THE EFFICACY OF SILDENAFIL CITRATE FOLLOWING RADIATION THERAPY FOR PROSTATE CANCER: TEMPORAL CONSIDERATIONS

0022-5347/05/1741-0258/0 THE JOURNAL OF UROLOGY® Copyright © 2005 by AMERICAN UROLOGICAL ASSOCIATION

Vol. 174, 258 –262, July 2005 Printed in U.S.A.

DOI: 10.1097/01.ju.0000164286.47518.1e

THE EFFICACY OF SILDENAFIL CITRATE FOLLOWING RADIATION THERAPY FOR PROSTATE CANCER: TEMPORAL CONSIDERATIONS MICHAEL OHEBSHALOM, MARILYN PARKER, PATRICIA GUHRING

AND

JOHN P. MULHALL*

From the Departments of Urology, Weill Medical College of Cornell University, New York, New York, and Loyola University Medical Center (MP), Maywood, Illinois

ABSTRACT

Purpose: Erectile dysfunction is a recognized complication of radiation therapy for prostate cancer. Sildenafil citrate is a well-known management strategy for erectile dysfunction that has been found to be efficacious across a wide spectrum of comorbidities, including post-radiation erectile dysfunction. We defined the efficacy of sildenafil citrate in patients with erectile dysfunction following radiation therapy for prostate cancer and assessed the impact of the interval after radiation on the success of this therapy. Materials and Methods: Baseline and followup data on 110 patients presenting with erectile dysfunction secondary to radiation for prostate cancer was obtained. A total of 68 patients underwent 3-dimensional conformal external beam irradiation (CRT), while 42 underwent brachytherapy (BT) without androgen deprivation. All patients were considered to have erectile dysfunction after radiotherapy, as assessed by the International Index of Erectile Function (IIEF), and they were prescribed sildenafil citrate. Mean time ⫾ SD between the completion of radiation therapy and the initiation of sildenafil was 8 ⫾ 4 months. The response to sildenafil was assessed using the IIEF questionnaire. Within and between group comparisons were done for 3 time points, that is less than 12, 13 to 24 and 25 to 36 months following the completion of radiation therapy. Results: The respective response rates in men who underwent BT/CRT at the 3 time points of less than 12, 13 to 24 and 25 to 36 months was 76%/68%, 54%/46% and 44%/38%, respectively. Mean IIEF erectile function domain scores for these 3 time points after BT/CRT was 26/23, 22/19 and 17/15, respectively. The percent of patients who achieved normalization of the IIEF erectile function domain at the 3 time points in the BT/CRT groups was 60%/50%, 48%/42% and 26%/19%, respectively. Conclusions: Sildenafil citrate improves erectile function in men in whom erectile dysfunction develops following radiation therapy for prostate cancer. There is a clear time dependence for the response to this therapy with a stepwise decrease in all end points examined serially in a 3-year period. KEY WORDS: prostate, impotence, brachytherapy, sildenafil, radiotherapy

Prostate cancer represents the second most common cause of malignancy related deaths in the United States.1 According to the American Cancer Society an estimated 220,900 men were diagnosed in 2003 and 28,900 died of it.2 Pelvic external beam radiotherapy and seed implant brachytherapy (BT) are recognized management strategies for prostate carcinoma. They are also well-known causes of erectile dysfunction (ED).3–5 Studies have demonstrated varying degrees of ED after radiation therapy, ranging from 34% to 62%.6 –9 The predictors of loss of erectile function following pelvic radiotherapy are patient age, pretreatment erectile function, mode and dose of radiation delivery, neoadjuvant androgen deprivation and the time point following radiotherapy at which the patient is assessed.10 ED has a significant negative impact of quality of life and sildenafil citrate has been shown to improve quality of life in the patient and partner.11 Sildenafil citrate, which was first introduced in 1998, has proved to be effective treatment in men with ED following pelvic radiotherapy.12–17 This study was done to define the efficacy of sildenafil citrate in men who underwent radiation therapy for prostate cancer. Also,

the impact of the interval from the completion of radiotherapy on the success of sildenafil response was assessed.

