Results of a Prospective Randomized Double-blind Placebo Controlled Trial Evaluating the Use Prophylactic Sildenafil Citrate During Radiation Therapy in the Treatment of Prostate Cancer

Reporter: Abigail T. Berman, MD
The Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 30 de octubre del 2012

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Presenting Author: Michael J. Zelefsky, MD
Presenting Author Affiliation: Sloan-Kettering Cancer Center, New York, NY

Purpose/Objective(s)

  • Penile rehabilitation has emerged as an important entity after prostate cancer therapy addressing the potential benefit of preservation of corpus cavernosal endothelial and smooth muscle tissue.
  • Several studies in animal models demonstrated PDE5 inhibitors are potent endothelial protectors for the tissues involved in erectile function (Mullhall et al. J Urol 2002).
  • There was one randomized controlled trial (Montorsi et al. Eur Urol 2008) which randomized RP patients to nightly vardenafil versus placebo and showed spontaneous erections with vardenafil.
  • In contrast to patients undergoing RP where significant component of post-treatment erectile dysfunction could be related to neurogenic dysfunction and injury, the etiology of post-RT ED appears to be related to vascular or arteriogenic dysfunction (Zelefsky and Eid 1998).
  • The purpose of this study was to prospectively evaluate the impact of daily sildenafil with daily radiotherapy compared to placebo.
  • The primary outcome of the trial was to determine if sexual function at 12 and 24 months after therapy was improved with prophylactic daily sildenafil.

Materials/Methods

  • There were 295 patients with clinically localized prostate cancer with a baseline international index of erectile function (IIEF) of greater than 17 treated with external beam radiotherapy and or permanent interstitial brachytherapy were enrolled.
  • Patients were stratified based on treatment (EBRT vs brachy vs EBRT+brachy vs +/- hormone therapy) and based on baseline IIEF score (17-21 vs 22+).
  • Patients were randomized in a 2:1 fashion to daily SC (50 mg) (2x) to placebo (1x). Treatment was initiated 3 days before treatment and continued daily for 6 months, after which the drug therapy was discontinued and taken on an as-needed basis.
  • Patients completed the IIEF, international prostate symptom score (IPSS), and quality of life questionnaires pre-therapy and at 3, 6, 12, 18, and 24 months post-treatment.
  • IIEF domains included erectile function (EF), orgasmic function (OF), sexual desire (SD), intercourse satisfaction (IS), and overall satisfaction (OS).
  • Univariate and multivariate linear regression models were fit to assess the effects of treatment and other variables on post-6-month scores on each scale.
  • Patient characteristics including age, use of brachytherapy, androgen deprivation therapy and baseline IIEF scores were balanced between the treatment groups. 

Results

  • 31 patients received ADT. There were no significant differences in EF scores for patients treated with ADT. These patients were therefore excluded from analysis.
  • Therefore, the authors limited their current analysis is limited to patients who have completed questionnaires at pre-therapy plus at least one post-treatment time-point and who did not receive hormone therapy (n=142). There were no statistically significant differences in the SC vs placebo cohorts with respect to mean baseline IIEF, brachytherapy, smoking, diabetes, or hypertension. 
  • The IIEF overall scores were significantly higher in the SC arm compared to placebo for the duration of the study, including at 24 months (p=0.04) after therapy.
  • Univariate analysis identified that the EF, OS, IIEF total score domains were superior in the SC cohort vs. placebo.
  • Multivariable analysis found that EF EF, OS, and IIEF total score domains continued to be superior in the SC cohort vs. placebo. 

Conclusions

  • This is the first randomized prospective controlled-trial to demonstrate the utility of a PDE5 inhibitor as a rehabilitation strategy in the prostate cancer patients who receive radiation. Daily SC administered during and after radiotherapy for prostate cancer resulted in improved overall sexual function compared to placebo at all time points.
  • When controlled for baseline IIEF and age, there were significant improvements in total IIEF and OS in the SC arm.
  • There was no apparent benefit was noted for patients treated with ADT.
  • Additional randomized trials will be needed to validate these findings.

Clinical Implications

  • This is an important study providing level I evidence to use PDE5 inhibitors to maintain erectile function after radiation. Of note, patients who receive ADT do not benefit from this approach and therefore this study cannot be applied to those patients.
  • Considering the etiology of erectile dysfunction is important when thinking about the clinical utility of PDG5 inhibitors. Erectile dysfunction may be a possible indication of atherosclerosis and increased mortality before radiotherapy. The pathogenesis of radiation-induced ED is not clear. The major mechanism described is vascular injury leading to arterial and venous leak. The decreased oxygenation from this then leads to increased TGF-beta production and cavernosal fibrosis. There is also neural injury leading to decreased neurotransmitters and decreased cGMP. It is not known how PDE5 inhibitors work but one proposed mechanism is vascular or neural protection.
  • The authors did an excellent job of accounting for some confounders (androgen suppression, age, urinary symptoms). There are additional possible confounders that are unmeasured and therefore were not accounted for in this analysis including comorbidities and RT dose to erectile structures.
  • This study is consistent with prior surgical studies of PDE5 inhibitors show that there are increased spontaneous erections with daily or on-demand early prophylactic PDE5 use (Hatzimouratidis Eur Urol 2009).
  • Limitations of this study include:
    • We do not have information on radiation treatment method including modality (3D CRT vs IMRT) or dose. We also do not have dosimetric data to the penile bulb or neurovascular structures which may be the targets in RT-induced ED.
    • Sildenafil has a half life of only 4 hours but was dosed once daily dosing. This may not be the idea dosing schedule. Likewise, perhaps a different PDG inhibitor with a longer half-life would be beneficial.
  • PDE5 inhibitors are known to cause cardiac risk. Patients who have low cardiac risk and no ED should be put on PDE5 inhibitors, however, if they have a higher cardiac risk, their cardiologist should be consulted and the pros and cons should be carefully considered.
  • This study represents a new standard for patients with erectile function and low cardiac risk who undergo radiotherapy. This finding should still be validated in other prospective trials.



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