RAPID COMMUNICATION
`CME ARTICLE
`
`TREATMENT OF ERECTILE DYSFUNCTION AFTER RADICAL
`PROSTATECTOMY WITH SILDENAFIL CITRATE (VIAGRA)
`
`CRAIG D. ZIPPE, ANURAG W. KEDIA, KALISH KEDIA, DAVID R. NELSON, AND ASHOK AGARWAL
`
`ABSTRACT
`Objectives. To determine whether the response to the new oral medication, sildenafil citrate (Viagra), was
`influenced by the presence or absence of the neurovascular bundles, as recent reports on its success did not
`specify the efficacy of the drug in patients with erectile dysfunction after radical prostatectomy.
`Methods. Baseline and follow-up data from 28 healthy patients presenting with erectile dysfunction after
`radical prostatectomy were obtained. Patients receiving any neoadjuvant/adjuvant hormones or adjuvant
`radiation therapy were excluded. Patients reported what their erectile status was before surgery, before
`sildenafil therapy, and after using a minimum of four doses of sildenafil. Both the patients and their spouses
`were interviewed using the Cleveland Clinic post-prostatectomy questionnaire, which includes questions
`about response to therapy, duration of intercourse, spousal satisfaction, side effects, and related topics. The
`patients were compared on the basis of the type of surgical procedure they had undergone—nerve sparing
`or non-nerve sparing. A positive response to sildenafil was defined as erection sufficient for vaginal
`penetration.
`Results. Of the 15 patients who had bilateral nerve-sparing procedures, 12 (80%) had a positive response
`to sildenafil, with a mean duration of 6.92 minutes of vaginal intercourse. These 12 patients also reported
`a spousal satisfaction rate of 80%. All 12 of the responders had a positive response within the first three
`doses, and 10 of the 12 responded with the first or second dose. None of the 3 patients who had undergone
`a unilateral nerve-sparing procedure responded, nor did any of the 10 patients who had undergone a
`non-nerve-sparing procedure. The two most common side effects of the drug were transient headaches
`(39%) and abnormal color vision (11%). No patients discontinued the medication because of side effects.
`Conclusions. Successful treatment of erectile dysfunction in a patient after prostatectomy with sildenafil
`citrate may depend on the presence of bilateral neurovascular bundles. No patient who had undergone a
`non-nerve-sparing procedure responded. Whether patients who undergo unilateral nerve-sparing proce-
`dures will respond to sildenafil is still unclear because of the small number of patients in our study. These
`findings should encourage urologists to continue to perform and perfect the nerve-sparing approach. The
`ability to restore potency with an oral medication after radical prostatectomy will impact our discussion with
`the patient on the surgical morbidity of radical prostatectomy. UROLOGY 52: 963–966, 1998. © 1998,
`Elsevier Science Inc. All rights reserved.
`
`The recent release of sildenafil citrate (Viagra,
`
`Pfizer Pharmaceuticals), an inhibitor of phos-
`phodiesterase 5, has dramatically changed the
`treatment options for patients with erectile dys-
`function. Despite the current enthusiasm for this
`drug, there are no reports on its effectiveness in the
`
`From the Departments of Urology and Biostatistics and Androl-
`ogy-Oncology Research Laboratory, The Cleveland Clinic Foun-
`dation; and Lutheran Hospital, Cleveland, Ohio
`Reprint requests: Craig D. Zippe, M.D., Department of Urol-
`ogy, A100, The Cleveland Clinic Foundation, 9500 Euclid Ave-
`nue, Cleveland, OH 44195
`Submitted: June 19, 1998, accepted (with revisions): July 17,
`1998
`
`subgroup of patients with erectile dysfunction after
`radical prostatectomy. Previous publications on
`the efficacy of sildenafil citrate did not separate the
`results of this subset of patients from patients with
`other causes of organic impotence.1
`We report our experience using this drug in this
`subset of patients. We wanted to determine
`whether the response to sildenafil citrate was influ-
`enced by the presence or absence of the neurovas-
`cular bundles. Among those who responded, we
`sought to determine how many doses of sildenafil
`were needed for a response, the duration of inter-
`course, and whether the spouse reported being sat-
`isfied.
`
`© 1998, ELSEVIER SCIENCE INC.
