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Prospective Pilot Study of Sildenafil for Treatment of Postradiotherapy Erectile Dysfunction in Patients With Prostate Cancer

From the Radiation Oncology Departments of the University Hospital, Geneva and the San Giovanni Hospital, Bellinzona, Switzerland.

Address reprint requests to Damien C. Weber, MD, Division de Radio-Oncologie, Hôpital Cantonal, 24 rue Micheli-du-Crest, 1211 Geneva 14, Switzerland; email Damien.Weber{at}hcuge.ch

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
PURPOSE: Erectile dysfunction is a common late complication patients may experience after external-beam radiotherapy for prostate cancer. The efficacy and safety of oral sildenafil to correct sexual dysfunction caused by external-beam radiotherapy was studied in patients participating in our prospective trial.

PATIENTS AND METHODS: Thirty-five assessable patients participated in this prospective pilot study. Using a 25-point scale based on the International Index of Sexual Function, erectile dysfunction was assessed weekly, during which time patients received sildenafil 100 mg orally once a week for 6 consecutive weeks. Response was defined as a score of 18 or more, corresponding to at least one successful attempt at sexual intercourse per week.

RESULTS: Thirty patients (86%) completed the 6-week study. Seventy-seven percent of these patients had significantly improved erectile function, allowing recovery of full capacity for sexual intercourse. Of 27 patients not receiving concomitant hormone treatment, failure to respond was observed in only four patients (15%) compared with four (50%) of eight patients receiving hormonal treatment during the study. The time course of response was gradual, with 40%, 57%, 66%, 69%, and 74% responding at weeks 1 through 5, respectively. Therapy was generally well tolerated. The most frequently reported side effects in patients were flushing (37%), transient headache (17%), and dyspepsia (9%). No patient reported priapism, and no cardiovascular event or death was observed. After response, 12 patients (34%) reported the ability to achieve and maintain an erection sufficient for intercourse in the absence of sildenafil (ie, 24 hours to 6 days after taking the medication).

CONCLUSION: This study suggests that oral sildenafil is well tolerated and can reverse erectile dysfunction after radiotherapy in a substantial proportion of prostate cancer patients.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
DATA FROM RETROSPECTIVE^1-4 and prospective studies⁵ indicate that erectile dysfunction may affect as many as 40% to 50% of prostate cancer patients treated with external-beam radiotherapy and, additionally, that the percentage of patients affected by erectile dysfunction may increase with longer follow-up. The decline in erectile capacity after radiotherapy impairs quality of life in a substantial percentage of patients.⁶ If the incidence of erectile dysfunction could be diminished or sexual function improved in patients suffering from this complication, the clinical gain would be of considerable importance.

Sildenafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)–specific type 5 phosphodiesterase. By selectively inhibiting cGMP catabolism in the cavernosal smooth-muscle cells,^7,8 sildenafil has been shown to restore the normal erectile response to sexual stimulation.⁹ Although its efficacy has been demonstrated by double-blind randomized trials⁹ and suggested by a recent study in a cohort of prostate cancer patients treated with radiotherapy,¹⁰ no data have yet been published concerning an evaluation of sildenafil that uses a validated sexual function assessment questionnaire in patients with postirradiation erectile dysfunction.¹¹ This prospective clinical trial was designed to evaluate the efficacy, subjective tolerance, and safety of sildenafil in this setting.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Patient Population and Study Cohort
Study patients were recruited between July 30 and November 15, 1998, from among patients who had been treated with radical external-beam radiotherapy for clinically localized prostate cancer between January 1989 and November 1997 in Switzerland at the University Hospital in Geneva and the San Giovanni Hospital in Bellinzona. To be eligible, patients were required to have had normal erectile capacity before radiotherapy, erectile dysfunction at time of study entry, and have a stable relationship with a sexual partner. Erectile dysfunction was defined as the inability to achieve or maintain an erection sufficient for satisfactory sexual performance. Patients were excluded if they were older than 80 years, presented with penile anatomical defects, received nitrate therapy, or had prior radical prostatectomy, a primary diagnosis of another sexual disorder (eg, premature ejaculation), spinal cord injury or metastasis, poorly controlled diabetes mellitus, active peptic disease, recent (within the previous 6 months) stroke, or myocardial infarction. Past or current hormonal therapy was not an exclusion criterion.