METHODS

Study population. Patients seen at the sexual medicine clinic at Loyola University Medical Center were enrolled prospectively between 1998 and 2001 if they met certain criteria, namely 1) they had undergone radiation therapy for prostate cancer in the form of 3-dimensional conformal external beam radiation therapy (CRT) or BT, 2) they reported functional erections prior to the initiation of pelvic radiation therapy, 3) they experienced the onset of ED following the completion of radiation therapy, 4) they underwent a comprehensive evaluation for ED, including a thorough history and physical examination, 5) they were candidates for sildenafil citrate use (adequate exercise tolerance for sexual activity and no nitrate use), 6) they were compliant with followup and attempted sildenafil periodically and 7) they completed the International Index of Erectile Function (IIEF) on at least 2 occasions throughout the first 3 years following the completion of radiation therapy. Patients were evaluated annually and at each visit they completed the IIEF questionnaire. A comprehensive patient medical record review was also performed to define patient age at radiation

Submitted for publication May 3, 2004. * Correspondence: Department of Urology, Weill Medical College of Cornell University, New York Presbyterian Hospital, 525 East 68th St., Starr 900, New York, New York 10021 (telephone: 212-7465653; FAX: 212-746-0403; e-mail: [email protected]). 258

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therapy, the radiation dose delivered, the interval between radiation therapy and the onset of erectile complaints, and vascular risk factor status. Patients were excluded if they had received any form of androgen deprivation therapy prior to receiving radiation or if they were scheduled to receive androgen deprivation after radiation therapy. Radiation therapy. Patients who underwent 3-dimensional CRT were treated with a mean dose of 72 ⫾ 10 Gy, while patients who underwent BT received a mean dose of 102 Gy. In all patients who underwent BT 125I seeds were implanted. Patients receiving CRT underwent the initial delivery of 1,600 to 2,400 cGy fractions to the prostate and seminal vesicles, followed by a booster dose with narrow margins (1 to 2 cm) up to the mean total tumor dose. The radiation dose was delivered in a 6 to 8 week period depending on tumor bulk. Seed implantation was done without neoadjuvant androgen deprivation in all enrollees. Outcome assessment. The primary end point was the erectile function domain of the IIEF. The IIEF is a 15-question validated inventory that has 5 domains, namely erectile function, libido, orgasmic function, sexual satisfaction and overall satisfaction. The questionnaire addresses patient sexual function in the 4-week period prior to completing the inventory. Each question is scored on a Likert scale with a maximum score of 5 and higher scores indicating better function. Thus, the maximum score is 75. The erectile function domain, specifically questions 1 to 5 and 15, has a maximum score of 30 and a minimum score of 6. Patients completed the IIEF at their annual visit and were instructed to answer the IIEF questions as they pertained to their sildenafil response. The followup schedule was identical in the BT and CRT groups. At each visit patients were asked about their ability to achieve sexual intercourse using sildenafil and were asked to grade erectile rigidity in response to sildenafil using a visual analog scale of 0% to 100%, where 60% indicates the first erectile rigidity permitting penetrating sexual relations. Statistical analysis. Within group comparison was done for the 3 time points, less than 12, 13 to 24 and 25 to 36 months, using the Wilcoxon matched pairs test (SPSS, Chicago, Illinois). Between group comparison for each time point was done using the Mann-Whitney U test. RESULTS

A total of 110 patients were included in this analysis, of whom 42 received BT and 68 received 3-dimensional CRT. All patients completed the IIEF on at least 2 occasions and more than 90% completed the IIEF on 3 occasions. Mean patient age was greater and time to post-radiation ED was shorter in the CRT group (see table). There was no significant difference in vascular comorbidity profiles between the 2 treatment groups. Mean baseline prostate specific antigen was 8.2 ⫾ 6.1 ng/ml and mean Gleason score was 6 ⫾ 2. The percent of men who were considered sildenafil responders at the 3 time points (BT vs CRT less than 12, 13 to 24 and 25 to 36 months) was 76% vs 68% (p ⫽ 0.03), 54% vs 46% (p ⫽ 0.02) and 44% vs 38% (p ⫽ 0.065), respectively. In each group there was a statistically significant difference between the percent of responders at the first 2 time points,