`ALL RIGHTS RESERVED
`
`0090-4295/98/$19.00
`PII S0090-4295(98)00443-9 963
`
`INTELGENX 1042
`
`

`
`TABLE II. Characteristics of 28 patients with
`erectile dysfunction after prostatectomy
`before sildenafil therapy
`Non-Nerve-
`Nerve-
`Sparing
`Sparing
`P
`Surgery
`Surgery
`(n 5 10)
`(n 5 18)
`Value*
`58.78 6 2.68 61.40 6 2.05 0.19
`13.5 6 2.68
`11.7 6 2.9
`0.87
`
`100 (18/18)
`0 (0/18)
`0 (0/18)
`
`70 (7/10)
`20 (2/10)
`10 (1/10)
`
`0.18
`
`0 (0/18)
`28 (5/18)
`62 (13/18)
`0 (0/18)
`
`0 (0/10)
`10 (1/10)
`90 (9/10)
`0 (0/10)
`
`0.45
`
`1.00
`
`Patient
`Characteristics
`Age (yr)
`Time from surgery
`to sildenafil
`(mo)
`Presurgical
`erectile status
`(%, n)
`Full
`Partial
`None
`Predrug erectile
`status (%, n)
`Full
`Partial
`None
`Nocturnal
`erections
`present (%, n)
`Able to penetrate
`(%, n)
`Data are presented as mean 6 SE unless otherwise noted.
`* P ,0.05 was considered as significant; Wilcoxon rank-sum test was used.
`
`TABLE I. The Cleveland Clinic post-
`prostatectomy questionnaire
`1. What was the date of your prostate surgery?
`2. What type of surgery was performed (bilateral nerve-
`sparing, unilateral nerve-sparing, or non-nerve-
`sparing)?
`3. Would you describe your erections before the surgery
`as full, partial, or none?
`4. Would you describe your erections after the surgery
`and before starting sildenafil as full, partial, or
`none?
`5. When did you start taking sildenafil?
`6. How many times have you taken it since?
`7. Did you engage in foreplay?
`8. After taking sildenafil, did you have an erection
`adequate for vaginal penetration?
`9. After taking sildenafil, how long would you estimate
`intercourse lasted?
`10.Did you have any side effects (choose from the
`following: headache, dizziness, flushing, dyspepsia,
`nasal congestion, abnormal color vision)?
`11.How many doses of sildenafil did you take before a
`positive response?
`12.Did you take sildenafil in the correct manner as
`prescribed?
`13.Was your spouse satisfied with the sexual intercourse?
`14.Have you discontinued the drug? Why?
`
`MATERIAL AND METHODS
`
`We selected 28 healthy patients who had undergone radical
`prostatectomy who had no erections or unsatisfactory erec-
`tions for this study. These patients were given a prescription
`for a 100-mg dose of sildenafil. Patients were instructed to take
`a sildenafil tablet approximately 1 hour before sexual activity
`per the manufacturer’s instructions. Patients were told to have
`adequate foreplay before sexual intercourse. After taking at
`least four doses of the drug, the patients were asked to call in
`for a telephone interview to report their response. None of the
`28 patients were on any concurrent form of therapy for their
`erectile dysfunction.
`The type of surgical procedure was determined by chart
`review and confirmed during the telephone interview. Of the
`28 patients, 10 had undergone a non-nerve-sparing procedure
`and 18 patients had undergone a nerve-sparing procedure. All
`nerve-sparing procedures and 3 of the 10 non-nerve-sparing
`procedures were performed by the same surgeon (C.D.Z.).
`Three of the 18 patients had undergone unilateral nerve-spar-
`ing procedures. None of the patients received neoadjuvant or
`adjuvant hormones or radiation therapy after prostatectomy.
`All telephone interviews were conducted by the same per-
`son (A.K.). Table I lists the questions asked. Both patients and
`spouses were interviewed about the patient’s presurgical and
`presildenafil erectile function, their use of sildenafil, their re-
`sponse to therapy, the duration of intercourse, side effects, and
`their spouse’s satisfaction with sex.
`Statistical methods consisted of demographic and baseline
`comparisons of the patients who had undergone nerve-spar-
`ing surgery with those who had undergone non-nerve-sparing
`procedures using Fisher’s exact and Wilcoxon rank-sum tests.
`Fisher’s exact test was used to compare the success rates in the
`two groups. Confidence intervals (95% CI) were also com-
`puted for rates.
