ADULT UROLOGY ROLE OF VIAGRA AFTER RADICAL PROSTATECTOMY
CRAIG D. ZIPPE, FAIYAAZ M. JHAVERI, ERIC A. KLEIN, SUMITA KEDIA,
FABIO F. PASQUALOTTO, ANURAG KEDIA, ASHOK AGARWAL, DROGO K. MONTAGUE, AND
ABSTRACT Objectives. To determine whether the response to sildenafil citrate (Viagra) in patients with erectile dysfunction after radical prostatectomy was influenced by the presence or absence of neurovascular bundles, the interval from surgery to the initiation of drug therapy, and the dose of the drug. Methods. Baseline and follow-up data from 91 patients presenting with erectile dysfunction after radical prostatectomy were obtained. The patients were stratified according to the type of nerve-sparing (NS) procedure: bilateral NS, unilateral NS, and non-NS. They were interviewed using the Cleveland Clinic Post Prostatectomy (CCPP) questionnaire and the International Index of Erectile Function (IIEF) questionnaire. Results. The presence or absence of the neurovascular bundles influenced the ability to achieve vaginal intercourse. In the patients who had undergone bilateral NS, 71.7% (38 of 53) responded; in those with unilateral NS, 50% (6 of 12) responded; and in those with non-NS, 15.4% (4 of 26) responded. The IIEF questionnaire confirmed the quality of the positive responses, with significant improvements in response to question 3 (frequency of penetration), question 4 (frequency of maintenance of erection), and question 7 (satisfaction with intercourse). The magnitude of improvement in responses was higher in the bilateral NS group than in the unilateral NS and non-NS groups (P <0.05). When the data of the 48 positive responders were analyzed, no difference in the response rate was found when the interval from surgery to drug therapy was stratified by the following three intervals: 0 to 6 months (44%), 6 to 12 months (55%), and greater than 12 months (53%). Of the positive responders, 14 (29.1 %) required the 50-mg dose, and 34 (70.9%) required the 100-mg dose. The most common side effects were transient headaches (28.6%), flushing (21.9%), dizziness (8.8%), dyspepsia (6.5%), and nasal congestion (5.4%), with an increase in the incidence of headaches seen at the higher dose (P = 0.04). Conclusions. Successful treatment of erectile dysfunction with sildenafil citrate after radical prostatectomy depends on the presence of the neurovascular bundles. Our data suggest that the response to sildenafil is not related to the interval between the surgery and initiation of drug therapy but is related to the dose. UROLOGY 55: 241-245, 2000. 2000, Elsevier Science Inc. The treatment algorithm for patients with erectile
This study was funded through an unrestricted
dysfunction has dramatically changed with the availability
educational grant by Pfizer Pharmaceuticals, Inc. M. M.
of sildenafil citrate (Viagra, Pfizer Pharmaceuticals), the
Lakin is on the speaker's bureau for the sponsor and
first effective oral medication. Following the landmark
holds custodial stock in the sponsor.
publication by Goldstein et al.1 in 1998, sildenafil citratebecame the first treatment option for eligible ,patients with
From the Department of Urology, Cleveland Clinic
erectile dysfunction resulting from a variety of organic and
psychogenic causes. However, their report did not stratify
Reprint requests: Craig D. Zippe, M.D., Prostate
the various types of organic etiologies and did not include
Center, Department of Urology, A100, Cleveland Clinic
pertinent data in the subset of patients who had undergone
Foundation, 9500 Euclid Avenue, Cleveland, OH 44195
radical prostatectomy, such as the impact of the presence
Submitted: April 23, 1999, accepted (with
or absence of the neurovascular bundles. Until recently, no
reports were available on the impact of nerve sparing (NS)versus non-NS on the response to sildenafil citrate.2,3
2000, ELSEVIER SCIENCE Inc. ALL RIGHTS RESERVED
TABLE I. Characteristics of 91 patients after prostatectomy who had erectile dysfunction before sildenafil therapy Bilateral NS Unilateral NS Patient Characteristics
Median time from surgery to treatment (mo)
Presurgery erectile status (%) Predrug erectile status (%)
Subsequent to our earlier publication, which involved 28 patients,2 we have updated our experience, with ananalysis of 91 patients treated with sildenafil after radical prostatectomy. In our earlier report, we reported that 80%of patients (12 of 15) would respond favorably if both neurovascular bundles were spared. We wanted to confirmthis observation in the bilateral NS group but also wanted to determine whether patients undergoing unilateral NSwould respond favorably as well. In this larger series, we also analyzed whether the interval from the surgery to theinitiation of the drug therapy affected the response and whether the dose of the drug had any impact on theresponse.