that is less than 12 and 13 to 24 months (fig. 1). However, only in the BT group was there a significant difference between the 13 to 24 and 25 to 36 month time points (fig. 1). With regard to mean IIEF erectile function domain scores ⫾ SD respective scores at the 3 time points in the BT group were 26 ⫾ 5, 22 ⫾ 6 and 17 ⫾ 9, respectively. In the CRT group these scores were 23 ⫾ 4, 19 ⫾ 4 and 15 ⫾ 8, respectively. In each group there was a statistically significant difference among the 3 time points (fig. 2). For all time points there was a statistically significant difference between BT and CRT (p ⫽ 0.02, ⬍0.01 and 0.03, respectively). With regard to the percent of patients who achieved normalization of the erectile function domain of the IIEF again the rates were higher in the BT vs the CRT group, that is 60% vs 50% (p ⬍0.02), 48% vs 42% (p ⬍0.03) and 26 vs 19% (p ⬍0.03), for the 3 time points. Within group differences were also statistically significant for the time points (fig. 3). DISCUSSION

ED is a recognized sequela of radiation therapy. Anatomically the penis and its vascular structures are situated in close proximity to the prostate on the opposite side of the urogenital diaphragm. Therefore, these vascular structures (arteries and crura) are placed at risk for exposure during radiation therapy for prostate cancer.5 Radiation therapy for prostate cancer has been found to cause sexual dysfunction steadily during the months following treatment.8, 18, 19 In a prospective study Turner et al found that 12 months after radiation therapy 90 of 146 men (62%) who were potent before radiation therapy had preserved potency.10 This value decreased to 41% after 24 months. They also suggested a trend toward stabilization of the decrease in potency with time beyond 2 years.10 Kedia et al examined 21 patients with ED after radiotherapy (BT in 2 and CRT in 19) for prostate cancer who were given a minimum of 4 doses of sildenafil at a mean of 24 months after radiation.15 Using the IIEF questionnaire they found an improvement in erectile function in 71% of their 21 patients. Zelefsky et al studied 50 patients after CRT and found improvement in erectile function in 74% after the administration of sildenafil on at least 3 occasions.20 They found that the response was more likely to occur in those with less severe ED vs those with absent erectile function after CRT. Valicenti et al studied 24 patients 12 months after CRT.13 Using the self-administered O’Leary Brief Sexual Function Inventory they found that 21 of 23 patients had significant improvement in erectile function after being prescribed sildenafil at a mean of 1 year after radiotherapy. Most recently Incrocci et al performed a randomized, doubleblind study of 60 men with ED who were treated with sildenafil at least 6 months after CRT.12 They found that for most questions on the IIEF questionnaire there was a significant increase in mean scores from baseline erectile function after radiation therapy. They found that 2 years after trial entry 24% of their population still used sildenafil because they considered it to still be effective. Thus, numerous studies have demonstrated that sildenafil treatment results in improved erectile function in men in whom ED develops following radiotherapy. Our data demonstrate that sildenafil is

Patient demographics

No. pts Mean pt age ⫾ SD Mean time to ED onset ⫾ SD (mos) % Hypertension % Diabetes % Dyslipidemia

Brachytherapy

External Beam

42 64 ⫾ 12 8⫾3 24 10 14

68 68 ⫾ 16 6⫾2 28 12 16

p Value (MannWhitney U test) 0.03 0.02 Not significant Not significant Not significant

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FIG. 1. Serial assessment of percent of men capable of intercourse in response to sildenafil using visual analog scale greater than 60% rigidity and patient self-reported ability to achieve sexual intercourse in patients who had received BT and 3-dimensional CRT. Asterisk indicates that CRT values at all time points were statistically significantly lower than BT values.

FIG. 2. Serial assessment of IIEF EF domain scores in response to sildenafil in patients who had received BT and 3-dimensional CRT. Asterisk indicates that CRT values at all time points were statistically significantly lower than BT values.

effective for improving erectile function in men with postCRT and post-BT ED. Furthermore, the response to sildenafil was inversely proportional to the time after radiation therapy. We also noted that response rates were appreciably higher in the BT vs the CRT group. It is worth noting that the latter comparison is open to criticism since the study was not a randomized trial and there was no controlling for differences between the BT and CRT groups. Furthermore, there was no placebo control group in this analysis, which failed to allow assessment of the natural history of erectile function in the 3-year period in the BT and CRT groups. Why might BT have a more favorable response to sildenafil than CRT? It may be that the amount of erectile tissue in the corpora cavernosa exposed to radiation in the CRT group was greater than in men who received BT. It is unlikely that any difference in serum testosterone would account for the difference in sildenafil response, given the fact that there was only a 4-year difference in mean age between the 2 groups (see table). The clinical implications of this study are that sildenafil is effective treatment for ED following radiotherapy and it is more effective in the early stages after radiation. In this medium term analysis it appeared to be more effective in