One hundred fifteen patients presenting with postradiotherapy erectile dysfunction were identified. Each patient received a nominative letter inviting participation in the study. A prestudy entry interview with a radiation oncologist was mandatory, during which the aim of the study and the potential side effects of sildenafil were explained. The interview was carried out by a single clinician at each site (D.C.W., University Hospital; S.B., San Giovanni Hospital). Fifty-two (45%) of the 115 potential candidates agreed to be interviewed for study entry evaluation, of whom 13 refused participation and three were ineligible because of current nitrate therapy. Reasons for refusal were lack of interest (seven patients) and fear of side effects (six patients). One eligible patient declined sexual intercourse because of his wife's current illness. Thus, 35 (67%) of the 52 interviewed patients entered onto the prospective study. Mean age of the cohort was 69 years (range, 54 to 79 years). Mean age of the sexual partner was 61 years (range, 34 to 78 years). Radiotherapy had been delivered using megavoltage photons to a median dose of 70 Gy (range, 66 to 74 Gy) in 2.0 Gy daily fractions with either a four-field box technique (49% of patients) or a six-field isocentric coplanar technique (51% of patients). No patient was treated with brachytherapy. Eight patients (23%) had received preradiotherapy hormonal treatment (median time of treatment, 4 months; range, 4 to 6 months), which consisted of bicalutamide 50 mg daily for the first month and depot intramuscular injections of goserelin 10.8 mg at 3-month intervals. Eight other patients (23%) were under hormonal treatment throughout the study, receiving subcutaneous injections of goserelin 3.6 mg monthly. Median elapsed times from the completion of androgen ablation or radiotherapy until the start of the study were 20.5 months (range, 6 to 50 months) and 18.5 months (range, 3 to 48 months), respectively.

Study Protocol
Before study entry and at 6 weeks, erectile function was assessed using the 15-question validated, multidimensional International Index of Erectile Function (IIEF; see Appendix). Erectile dysfunction was classified as severe, moderate, or slight if the sum of the scores of questions 1 through 5 and 15 were between 6 to 10, 11 to 16, or 17 to 25, respectively. Patients were given a single 100-mg sildenafil tablet once a week for a total of 6 consecutive weeks. Sildenafil was to be self-administered at a propitious moment of the patient's choice, the patients having been informed of the expected time course of the pharmacologic effect. Erectile function was assessed weekly by the same radiation oncologists and side effects were prospectively evaluated using the IIEF questionnaire. The weekly evaluation of efficacy used a shorter form of the IIEF questionnaire based on questions 1 (erection during sexual activity), 5 (difficulty in maintaining erection), 6 (frequency of sexual intercourse), 7 (satisfaction with sexual intercourse) and 15 (confidence in maintaining an erection) (Table 1). Significant improvement in sexual function was prospectively defined as a score of at least 18 out of a maximum of 25 points. This cutoff was chosen because it represents a minimal mean score of 3.6 points, corresponding to one successful and satisfactory attempt at sexual intercourse per week. In addition, sexual desire was assessed at 6 weeks both by direct questioning and by means of questions 11 and 12 of the IIEF (see Appendix).

Statistical Evaluation
Response to treatment was evaluated as a function of four patient characteristics, namely severity of erectile dysfunction at study entry, hormonal treatment, age, and prior transurethral resection (TURP). Results were compared for these categories using Fisher's exact test or ² tests.¹²

All patients gave informed consent, according to the requirements of the local medical ethical committee. The protocol was approved by the institutional review board at each center.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Baseline Sexual Function and Comorbidity
Erectile function was assessed at time of study entry using the full, 15-question IIEF questionnaire.¹⁰ Out of a maximum of 75 points, the median score was 21 (range, 6 to 47). Erectile dysfunction was reported as severe, modest, and slight in 28 (80%), five (14%), and two (6%) patients, respectively. For the five questions subsequently used in weekly assessment of response (Table 1), the mean pretreatment score was 6 (range, 1 to 14). Ten patients (29%) had essential hypertension, six patients (17%) had hypercholesterolemia, four patients (11%) had a history of myocardial infarction (> 6 months), and three patients (9%) had controlled diabetes.