We assessed the change in the quality of the erectile status, before and after treatment with sildenafil, using twoquestionnaires, the International Index of Erectile Function (IIEF)4 and the Cleveland Clinic Post Prostatectomy(CCPP). In our earlier report, we used only the CCPP questionnaire, a nonvalidated, practical questionnaire that isa shorter version of the IIEF but is clinically useful in an office practice. In the CCPP questionnaire, a positiveresponse was defined as the ability to achieve vaginal intercourse. We assessed the quality of the erection byinquiring about the duration of intercourse and directly interviewed the spouse (or partner) to assess her satisfaction. In the updated series, we reanalyzed the entire group using both the CCPP questionnaire and the. IIEFquestionnaire. The IIEF questionnaire is a comprehensive, 15-question research questionnaire, which has a highdegree of sensitivity and specificity for detecting treatment-related changes in men with erectile dysfunction. Thesetwo questionnaires provided us with a comprehensive, sensitive assessment of any changes in erectile function. MATERIAL AND METHODS
Since 1996, an estimated 350 patients have presented to our urologic clinic with unsatisfactory erectile dysfunctionafter radical prostatectomy. Of these 350 patients, 91 patients (26%) agreed to a trial of oral sildenafil citrate. Allpatients were offered treatment without regard to the status of their neurovascular bundles. The 91 patients whoagreed to use sildenafil were a self-selected, nonrandomized group, with nearly 90% of their being sexually activebefore surgery (Table I). Most of these patients (53 of 91), on the basis of their preoperative sexual status and lowrisk of positive surgical margins, had undergone a bilateral NS procedure. None of the patients were using any ofthe standard treatments for erectile dysfunction.
All patients were given a prescription for sildenafil at a dosage of 50 mg, with a titration to 100 mg if needed to geta positive response. None of the patients were using oral, sublingual, or transdermal nitrates. Patients wereinstructed to take a sildenafil tablet approximately 1 to 2 hours before sexual activity, per the manufacturer'sinstructions. Patients were requested to have manual or visual foreplay before sexual intercourse and to call in for atelephone interview to report their response only after taking a minimum of four doses.
Retrospectively, the patients were stratified according to the type of NS procedure they had undergone: bilateralNS, unilateral NS, and non-NS. The type of surgical procedure was determined by chart review and confirmedduring the telephone interview. All the NS procedures were done by two experienced surgeons. The anatomic statusof the neurovascular bundles was recorded by the surgeon at the time of the surgery; no intraoperative functiontests were performed. Of the 91 patients, 53 patients (58.2%) had bilateral NS procedures, 12 (13.2%) hadunilateral NS procedures, and 26 (28.6%) had non-NS procedures. None of the patients received neoadjuvant oradjuvant hormones or radiation therapy. The patients were also stratified into three groups, according to the timeinterval from the date of surgery to the initiation of drug therapy: 3 to 6, 6 to 12, and greater than 12 months. Allpatients had a postoperative interval of at least 3 months before beginning sildenafil.
All telephone interviews were conducted by the same person (S.K.). We used two questionnaires to assess thepatient's response to sildenafil and the efficacy of the drug: the CCPP questionnaire2 and the IIEF questionnaire.4On the CCPP questionnaire, patients were asked about their erectile function before and after surgery, their use ofsildenafil, their response to therapy, the duration of intercourse, and side effects. All spouses (or partners) weredirectly asked about their sexual satisfaction. The patient was designated as a "responder" or "nonresponder" on thebasis of his ability to have vaginal intercourse. TABLE II. Comparison between patients with NS and non-NS prostatectomies in response to Sildenafil Variable Bilateral NS Unilateral NS P Value * KEY: NS = nerve sparing; NSF = not significant. * Bilateral NS vs. unilateral NS/non-NS.
The IIEF questionnaire is a validated 15-question research questionnaire that is a sensitive indicator of changes inerectile function and treatment outcomes. We assessed the efficacy of sildenafil citrate by analyzing the responses,particularly to question 3 (frequency of penetration), question 4 (frequency of maintenance of erections), andquestion 7 (satisfactory intercourse). The responses to the questions were rated on a scale of 1 (almost never ornever) to 5 (almost always or always). A score of 0 indicated no sexual activity. The mean baseline scores to thequestions were calculated and compared with the final scores to determine the change in response.