men following BT compared to those who had received CRT. This may have resulted from the postulate that the radiation dose to periprostatic tissues (the crura in particular) with BT may be less than in patients exposed to CRT. The issue of the decreasing efficacy of sildenafil in the first 3 years following radiation therapy is an interesting one. There is no tachyphylaxis to sildenafil and, therefore, it is probable that the serial decrease in sildenafil efficacy is the result of progressive arterial and erectile tissue damage. The strengths of our study are the fact that it was prospective, following patients serially with questionnaires and using validated end points, and also that the study population was relatively homogenous because patients were excluded if any androgen deprivation had been used. Many prior studies are difficult to interpret because of the inclusion of patients exposed to neoadjuvant androgen deprivation, which is well recognized to result in structural alterations in the corporeal smooth musculature. Our patient population of 100 patients (BT in 42 and CRT in 68) is larger than in most other analyses, allowing us to compare the 2 treatment modalities (BT vs CRT). There were limitations of the study. 1) Patients were followed for only 3 years. We believe that even longer data

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FIG. 3. Serial assessment of percent of patients in whom IIEF EF domain score normalized (26 or greater) in response to sildenafil following BT and 3-dimensional CRT. Asterisk indicates that CRT values at all time points were statistically significantly lower than BT values.

collection is required to assess the true long-term efficacy of sildenafil in this patient population. 2) We do not have preradiation therapy IIEF scores. The patients were referred from many centers and there was some heterogeneity in the pre-radiation therapy evaluation. Following presentation they were followed and data were collective prospectively. 3) As mentioned, the study was not randomized, undermining the value of BT vs CRT comparisons, and there was no placebo control group. CONCLUSIONS

In patients with ED after radiotherapy using validated end points sildenafil was found to be effective for improving erectile function. Sildenafil was more efficacious in the early stages after the completion of radiation therapy but it continued to maintain significant efficacy even 3 years after radiotherapy. The positive response to sildenafil, and increase in and normalization of IIEF EF domain scores depended on the interval after radiation. Based on these data sildenafil should be offered to patients with ED after radiation therapy. Furthermore, these data permit the clinician to give patients realistic expectations regarding long-term success with this drug. Ongoing and future research is aimed at defining the factors that result in decreased efficacy with time and those that result in higher efficacy in the brachytherapy group and at assessing the impact of androgen deprivation on the parameters analyzed in this study.

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1. Greenlee, R. T., Murray, T., Bolden, S. and Wingo, P. A.: Cancer statistics 2000. CA Cancer J Clin, 50: 7, 2000 2. Crawford, E. D.: Epidemiology of prostate cancer. Urology, suppl., 62, 3, 2003 3. Incrocci, L., Slob, A. K. and Levendag, P. C.: Sexual (dys)function after radiotherapy for prostate cancer: a review. Int J Radiat Oncol Biol Phys, 52: 681, 2002 4. Vale, J.: Erectile dysfunction following radical therapy for prostate cancer. Radiother Oncol, 57: 301, 2000 5. Mulhall, J. P., Yonover, P., Sethi, A., Yasuda, G. and Mohideen, N.: Radiation exposure to the corporeal bodies during 3-dimensional conformal radiation therapy for prostate cancer. J Urol, 167: 539, 2002 6. Beard, C. J., Propert, K. J., Reiker, P. P., Clark, J. A., Kaplan, I., Kantoff, P. W. et al: Complications after treatment with external-beam irradiation in early-stage prostate cancer patients: a prospective multiinstitutional outcomes study. J Clin Oncol, 15: 223, 1997 7. Crook, J., Esche, B. and Futter, N.: Effect of pelvic radiotherapy