Erectile Function Response
Thirty patients (86%) completed the 6-week study; 31 (89%), 32 (91%), and 35 (100%) patients were assessed through weeks 5, 4, and 3, respectively. Two patients discontinued participation because of insufficient response. Another three patients dropped out prematurely because of the inconvenience of the weekly study check; however, all three patients reported improved erectile function. Twenty-three of the 30 patients who completed the study reported significantly improved erectile function at 6 weeks, corresponding to satisfactory sexual intercourse at least once weekly. Response rate increased progressively from 40% during the first week to 77% at 6 weeks (Table 2). The mean weekly questionnaire score was 13.8, 16.0, 17.0, 16.8, 17.0, and 17.6 at weeks 1 to 6, respectively. At 6 weeks, the mean score was 20.7 in responders and 7.3 in nonresponders.

We were unable to identify factors correlated with response to sildenafil. Absence of response was reported in 19% of patients under 68 years of age compared with 26% of patients 69 years or older (P = .90). The sexual partner's age seemed unrelated to improvement; the partner's median age was 59.1 years (range, 34 to 73 years) and 60.5 years (range, 48 to 78 years) for responders and nonresponders to sildenafil, respectively. Failure to respond was reported by four (50%) of eight patients who received concomitant hormonal therapy compared with four (15%) of 27 patients who received no current hormonal treatment (P = .11). Only one (13%) of the eight patients treated with preradiotherapy hormonal treatment did not achieve improved erectile function. Four of 10 patients who had TURP before radiotherapy failed to respond; two of these patients received concomitant hormonal therapy. In comparison, of 25 patients irradiated without prior TURP, four (16%) reported lack of response (P = .28). Prestudy erectile function seemed predictive of response, but the association was not statistically significant (P = .41). All seven patients with slight or moderate erectile dysfunction responded to sildenafil, whereas eight (29%) of the 28 patients with severely impaired erectile capacity did not respond to the medication.

Fifteen (56%) of the 27 responding patients reported a "delayed" action of more than 2 but less than 6 hours before achieving erection. Moreover, 12 responding patients reported the ability to achieve and maintain an erection sufficient for sexual intercourse in the absence of sildenafil, ie, 24 hours to 6 days after taking the medication. All but one of these patients were not receiving concurrent hormonal therapy. In the absence of sildenafil, the median number of attempts at sexual intercourse was one per week (range, one to three attempts).

Sexual Desire
On direct questioning at 6 weeks, seven (26%) of the 27 responders reported an increase in sexual desire, but none had erections in the absence of sexual stimulation. Moreover, based on the composite scores of questions 11 and 12 of the IIEF scale (see Appendix), the median score for this group of patients was 5.5 (range, 5 to 7) before study entry and 8 (range, 6 to 10) at 6 weeks. All patients responding positively to direct questioning showed an increase in their composite sexual desire score.

Side Effects
All patients were assessable for adverse effects. In general, sildenafil was well tolerated, and no patient discontinued treatment because of side effects, which are listed in Table 3. The most frequently reported adverse effects were flushing, transient headache not requiring medication, and dyspepsia. One patient repeatedly experienced a transient change in the perception of blue color. No patient reported priapism, and no cardiac event or death was observed.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
The results of this prospective clinical trial support our prestudy hypothesis that sildenafil improves sexual function in prostate cancer patients presenting with impotence after external-beam radiation therapy. The response rates to oral sildenafil in this setting, assessed over a 6-week period, seem similar to the results reported in two sequential double-blind studies of men with a broad variety of erectile dysfunction.⁹ Our results also correlate with those reported by Zelefesky et al¹⁰ in a study of patients who had been treated with radiotherapy for prostate cancer. To our knowledge, our article is the first report of a prospective study that specifically addresses the problem of erectile dysfunction presumed to be a consequence of high-dose pelvic radiotherapy using a validated erectile function questionnaire.¹¹ As such, certain aspects of the results deserve further commentary.

