Early intervention with phosphodiesterase-5 inhibitors after prostate brachytherapy improves subsequent erectile function

Authors


Craig D. Zippe, University Hospitals Bedford Medical Center, Medical Office Building, 88 Center Road, Suite 360, Bedford, OH 44146, USA.
e-mail: craig.zippe@uhhospitals.org

Abstract

Study Type – Therapy (case series)
Level of Evidence 4

OBJECTIVE

To examine the early use of phosphodiesterase-5 inhibitor (PDE-5i; sildenafil citrate) in preventing subsequent erectile dysfunction (ED) after (monotherapy) prostate brachytherapy (PB, an accepted option for Gleason 6 or low-volume Gleason 7 prostate cancer), as PB is currently being offered more frequently in younger patients, and ED can be a side-effect often within the first 12 months after treatment.

PATIENTS AND METHODS

We examined a single-surgeon series of 69 patients who had been treated with PB from 2002 to 2005. All patients had a follow-up of ≥1 year; prospectively, and patients had baseline, 6- and 12-month assessments using the Sexual Health Inventory for Men (SHIM) and International Index of Erectile Function (IIEF)-6 scores. The 69 patients were divided into early treatment with PDE-5i (31) and not treated with PDE-5i (38), and their SHIM and IIEF-6 scores were compared at baseline, 6 and 12 months. Daily sildenafil (25–50 mg) was given immediately after PB for 12 months. Overall, for the entire group, the mean prostate-specific antigen (PSA) level was 6.8 ng/mL; 78% had Gleason 6 cancer and 20% had Gleason 7 (3 + 4) cancer. The mean age in the early PDE-5i group was 64.8 years, and was 66.0 years in the no-PDE-5i group. The mean radiation dose in the early PDE-5i group was 50.2 Gy, and 43.9 Gy in the other group (P= 0.08).

RESULTS

In the no-PDE-5i group, the mean baseline SHIM score of 17.1 decreased rapidly to 9.1 at 6 months (P= 0.01) and stayed at 9.3 at 12 months (P= 0.01). In the early PDE-5i group, the mean baseline SHIM score of 21.8 decreased slightly to 17.6 at 6 months (P= 0.2), and was maintained at 17.9 at 12 months (P= 0.2). Using the Wilcoxon rank-sum test, the 6- and 12-month SHIM scores in the two groups (P < 0.001). The IIEF-6 questionnaire confirmed the SHIM analysis.

CONCLUSIONS

After PB patients had a significant decline in SHIM/IIEF-6 scores at 6 and 12 months. Our results indicate a 50% decrease in the quality of their erections. This provides an opportunity to initiate early intervention with PDE-5i or perhaps vacuum constriction devices or intraurethral alprostadil. In this study, the early use of PDE-5i after PB maintained erectile function at both 6 and 12 months.

Abbreviations
ED

erectile dysfunction

PB

prostate brachytherapy

RP

radical prostatectomy

EBRT

external beam radiotherapy

PDE-5i

phosphodiesterase-5 inhibitor(s)

SHIM

Sexual Health Inventory for Men

IIEF

International Index of Erectile Function.

INTRODUCTION

Erectile dysfunction (ED) is an important outcome measure among patients with localized prostate cancer who are treated with prostate brachytherapy (PB) [1,2]. Previous reports on ED after PB showed a broad range of potency rates, of 32–76% (Table 1) [1–6]. In 2001, Stock et al. [4] reported that 21% of the men had ED at 3 years after PB and 41% had ED at 6 years of follow-up. In another report, Zelefsky et al. [3] reported a 29% rate of ED at 5 years after implantation. Recently Sanda et al. [7] compared the sexual outcomes for various prostate cancer treatments. At 24 months of follow-up they found significantly better results with PB than with radical prostatectomy (RP) and external beam radiotherapy (EBRT). The partner’s distress related to the patient’s ED was minimum with PB (13%), compared with RP or EBRT (44% and 22%, respectively). While these studies show that PB can adversely effect erectile function, it does so to a lesser extent than other standard treatments.