`
`0 (0/18)
`
`0 (0/10)
`
`1.00
`
`RESULTS
`Before sildenafil therapy, no significant differ-
`ences were seen between the non-nerve-sparing or
`nerve-sparing groups in age, interval between rad-
`ical prostatectomy and start of sildenafil, presurgi-
`cal and predrug erectile status, nocturnal erec-
`tions, and the ability to penetrate (Table II).
`The presence of the neurovascular bundles bilat-
`erally had a significant impact on the efficacy of
`sildenafil (P , 0.001; Table III). Of the 18 pa-
`tients who had undergone a bilateral nerve-sparing
`procedure, 12 (67%, 95% CI 41% to 87%) had a
`positive response, defined as an erection sufficient
`for penetration. Three of the 18 had undergone a
`unilateral nerve-sparing procedure, and none of
`them responded to sildenafil. Thus, the percentage
`of patients with bilateral nerve-sparing surgery
`who had a positive response was 80% (12 of 15,
`95% CI 52% to 96%, P , 0.001; Table III).
`The quality of the erection with sildenafil was
`excellent, as shown by the mean duration of vagi-
`nal intercourse, which was 6.92 minutes. Interest-
`ingly, the effect of sildenafil on the ability to
`achieve vaginal intercourse, as well as the quality
`of the erection, correlated with the high spousal
`satisfaction rate of 80%. The maximum number of
`doses required to achieve a positive response was
`three, with 10 (83%, 95% CI 52% to 98%) of the 12
`
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`TABLE III. Comparison between patients with nerve-sparing and non-nerve-sparing
`prostatectomies in response to sildenafil
`Nerve-Sparing
`Bilateral
`Unilateral
`(n 5 15)
`(n 5 3)
`Patient Characteristic
`4.9 6 0.5
`4.0 6 0.0
`No. of doses taken
`100 (15/15)
`100 (3/3)
`Adequate foreplay (%, n)
`80 (12/15)
`0 (0/3)
`Able to penetrate (%, n)
`6.92 6 2.32
`0 (0/3)
`Estimated duration of intercourse (min)
`80 (12/15)
`0 (0/3)
`Spouse satisfaction (%, n)
`* Comparison of nerve-sparing and non-nerve-sparing patient groups; P ,0.05 was considered as significant.
`
`Non-Nerve-Sparing
`(n 5 10)
`4.7 6 0.9
`100 (10/10)
`0 (0/10)
`0 (0/10)
`0 (0/10)
`
`P
`Value*
`0.86
`1.00
`,0.001
`,0.001
`,0.001
`
`TABLE IV. Side effects and discontinuation of
`sildenafil
`Frequency
`(n 5 28)
`11/28 (39)
`3/28 (11)
`2/28 (7)
`1/28 (4)
`3/28 (11)
`
`Side Effects
`Headache
`Abnormal color vision
`Flushing
`Dyspepsia
`Discontinuation
`KEY: CI5 confidence interval.
`Numbers in parentheses are percentages.
`
`95% CI
`22%–59%
`2%–28%
`1%–24%
`0%–18%
`2%–28%
`
`patients describing a positive response with the
`first or second dose (Table III).
`Sildenafil had no effect in the non-nerve-sparing
`group of 10 patients (0%, 95% CI 0% to 31%).
`Despite adequate foreplay and multiple doses,
`none of these patients reported any improvement
`in their erectile status.
`About 39% of the patients experienced transitory
`headaches. The other common side effect was ab-
`normal color vision, experienced by 11% of pa-
`tients. No patients discontinued sildenafil because
`of side effects. Overall, the 3 patients (11%, 95% CI
`2% to 28%) who did discontinue sildenafil believed
`the drug was ineffective (Table IV). The remaining
`patients who did not respond to sildenafil contin-
`ued to use it in hopes of a future response.
`
`COMMENT
`The release of sildenafil has created a tremen-
`dous market for the treatment of erectile dysfunc-
`tion. A recent report described a dose-response/
`escalation study using sildenafil
`in men with
`erectile dysfunction from various causes, but they
`did not specify the effect of sildenafil in the post-
`radical prostatectomy group.1 Our study investi-
`gated the use of sildenafil in this patient group, and
`determined whether the presence or absence of the
`neurovascular bundles affected the response.