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for prostate cancer on bowel, bladder, and sexual function: the patient’s perspective. Urology, 47: 387, 1996 Beard, C. J., Lamb, C., Buswell, L., Schneider, L., Propert, K. J., Gladstone, D. et al: Radiation-associated morbidity in patients undergoing small-field external beam irradiation for prostate cancer. Int J Radiat Oncol Biol Phys, 41: 257, 1998 Mantz, C. A., Song, P., Farhangi, E., Nautiyal, J., Awan, A., Ignacio, L. et al: Potency probability following conformal megavoltage radiotherapy using conventional doses for localized prostate cancer. Int J Radiat Oncol Biol Phys, 37: 551, 1997 Turner, S. L., Adams, K., Bull, C. A. and Berry, M. P.: Sexual dysfunction after radical radiation therapy for prostate cancer: a prospective evaluation. Urology, 54: 124, 1999 Rosen, R. C. and Kostis, J. B.: Overview of phosphodiesterase 5 inhibition in erectile dysfunction. Am J Cardiol, 92: 9M, 2003 Introcci, L., Hop, W. C. and Slob, A. K.: Efficacy of sildenafil in an open-label study as a continuation of a double-blind study in the treatment of erectile dysfunction after radiotherapy for prostate cancer. Urology, 62: 116, 2003 Valicenti, R. K., Choi, E., Chen, C., Lu, J. D., Hirsch, I. H., Mulholland, G. S. and Gomella, L. G.: Sildenafil citrate effectively reverses sexual dysfunction induced by three-dimensional conformal radiation therapy. Urology, 57: 769, 2001 Incrocci, L., Koper, P. C., Hop, W. C. and Slob, A. K.: Sildenafil citrate (Viagra) and erectile dysfunction following external beam radiotherapy for prostate cancer: a randomized, doubleblind, placebo-controlled, cross-over study. Int J Radiol Oncol Biol Phys, 51: 1190, 2001 Kedia, S., Zippe, C. D., Agarwal, A., Nelson, D. R. and Lakin, M. M.: Treatment of erectile dysfunction with sildenafil citrate (Viagra) after radiation therapy for prostate cancer. Urology, 54: 308, 1999 Merrick, G. S., Butler, W. M., Lief, J. H., Stipetich, R. L., Abel, L. J. and Dorsey, A. T.: Efficacy of sildenafil citrate in prostate brachytherapy patients with erectile dysfunction. Urology, 53: 1112, 1999 Weber, D. C., Bieri, S., Kurtz, J. M. and Miralbell, R.: Prospective pilot study of sildenafil for treatment of postradiotherapy erectile dysfunction in patients with prostate cancer. J Clin Oncol, 17: 3444, 1999 Mettlin, C. J., Murphy, G. P., McDonald, C. J. and Menck, H. R.: The National Cancer Data base Report on increased use of brachytherapy for the treatment of patients with prostate carcinoma in the U. S. Cancer, 86: 1877, 1999 Talcott, J. A., Manola, J., Clark, J. A., Kaplan, I., Beard, C. J., Mitchell, S. P. et al: Time course and predictors of symptoms after primary prostate cancer therapy. J Clin Oncol, 21: 3979, 2003 Zelefsky, M. J., McKee, A. B., Lee, H. and Leibel, S. A.: Efficacy of oral sildenafil in patients with erectile dysfunction after

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These authors confirm that sildenafil can treat ED following radiation therapy for prostate cancer. However, the news is not all that good. They noted a progressive decrease in erectile function despite sildenafil therapy in the 3-year period for men treated with BT or external beam radiation. This progressive, stepwise decrease is similar to the radiation therapy related decreases in erectile function noted by others (reference 19 in article). In this study sildenafil was noted to be more efficacious early in the post-radiation therapy period. The preemptive use of sildenafil immediately after radical prostatectomy may decrease the long-term incidence of ED.1 Perhaps this strategy would also be beneficial for decreasing ED following radiation therapy. While the mechanism of ED following radical prostatectomy or radiation

therapy may not be the same, this preemptive approach is reasonable to try to minimize ED associated with all prostate cancer therapy. This study used sildenafil. Further investigation using other phosphodiesterase-5 inhibitors, such as vardenafil or tadalafil, are warranted in this setting to determine if these agents would be more beneficial. Leonard G. Gomella Department of Urology Kimmel Cancer Center Thomas Jefferson University Philadelphia, Pennsylvania 1. Padma-Nathan, H., McCullough, A. and Forest, C.: Erectile dysfunction secondary to nerve-sparing radical retropubic prostatectomy: comparative phosphodiesterase-5 inhibitor efficacy for therapy and novel prevention strategies. Curr Urol Rep, 5: 467, 2004