Table 1.  The overall potency outcomes after PB in previous reports
StudyNMedian age, yearsMean follow -up, monthsPotency, %
  • *

    Potency defined by validated IIEF questionnaire.

[3]248653660
[4]416663159
[5]105706232
   18 (+EBRT) 
[6]482683276
   56 (+EBRT) 
[2]22629.1 50.5*
 (overall)<60 60.8
  60–70 48.6
  >70 32.0
[1]325 8450.6*
 (overall)<60 84
  60–70 60
  >70 40

In the recent decade of oral phosphodiesterase-5 inhibitors (PDE-5i), various studies were conducted to assess the role of oral PDE-5i for managing delayed ED after PB. Merrick et al. [8] reported that PB-induced ED was amenable to sildenafil treatment. With a mean follow-up of 17 months, 80.6% of patients maintained potency with sildenafil citrate. Potters et al. [6] reported that sildenafil effectively restored sexual function in 80% of the patients with ED who were sexually potent before permanent PB for localized prostate cancer. Interestingly, Ohebshalom et al. [9] reported that sildenafil use at any time after PB improved erectile function, but there was a decreased response to oral pharmacotherapy with time. Currently, the time to initiation of oral PDE-5i therapy after PB has not been investigated as a factor in preserving erectile function.

Based on data from several small retrospective studies, it is not unreasonable to consider the role of ‘early penile rehabilitation’ in patients undergoing any treatment for prostate cancer. Reports suggest that after RP significant fibrotic changes occur in the corpus cavernosum. Data from contemporary studies evaluating the chronic use of oral PDE-5i suggest a beneficial effect on endothelial cell function among men with ED from various causes [10,11]. Limited data on radiation injury to the neurovascular bundle and consequent penile atrophy suggest a possible role for these agents in enhancing the return of sexual function in such men.

We hypothesized that the earlier initiation of oral pharmacotherapy would result in a faster return of erectile function and preserve erectile function better than not using any therapy. We conducted this study to assess the role of early PDE-5i immediately after PB (monotherapy), comparing sexual outcomes with a contemporary control group. We assessed the time-dependent attrition in erectile function between the two groups.

PATIENTS AND METHODS

This study, which was approved by the ethics committee, included 69 patients with low-intermediate grade prostate cancer who were treated with 125I-seed implantation PB at Cleveland Clinic from September 2002 to May 2005. Any patient receiving neoadjuvant hormonal ablation was excluded from analysis. We requested that all patients with prostate cancer complete the Sexual Health Inventory for Men (SHIM) and International Index of Erectile Function (IIEF)-6 questionnaire before (baseline) and after treatment (6 and 12 months) as part of their initial and routine follow-up evaluation. The 69 patients who agreed and signed the informed consent form to participate in the study were initially evaluated with a comprehensive sexual history, physical examination, and pertinent laboratory testing. Calculation algorithms and seed parameters used in pre-planning and postoperative dosimetry were those recommended by the American Association of Physicists. All these patients underwent PB using 125I; the prescription dose for 125I was set at 144 Gy.

Variables assessed included: age at the start of PB, radiation dose, PSA level at the time of diagnosis, and follow-up PSA levels. The use of oral and other therapies to promote erectile function was also recorded. All 69 patients had completed the SHIM and IIEF-6 questionnaire in the office before seed implantation, and at a mean interval of 6 and 12 months after seed implantation. The data of all patients were entered into the database of the Prostate Cancer Registry of Cleveland Clinic to ensure appropriate follow-up.

There were 31 patients in the early PDE-5i group and 38 in the no-PDE-5i group; the former group were self-selected and not randomized, who desired treatment with an oral medication. None had received any concurrent form of therapy for their ED or had any contraindications for the use of sildenafil (e.g. ischaemic cardiovascular disease and use of oral, sublingual, or transdermal nitrates).