`The most salient finding of this study is how well
`patients who underwent a bilateral nerve-sparing
`procedure responded to sildenafil. After one to three
`
`doses, most of these patients (80%) achieved erec-
`tions sufficient for vaginal intercourse. This response
`was directly related to spousal satisfaction, again con-
`firming the quality of the erection. Conversely, no
`patient who underwent a non-nerve-sparing proce-
`dure responded. The lack of a response to sildenafil in
`the 3 patients who underwent a unilateral nerve-
`sparing procedure is unclear because of the small
`sample size. More patients will have to be studied in
`this subgroup to accurately determine the efficacy of
`sildenafil. However, in a unilateral nerve-sparing pro-
`cedure, there may be insufficient functioning nerve
`tissue for the optimal release of nitric oxide and sub-
`sequent conversion of guanosine triphosphate to cy-
`clic guanosine monophosphate.
`The mean time interval from radical prostatec-
`tomy to the initiation of sildenafil was roughly 1
`year in both the nerve-sparing and non-nerve-spar-
`ing groups. It is quite possible that earlier initiation
`of sildenafil might increase the positive response
`rate in both groups. Prospective studies have al-
`ready been started to assess the efficacy of sildenafil
`at an earlier interval after radical prostatectomy.
`This study has important implications in the sur-
`gical management of prostate cancer at a time
`when the morbidity of radical prostatectomy is be-
`ing severely scrutinized. Although potency rates of
`50% to 70% after nerve-sparing radical prostatec-
`tomy have been reported,2,3 these figures are not
`universally accepted. Jonler and associates,4 from
`the University of Wisconsin, report that only 9% of
`their patients had full erections and 38% had par-
`tial erections after nerve-sparing prostatectomy.
`Similar figures were reported by Fowler et al.5 in
`1993 in a Medicare population. In another report,
`Talcott et al.6 described inadequate erections and
`vaginal penetration in 79% of men who underwent
`a bilateral nerve-sparing procedure and found no
`benefit after the unilateral nerve-sparing proce-
`dure. Sildenafil offers a chance to salvage roughly
`80% of our impotent patients if a bilateral nerve-
`sparing procedure is done.
`Our findings helped us reexamine the role for
`nerve-sparing radical prostatectomy. Generally, an
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`inexperienced surgeon, when performing a nerve-
`sparing procedure, will have greater blood loss,
`more iatrogenic positive margins, and require
`more operative time. These findings should en-
`courage urologists to continue to perform and per-
`fect the nerve-sparing approach to give their pa-
`tients the best chance of successful treatment for
`impotence after prostatectomy.
`
`CONCLUSIONS
`Patients with erectile dysfunction after prosta-
`tectomy responded well to sildenafil if both neuro-
`vascular bundles were spared during surgery. After
`a minimum trial of four doses of sildenafil, 80% of
`the patients who had undergone a bilateral nerve-
`sparing procedure could sustain erections suffi-
`cient for vaginal penetration with a mean duration
`of nearly 7 minutes. This positive response re-
`sulted in an 80% spousal satisfaction rate. Men in
`the non-nerve-sparing group showed no response
`to sildenafil nor did the patients who had under-
`gone a unilateral nerve-sparing procedure. How-
`ever, the unilateral nerve-sparing group was too
`small to draw any firm conclusions. The main side
`
`effects of sildenafil were headaches and abnormal
`color vision, but none of the patients discontinued
`the medication because of side effects. This study
`has important implications concerning the benefit
`of a nerve-sparing radical prostatectomy.
`
`ACKNOWLEDGMENT. To Robin Verdi for secretarial assistance.
`
`REFERENCES
`1. Goldstein I, Lue TF, Padma-Nathan H, et al: Oral silde-
`nafil in the treatment of erectile dysfunction. Sildenafil study
`group. N Engl J Med 338: 1397–1404, 1998.
`2. Catalona WJ, and Basler JW: Return of erections and
`urinary continence following nerve-sparing radical retropubic
`prostatectomy. J Urol 150: 905–907, 1993.
`3. Quinlan DM, Epstein JI, Carter BS, et al: Sexual function
`following radical prostatectomy: influence of preservation of
`neurovascular bundles. J Urol 145: 998 –1002, 1991.
`4. Jonler M, Messing EM, Rhodes PR, et al: Sequelae of
`radical prostatectomy. Br J Urol 74: 352–358, 1994.
`5. Fowler JF, Barry MJ, Lu-Yao GL, et al: Patient reported
`complications and follow-up treatment following radical pros-
`tatectomy: the national Medicare experience. Urology 42:
`622– 629, 1993.
`6. Talcott JA, Rieker P, Propert KJ, et al: Patient reported
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`tatectomy. J Natl Cancer Inst 89: 1117–1123, 1997.
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