Erectile dysfunction seen after radiotherapy is considered to be a multifactorial phenomenon, in which an arteriogenic etiology is probably predominant.¹³ Among 24 irradiated patients evaluated at Memorial Sloan-Kettering Cancer Center, 63% were shown to have arteriogenic dysfunction, with a minority having neurogenic or mixed arteriogenic/cavernosal dysfunction. Thus, it is not unexpected that sildenafil is effective in many patients with postradiotherapy impotence. Phase III pharmacodynamic studies¹⁴ have shown that peak plasmatic concentration was obtained after 30 minutes to 2 hours (median, 1 hour) in healthy subjects, with a mean terminal half-life of 3 to 5 hours. Severe renal insufficiency, cirrhosis, or old age (> 65 years) have been correlated with significantly modified pharmacodynamics, including higher maximal blood concentration and diminished clearance (unpublished data; Pfizer AG Laboratories, Zuerich, Switzerland). The advanced age of patients in our study (mean, 69 years) could at least partly explain why a substantial number of them reported a delayed action in time. This may also reflect the hemodynamic consequences of radiation-induced changes in the pelvic vasculature.

When selecting the patients for this study, we chose not to consider concomitant hormonal treatment as an exclusion criterion. In the light of the possible benefits of long-term adjuvant androgen suppression in patients with locally advanced disease,¹⁵ our documentation of the response rate in this group of patients is of considerable interest. Although in such patients erectile impairment might result from postradiation changes, from depressed testosterone levels, or from both, it is noteworthy that approximately half of these patients seem to derive benefit from sildenafil.

In this trial, response rate increased progressively throughout the study period, with roughly twice as many patients responding at 6 weeks compared with the first week of treatment (Table 2). This aspect of the time course to response has apparently not been previously reported. In the American dose-response and dose-escalation trials,⁹ the efficacy of sildenafil was analyzed only on the 12th and 24th weeks of treatment. Our study indicates that a substantial proportion of apparently resistant patients will respond to sildenafil in time. Thus, treatment should not be stopped prematurely because of presumed inefficacy.

Although patient age did not seem to have an adverse effect on response, certain other factors may account for the failure of approximately one forth of patients to derive significant benefit from sildenafil. Both concomitant hormonal treatment and TURP will result in erectile dysfunction in a variable percentage of patients.¹⁶ Although our data tend to show poorer results in patients with prior TURPs or with concurrent antiandrogen therapy, these findings did not reach statistical significance, perhaps because of the weak statistical power of this small trial. For the same reason, no correlation could be unequivocally demonstrated between response and the severity of erectile dysfunction, although no patients with slight or moderate erectile dysfunction failed to respond to sildenafil. The latter observation would support the suggestion of Zelefesky et al,¹⁰ which states that the extent of residual erectile capacity could be a predictor of response to sildenafil. The proportion of younger sexual partners was not different between responders and nonresponders.

In contrast with the findings from the multicentric double-blind studies⁹ and in accordance with the findings of Zelefsky et al,¹⁰ our data also suggest that sildenafil improves the level of sexual desire in responding patients. Sildenafil's mechanisms of action, namely selective inhibition of cGMP catabolism and potentiation of the nitric oxide–stimulated cGMP signal in cavernosal smooth-muscle cells,^7,8 provide no ready explanation for this observation. Although no screening for psychologic distress was reported in this cohort, psychogenic factors may clearly influence sexual function. Anxiety is a prominent symptom of cancer patients.¹⁷ Recovering erectile capacity may potentially improve subclinical anxiety disorders, which are known to affect subjective sexual desire in men.¹⁸ Psychogenic factors may also be responsible for the observation that a proportion of responders reported erections in the absence of sildenafil, as these patients may have been suffering from impotence of a predominantly nonorganic cause.

The side effects of sildenafil were predominantly mild or moderate in nature and apparently always transient (Table 3). No patients withdrew because of adverse events. In particular, in light of the public concern for sildenafil's safety reported in the lay press and medical literature^19,20 and considering the high cardiovascular morbidity in this cohort of patients, it is reassuring that no acute myocardial infarction or death was observed.