Daily sildenafil (25–50 mg) was advised after starting PB (immediately after seed implantation) for 12 months; patients were advised to take sildenafil at bed time. Due to financial constraints, patients’ compliance ranged from 16 to 30 doses a month. If sexually active, patients were instructed to take one sildenafil dose (50–100 mg) ≈1 h before sexual activity, as per the product insert, and to engage in adequate and typical foreplay before attempting sexual intercourse.

All the patients’ sexual responses were assessed using the SHIM and IIEF-6 questionnaire. We compared SHIM and IIEF-6 scores in men in the two groups at baseline, 6 and 12 months, using Wilcoxon matched-pairs test for within groups and between groups using the Mann–Whitney U-test.

RESULTS

Overall, for the entire group, the mean (range) PSA level was 6.8 (0.9–18.8) ng/mL; 78% had Gleason 6 cancer and 20% had Gleason 7 (3 + 4) cancer. The mean (range) age in the early PDE-5i group was 64.8 (49–70) years and in the no-PDE-5i group was 66.0 (53–74) years. The mean radiation dose in the early PDE-5i group was 50.2 Gy and in the no-PDE-5i group was 43.9 Gy. There were no significant differences in mean patient age, radiation dose, comorbidity profile, and mode of technique of administrating PB.

In the no-PDE-5i group the mean (range) baseline SHIM score of 17.1 (8–23) decreased rapidly to 9.1 (8–21) at 6 months (P= 0.01) and stayed at 9.3 (8–21) at 12 months (P= 0.01). In the early PDE-5i group, the mean baseline SHIM score of 21.8 (9–25) decreased slightly to 17.6 (9–24) at 6 months (P= 0.2) and was maintained at 17.9 (9–24) at 12 months (P= 0.2). The 6- and 12-month SHIM scores in the early PDE-5i group were significantly different from the no-PDE-5 group (Wilcoxon rank-sum test, P < 0.001). The IIEF-6 questionnaire confirmed the SHIM analysis (Table 2).

Table 2. 
The demographic details, and SHIM and IIEF-6 scores after PB, in the early PDE-5i and no-PDE-5i groups
Mean (sd) variableEarly PDE-5i (31)No-PDE-5i (38)
  • *

    P= 0.2, 6/12 months vs baseline;

  • P= 0.2, 6/12 months vs baseline;

  • P= 0.01, 6/12 months vs baseline;

  • P= 0.01 6/12 months vs baseline.

Age, years64.8 (5.1)66.0 (5.3)
PB dose, Gy50.2 (12.9)43.9 (11.5)
SHIM score  
 Baseline21.8 (3.7)17.1 (5.3)
 6-month17.6 (4.2)*9.1 (4.7)
 12-month17.9 (4.0)*9.3 (4.7)
IIEF-6  
 Baseline26.0 (4.3)21.3 (5.6)
 6-month 21.7 (4.3) 11.5 (5.4)
 12-month 21.8 (4.4) 11.2 (5.7)

DISCUSSION

PB using 125I or 103Pd seed implantation has been an increasingly popular method for treating prostate cancer, with excellent 10-year biochemical control rates for low-stage disease [12,13]. In addition to the favourable biochemical outcome, PB has been attractive to patients because of its low major complication rate, specifically, urinary stress incontinence and severe ED, a well-known side-effect of treatment for localized prostate cancer, regardless of the treatment used. Only recently have cancer reviews on PB reported potency rates as an outcome measure.