Statistical methods consisted of demographic and baseline comparisons of the patients who had undergone NSsurgery with those who had undergone non-NS procedures using Fisher's exact test and the Wilcoxon rank sumtest. Fisher's exact test was used to compare the success rates in the two groups. Ninety-five percent confidenceintervals were also computed for rates. IMPACT OF NEUROVASCULAR BUNDLE PRESENCE
After treatment with sildenafil, the presence or absence of the neurovascular bundles significantly influenced theability to achieve vaginal intercourse. In the patients who had bilateral NS, 71.7% (38 of 53) responded; in thosewith unilateral NS, 50% (6 of 12) responded; in those with non-NS, 15.4% (4 of 26) responded (Table II). Whether this 15% response in the non-NS group was a placebo effect, unrecognized residual nerve tissue, or anon-neurogenic mechanism is unclear. The quality of the erection was excellent in the 48 responders, with a meanduration of intercourse ranging from 4.5 to 12 minutes. The ability to achieve vaginal penetration (71.9%)
correlated directly with the spousal satisfaction rate (66.0%).
The IIEF questionnaire similarly confirmed the quality of the positive responses, with improvements in response toquestion 3 (frequency of penetration), question 4 (frequency of maintenance of erection), and question 7(satisfactory intercourse) (Table II). The magnitude of the improvement for all three questions was significantlyhigher in the bilateral NS group than in those who had undergone a unilateral or non-NS procedure (P <0.05). Patients who had undergone a bilateral NS procedure answered "almost always" to these three questions comparedwith "occasionally" in the unilateral NS and non-NS groups. IMPACT OF INTERVAL FROM SURGERY AND DOSE OF DRUG
When the 48 positive responders were analyzed, no difference in the response rate was found when the intervalfrom surgery to drug therapy was stratified by the following three intervals: 3 to 6 months (4 of 9, 44%), 6 to 12months (12 of 22, 55%), and greater than 12 months (32 of 60, 53%). Of these 48 positive responders, 14 (29.1%)required only a 50-mg dose, and 34 (70.9%) required the 100-mg dose. SIDE EFFECTS
The most common side effects of the drug were transient headaches (28.6%), flushing (21.9%), dizziness (8.8%),dyspepsia (6.5%), and nasal congestion (5.4%), with an increase in the incidence of headaches seen at the higherdose (P = 0.04). The 8 patients (8.8%) who discontinued the drug because of side effects were also nonresponders. None of the patients had any serious cardiovascular effects (defined as fainting, strokes, or myocardial infarction).
The release of sildenafil has created a tremendous market for the treatment of erectile dysfunction. Previous reportshave described a dose-response/escalation study using sildenafil in men with erectile dysfunction of variouspsychogenic and organic causes.1 Our updated series of 91 patients investigated the use of sildenafil in patients witherectile dysfunction after radical prostatectomy. We wanted to confirm our initial impression that- the presence orabsence of the neurovascular bundles affected the response. In our earlier series of 15 patients who underwentbilateral NS, we reported an 80% potency rate (12 of 15) after treatment with sildenafil citrate .2 In this report,none of the 3 patients who underwent unilateral NS procedures responded, but the limited sample size did not allowfor any conclusions to be drawn. In this updated series, we report a 50% response rate in patients (6 of 12) whohad undergone unilateral NS. In this larger series, we determined that the interval from the surgery to the initiationof sildenafil therapy did not significantly influence the positive response rate. However, the dose of the drug didinfluence the response rate, with 71% of the patients requiring the 100-mg dose.
The patients with impotence after prostatectomy were an excellent subset to investigate the effects of this new oralmedication. The surgical patient is typically younger than 65 years and in reasonably good health, without a highincidence of comorbid diseases such as diabetes or hypertension. Most of the patients were sexually active beforesurgery, without any pre-existing organic or psychogenic problems contributing to their erectile dysfunction. Although many patients may have refused to consider one of the standard treatment options, the idea of taking anoral medication on demand was more appealing.