In conclusion, these preliminary data suggest that oral sildenafil is an effective and well-tolerated treatment in men with prostate cancer presenting with erectile dysfunction after external-beam radiotherapy and, although it may take several weeks for significant response to be observed, sildenafil also seems to increase sexual desire in responding patients. As a result, sildenafil can produce a significant improvement in sexual function in a substantial proportion of patients. The effectiveness and safety of long-term sildenafil use will require further study. Larger studies will also be required to understand why some patients fail to derive significant benefit from the drug. Clearly, a multidisciplinary, multidimensional evaluation of patients with postradiotherapy impotence will be required to make additional progress in this area.

	APPENDIX

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

2. Fransson P, Widmark A: Self-assessed sexual function after pelvic irradiation for prostate cancer. Cancer78:1066-1078, 1996[Medline]

3. Chinn DM, Holland J, Crownover RL, et al: Potency following high-dose three-dimensional conformal radiotherapy and the impact of major urologic surgical procedures in patients treated for prostate cancer. Int J Radiat Oncol Biol Phys33:15-22, 1995[Medline]

4. Zinreich ES, Derogatis LR, Herpst J, et al: Pre and posttreatment evaluation of sexual function in patients with adenocarcinoma of the prostate. Int J Radiat Oncol Biol Phys19:729-732, 1990[Medline]

5. Talcott JA, Rieker P, Clark JA, et al: Patient-reported symptoms after primary therapy for early prostate cancer: Results of a prospective cohort study. J Clin Oncol16:275-283, 1998[Abstract/Free Full Text]

6. Helgason AR, Fredrikson M, Adolfsson J, et al: Decreased sexual capacity after external radiation therapy for prostate cancer impairs quality of life. Int J Radiat Oncol Biol Phys32:33-39, 1995[Medline]

7. Carter AJ, Ballard SA, Naylor AM: Effect of the selective phosphodiesterase type 5 inhibitor sildenafil on erectile dysfunction in the anesthetized dog. J Urol160:242-246, 1998[Medline]

8. Ballard SA, Gingell CJ, Tang K, et al: Effects of sildenafil on the relaxation of human corpus cavernosum tissue in vitro and on the activity of cyclic nucleotide phosphodiesterase isozymes. J Urol159:2164-2171, 1998[Medline]

9. Goldstein I, Lue TF, Padman-Nathan H, et al: Oral sildenafil in the treatment of erectile dysfunction. N Engl J Med338:1397-1404, 1998[Abstract/Free Full Text]

10. Zelefsky MJ, McKee AB, Lee H, et al: Efficacy of oral sildenafil in patients with erectile dysfunction after radiotherapy for carcinoma of the prostate. Urology53:775-778, 1999[Medline]

11. Rosen RC, Riley A, Gorm W, et al: The international index of erectile function (IIEF): A multidimentional scale for assessment of erectile dysfunction. Urology49:822-830, 1997[Medline]

12. Buyse ME, Staquet MJ, Sylvester RJ: Cancer Clinical Trials Methods and Practice. Oxford, United Kingdom, Oxford, University Press, 1984

13. Zelefsky MJ, Eid JF: Elucidating the etiology of erectile dysfunction after definitive therapy for prostatic cancer. Int J Radiat Oncol Biol Phys40:129-133, 1998[Medline]

14. Boolell M, Allen MJ, Ballard SA, et al: Sildenafil: An orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int J Impot Res8:47-52, 1996[Medline]

15. Bolla M, Gonzalez D, Warde P, et al: Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med337:295-300, 1997[Abstract/Free Full Text]

16. Bieri S, Miralbell R, Rohner S, et al: Influence of transurethral resection on sexual dysfunction in patients with prostate cancer. Br J Urol78:537-541, 1996[Medline]

17. Aass N, Fossa SD, Dahl AA, et al: Occurrence of anxiety and depression in cancer patients. Tidsskr Nor Laegeforen118:696-703, 1998

18. Beck JG, Bozman AW: Gender differences in sexual desire: The effects of anger and anxiety. Arch Sex Behav24:595-612, 1995[Medline]

19. Utiger RD: A pill for impotence. N Engl J Med338:1458-1459, 1998 (editorial) [Free Full Text]

20. Feenstra J, van Dri-Perik RJ, Lacle CF, et al: Acute myocardial infarction associated with sildenafil. Lancet352:957-958, 1998[Medline]

Submitted January 29, 1999; accepted June 21, 1999.

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