil citrate effectively reverses sexual dysfunction induced by threedimensional conformal radiation therapy. Urology 2001;57: [24] Incrocci L, Hop WCJ, Slob AK. Efficacy of sildenafil in an open-label study as a continuation of a doubleblind study in the treatment of erectile dysfunction after radiotherapy for prostate cancer. Urology 2003;62: [25] Montorsi F, Briganti A, Salonia A, et al. Can phosphodiesterase type 5 inhibitors cure erectile dysfunction? Eur Urol 2006;49: [26] Zelefsky MJ, Eid JF. Elucidating the etiology of erectile dysfunction after definitive therapy for prostatic cancer. Int J Radiat Oncol Biol Phys 1998;40: Editorial Comment on: Erectile Dysfunction After External Beam Radiotherapy for Prostate Cancer Eric Meuleman Free University Medical Centre, Amsterdam, The Netherlands E.Meuleman@vumc.nl Modern curative therapies for clinically localized prostate cancer include radical prostatectomy (RP), external beam radiotherapy (EBRT), and brachytherapy (BT). Although randomized comparisons of the oncologic efficacy are not available, there is ample evidence from the literature that each of these treatments can provide excellent cancer control in properly selected patients. The lack of strong evidence for either radiation or surgery presents patients with newly diagnosed, clinically localized prostate cancer with a difficult decision for treatment selection. Because there may be no clear benefit with regard to cancer cure, patients have increasingly focused on the ramifications of their choices for quality of life (QoL) particularly sexual functioning and they expect urologists to provide them with valid data regarding posttreatment expectations. In pretreatment counseling of patients, the urologist is faced with a wide disparity of results in the literature regarding the impact of the different therapies on sexual functioning [1,2]. This disparity results from a lack of robust comparative studies. When available, such studies have cross-sectional designs that provide only snapshots in time. A much-neglected parameter in many studies is the period of evaluation of sexual function following treatment. It is obligatory to wait at least mo before final conclusions can be drawn. In the most recent longitudinal comparative study with a sufficiently long-term follow-up in the literature, EBRT, BT, and RP were found to

9 european urology 55 (2009) differentially affect health-related QoL outcomes. Urinary control and sexual function were better after EBRT, although bilateral nerve-sparing (NS) surgery diminished these differences among potent men undergoing RP. BT caused more obstructive and irritative symptoms, and both forms of radiation caused more bowel dysfunction. These results may inform medical decision-making for men with localized prostate cancer [3]. In their longitudinal study, Pinkawa and coauthors [4] confirmed the common belief that if one waits long enough, the percentages of men developing erectile dysfunction following EBRT will reach similar values as after NSRP [5]. Unfortunately, the study misses the sexologic perspective. It seems to me that the authors have collected data on sexual functioning of their patients without taking active care of their sexual health. This aspect is the more disappointing because it is well established that sexologic counselling is an important determinator of regaining postoperative sexual functioning [6]. It leaves me with the hope that this study will stimulate the radiotherapy community to design and apply sexologic support programmes for their patients. References [1] Burnett AL, Aus G, Canby-Hagino ED, et al. Erectile function outcome reporting after clinically localized prostate cancer treatment. J Urol 2007;178: [2] Efficace F, Bottomley A, Osoba D, et al. Beyond the development of health-related quality of life (HRQOL) measures: a checklist for evaluating HRQOL outcomes in cancer clinical trials: Does HRQOL evaluation in prostate cancer research inform clinical decision making? J Clin Oncol 2003;21:3502. [3] Litwin MS, Gore JL, Kwan L, et al. Quality of life after surgery, external beam irradiation, or brachytherapy for early-stage prostate cancer. Cancer 2007;109: [4] Pinkawa M, Gagel B, Piroth MD, et al. Erectile dysfunction after external beam radiotherapy for prostate cancer. Eur Urol 2009;55: [5] Incrocci L. Sexual function after external-beam radiotherapy for prostate cancer: What do we know? Crit Rev Oncol Hematol 2006;57: [6] Zippe CD, Pahlajani G. Penile rehabilitation following radical prostatectomy: role of early intervention and chronic therapy. Urol Clin North Am 2007;34:601 18; review, viii. DOI: /j.eururo DOI of original article: /j.eururo Editorial Comment on: Erectile Dysfunction After External Beam Radiotherapy for Prostate Cancer Alberto Briganti Department of Urology, Vita-Salute University, Milan, Italy briganti.alberto@hsr.it Erectile dysfunction (ED) represents a common sequela following external beam radiotherapy (EBRT) for prostate cancer [1 3]. However, despite its significant impact on quality of life, only a few studies have assessed the rate and the determinants of ED after EBRT [2,3]. In the study by Pinkawa et al [4], 123 patients treated with EBRT for ct1 3N0M0 prostate cancer not receiving any antiandrogen treatment were evaluated. Patient sexual function was evaluated up to 22 mo after EBRT by means of the Expanded Prostate Cancer Index Composite (EPIC) questionnaire. Important data can be derived from this study. First, this study represents one of the few prospective assessments of erectile function after EBRT. Second, this study reinforces previous evidence reporting a progressive decline of erectile function after EBRT [2,3]. Third, the importance of patients stratification according to preoperative erectile function has been clearly shown. A significant positive correlation has indeed been found between preoperative and postoperative sexual function. Despite these advantages, the study is limited by important methodologic biases. The major limitation stems from lack of a stringent definition of posttreatment ED. The authors indeed used different definitions in the assessment of posttreatment ED. These were separately tested in univariable and multivariable logistic regression models. However, these definitions were strongly influenced by subjective patient self-assessment (ie, loss of nightly erections). This bias could have been avoided by clearly categorizing erectile function on the basis of different scores, such as those derived by the internationally known International Index of Erectile Function. Further-

10 236 european urology 55 (2009) more, as for radical prostatectomy, pretreatment erectile function was a major determinant of posttreatment erectile status. Indeed, 70% of the patients with at least poor pretreatment erectile ability (n = 96) retained this ability 1 yr after treatment. However, how did the authors define at least poor ability? Can it be considered an objective and reliable assessment of erectile function? I doubt it. Moreover, if a correlation between preoperative and postoperative erectile function was found, this should have been confirmed by multivariable analyses, after accounting for other key variables associated with erectile function recovery after treatment (ie, age, comorbidities). However, this has not been done by Pinkawa et al [4]. Finally, we should also consider that erectile function recovery after primary treatment for prostate cancer is strictly related to the time of erectile status assessment [5]. However, in the study by Pinkawa et al [4], patients were not assessed at the same time after EBRT (range of evaluation: mo after EBRT). Therefore, a time to event analysis (namely, Cox regression) would have been more appropriate for posttreatment erectile function predictions. References [1] Wespes E, Amar E, Hatzichristou D, Hatzimouratidis K, Montorsi F, Pryor J, Vardi Y. EAU Guidelines on erectile dysfunction: an update. Eur Urol 2006;49: [2] Van der Wielen GJ, van Putten WL, Incrocci L. Sexual function after three-dimensional conformal radiotherapy for prostate cancer: results from a dose-escalation trial. Int J Radiat Oncol Biol Phys 2007;68: [3] Litwin MS, Flanders SC, Pasta DJ, Stoddard ML, Lubeck DP, Henning JM. Sexual function and bother after radical prostatectomy or radiation for prostate cancer: multivariate quality-of-life analysis from CaPSURE. Cancer of the Prostate Strategic Urologic Research Endeavor. Urology 1999;54: [4] Pinkawa M, Gagel B, Piroth MD, Fischedick K, Asadpour B, et al. Erectile dysfunction after external beam radiotherapy for prostate cancer. Eur Urol 2009; 55: [5] Dubbelman YD, Dohle GR, Schröder FH. Sexual function before and after radical retropubic prostatectomy: A systematic review of prognostic indicators for a successful outcome. Eur Urol 2006;50: DOI: /j.eururo DOI of original article: /j.eururo