The most salient finding in this updated series was that the response rate to sildenafil was much better in patientswho had undergone either bilateral or unilateral NS procedures than in patients who had undergone non-NS,procedures. In the bilateral NS group, 71.7% (38 of 53) achieved vaginal intercourse; in the unilateral NS group,50% (6 of 12) did so; and in the non-NS group, only 15.4% (4 of 26) achieved vaginal intercourse. Whether this15% response in the non-NS group was a placebo effect or reflects unrecognized residual nerve tissue is unclear. The .functional status of the neurovascular bundles was not documented in this series. The ability to achievevaginal intercourse correlated directly with the spousal (or partner) satisfaction rate. The functional status of theerection in the sildenafil responders was excellent, with the duration of vaginal intercourse ranging from 4.5 to 12minutes.
The sensitivity of the IIEF questionnaire was seen in comparing the quality of the erectile response in the 48responders between the bilateral NS group (n = 38) and the unilateral NS group (n = 6) and non-NS group (n = 4). In each of the three questions, the improvement in response was significantly higher in the bilateral NS group thanin the other two groups. In general, the patients in the bilateral NS group answered "almost always" to each of thethree questions: frequency of erection, frequency of maintenance of the erection, and sexual satisfaction. Incontrast, the responders in the unilateral NS and non-NS groups most frequently answered "about one half of thetime" to these same three questions.
No change in the response rate was observed when the patients were stratified into three categories (3 to 6 months[44%], 6 to 12 months [55%], greater than 12 months [53%]), depending on the interval from surgery to theinitiation of sildenafil therapy. Although only 9 patients were included in the 3- to 6-month group, 4 patients (44%)responded favorably, encouraging us to offer sildenafil therapy at an earlier time in the postoperative period. Thisfavorable response in this earlier time interval will need to be analyzed further. It will be interesting to see if evenearlier treatment, immediately after surgery, may have a prophylactic benefit in preventing vasogenic insufficiencysecondary to postoperative scarring.
A definite dose-related response was seen among the responders. In the dose-response study, increasing doses ofsildenafil were associated with higher mean scores for the questions on the IIEF questionnaire. Seventy-one percentof the patients required a titration in their dose, from 50 to 100 mg for a positive response. This increase was welltolerated, with only an increase in the incidence of headaches seen at the 100-mg dose.
This study has important implications in the surgical management of localized prostate cancer at a time when themorbidity of radical prostatectomy is of concern. Our findings force us to re-examine the role of NS radicalprostatectomy. The use of sildenafil citrate offers a chance to salvage roughly 70% of our impotent, motivatedpatients if a bilateral NS procedure is done and 50% of patients if a unilateral NS procedure is done. Our resultssuggest that urologists can initiate treatment with sildenafil at any time after the surgery and should not be hesitantto increase the dose to the maximal 100-mg dose. Furthermore, these findings should encourage urologists tocontinue to perform and perfect the NS approach to give their patients the best chance of resuming sexual activityafter radical prostatectomy. CONCLUSIONS
In our study, the patients with good preoperative sexual function who became dysfunctional after radicalprostatectomy responded well to sildenafil citrate if one or both neurovascular bundles were spared. After aminimum of four doses of sildenafil, 71.9% of patients with bilateral NS and 50% of patients with unilateral NSprocedures could sustain erections sufficient for vaginal penetration, with a mean duration of 10 and 4.5 minutes;respectively. This resulted in a high spousal satisfaction rate. When the patients were stratified into three groups (3to 6, 6 to 12, and greater than 12 months, according to the interval from surgery to initiation of drug therapy), nosignificant difference in the percentage of responders was observed. This response rate was obtained at the maximaldose, with most (70.9%) patients requiring titration to the 100-mg dose. The most common side effects of sildenafilwere headaches (28.6%) and flushing (21.9%), with an increase in headaches seen as the dose increased. Thisstudy has important implications for the surgical management of localized prostate cancer and the benefit of a NSprocedure. REFERENCES
1. Goldstein 1, Lue TF, Padma-Nathan H, et al, for the Sildenafil Study Group: Oral sildenafil in the treatment of
erectile dysfunction. N Engl J Med 338: 1397-1404, 1998.
2. Zippe C, Kedia AW, Kedia K, et al: Treatment of erectile dysfunction after radical prostatectomy with sildenafil
citrate (Viagra). Urology 52: 963-966, 1998.
3. Marks LS, Duda C, Dorey FJ, et al: Treatment of erectile dysfunction with sildenafil. Urology 53: 19-24, 1999. 4. Rosen RC, Riley A, Wagner G, et al: The International Index of Erectile Function (IIEF): a multidimensional scale
for assessment of erectile dysfunction. Urology 49: 822-830, 1997.
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