When analysing erectile function after PB, various authors reported potency rates of 32–76% (Table 1) [1–6]. Only recent studies [1,2] used a validated questionnaire to assess this outcome. Merrick et al. [2] reported a 3-year overall potency rate of 50.5% in 128 patients after PB, with a mean time for the onset of ED of 5.4 months. In selected patients with an IIEF score before implantation of 29–30, they reported preservation of potency in 78.8% of the patients [2]. In another series, Stone et al. [1] reported a 7-year overall potency rate of 50.6%. When their data were stratified by age, 84% of patients aged <60 years with good erectile function before PB had preserved potency at 7 years, with a sexual function score equivalent to baseline. In those aged 60–70 years, 60% of the patients with good initial erectile function had a sexual function score equivalent to baseline, and in those aged >70 years, 40% with good initial function had a sexual score equivalent to baseline. That study shows the importance of age and initial erectile function in predicting a patient’s erectile function and sexual satisfaction after PB. These 7-year results on erectile function are significant when compared to other treatment options (i.e. robotic or retropubic RP, cryotherapy, intensity modulated RT). There are few, if any, long-term studies reporting potency rates with these other treatments for prostate cancer. Due to the discrepancy in short-term reports and unknown long-term morbidity of these other treatments on erectile function, more younger patients are choosing PB (monotherapy) as their minimally invasive treatment of choice. These data also suggest that any deterioration in ED after PB appears to occur earlier rather than later in the recovery process, providing an opportunity for early rehabilitation after implantation.

An emerging concept is the importance of penile rehabilitation after RP. This theory suggests that early use of erectile aids, including PDE-5i, helps to preserve healthy erectile tissue, leading to improved erectile function after surgery [10,14]. Schwarz et al. [14] analysed the cavernous smooth muscle content in patients after RP; they concluded that early use of sildenafil (50 mg daily) after RP preserves the smooth muscle content, and at higher doses (100 mg daily) it increases the smooth muscle content. The benefit of early sildenafil was described by Padma-Nathan et al. [10]; they reported that 2 months after taking sildenafil, 27% of patients had natural erections sufficient for intercourse, compared to 4% in the placebo group. We also reported the benefit of early intraurethral alprostadil, vacuum erection devices, and penile injections after RP [15–17].

Overall, the circumstantial or indirect evidence from many studies is that early intervention can improve sexual activity, improve the return of natural spontaneous erections, and can improve, at least marginally (10–25%), the return of natural erections sufficient for vaginal penetration or vaginal intercourse. Unfortunately, the available clinical data are derived from several small studies with relatively few patients, and often not randomized.

Considering the above results of early intervention after RP, we hypothesised that using oral PDE-5i soon after PB might help to preserve the endothelium of the erectile tissue, and to preserve penile blood flow. As seen in the present study, erectile function usually deteriorates in the first 6–12 months. This was confirmed by Merrick et al. [2], who reported that the mean onset of ED was at 5.4 months. We used this window of opportunity and hypothesised that the use of PDE-5i immediately after PB might decrease the early onset of ED. In the present study, the early PDE-5i group had significantly higher SHIM scores than those who were not treated, at both 6 and 12 months. We choose to use a daily dose of 25–50 mg sildenafil for 1 year; whether this is the optimum dose or treatment period is unclear.

Our data suggest that the first 6 months after PB are very important for potency outcomes; this is the period when fibrotic changes and penile atrophy might occur. In addition to using PDE-5i, it might also be an opportunity to preserve penile length and girth. Unpublished data suggest that there is a significant decrease in penile length and girth in the first 6–12 months. Currently, we have ongoing research to use a vacuum constriction device to preserve length and girth, in addition to using early PDE-5i to help preserve erectile function and rigidity.

Our study is limited by the retrospective, non-randomized sample of patients; also, all patients were treated with 125I, so the findings might not be applicable to patients treated with other radioactive isotopes or who have had combined PB and EBRT. Finally, all patients were treated by a one surgeon with extensive and long-standing experience in PB.

In conclusion, ED is an important complication and outcome measure after treatment for localized prostate cancer. As the mean age decreases with the earlier diagnosis, reporting sexual outcomes becomes more important in decision making. While sexual outcomes after PB are generally very good, our data indicate a 50% decrease in the quality of erections. This provides a potential window of opportunity to initiate early intervention with PDE-5I, or perhaps vacuum constriction devices or intraurethral alprostadil. Our data using a daily PDE-5i after PB show that early oral pharmacology can prevent the subsequent loss in sexual satisfaction often apparent after PB.

CONFLICT OF INTEREST

None declared.

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