Patel HD, Schwen ZR, Campbell JD et al: Effect of erythropoietin on erectile function after radical prostatectomy: the ERECT randomized clinical trial. J Urol 2021; doi: 10.1097/JU.0000000000001586.

While survival outcomes are generally excellent for patients diagnosed with clinically localized prostate cancer, functional outcomes are more variable. Optimization of the bilateral nerve-sparing approach has enabled erectile function recovery for patients undergoing radical prostatectomy, and urologists have several management options for post-surgical erectile dysfunction to help patients after definitive cancer treatment. However, the goal of further impacting the natural history of erectile dysfunction after radical prostatectomy has remained elusive.

Even with bilateral nerve-sparing radical prostatectomy, some degree of crush, stretch, or thermal injury may occur to the neurovascular bundles with known variation in outcomes between providers.¹ Several groups have recently turned to evaluating agents or strategies that could have neuroprotective effects on the periprostatic structures. Preclinical studies on erythropoietin found the glycosylated cytokine hormone to have receptor expression in both human penile tissue as well as the neurovascular bundles.² Followup evaluations showed promise in a rat cavernous nerve injury model and on retrospective evaluation for use in humans.^3,4 Based on these findings, we designed and pursued ERECT (NCT00737893) as a phase 2, double blinded, placebo-controlled randomized clinical trial to evaluate the efficacy and safety of perioperative erythropoietin to enhance erectile function recovery after radical prostatectomy.^5,6

A total of 56 patients without baseline erectile dysfunction scheduled to undergo radical prostatectomy were randomized to arms receiving erythropoietin (29) or placebo (27). Subcutaneous injections of 20,000 units of erythropoietin or a saline placebo were given the day before, day of, and day after radical prostatectomy, of which most patients received a robotic approach (50). The primary outcome of interest was International Index of Erectile Function (IIEF)-erectile function (EF) domain score at 6 months after surgery, with secondary outcomes evaluated by several other validated survey instruments for up to 12 months after surgery.

Notably, median IIEF-EF scores nearly doubled from 12.5 at 3 months after surgery to 24.5 at 12 months, and there was an increase in 2-week serum hemoglobin values in the erythropoietin arm compared to the placebo arm, as would be expected. However, there were no statistically significant differences in IIEF-EF scores at any time point evaluated (see figure). Other patient-reported outcomes were also similar during followup, including urinary function, mental health component scores, and physical health component scores.

Figure. Select patient-reported outcomes evaluated in the ERECT trial, including International Index of Erectile Function-Erectile Function Domain (IIEF-EF; primary outcome), American Urological Association Symptom Index (AUA-SI), 12-Item Short Form Health Survey (SF-12) Mental Component Score (MCS) and SF-12 Physical Component Score (PCS). Mean values with 95% confidence intervals are shown.

The primary factor associated with better IIEF-EF scores was excellent nerve-sparing rating (a rating of 10/10 in 24 patients [43%]), which was associated with a 5.2-point improvement. This is notable as nerve-sparing was still subjectively quite good in the remaining patients (12 [21.4%] had 9/10, 17 [30.4%] had 8/10, and 3 [5.4%] had 6-7/10). Additionally, no safety or oncologic concerns were identified among patients studied, and use of erectile dysfunction therapies did not differ between arms.

While ERECT was a negative trial, it does raise the question of whether alternative dosing regimens or combination with local adjuncts could provide improved efficacy. For example cryopreserved placental membrane is a candidate for local placement during surgery, which may carry tissue, growth, and cellular factors. One retrospective study reported that use of dehydrated human amnion/chorion membrane was associated with improvement in IIEF-5 after radical prostatectomy.⁷

At the same time, our experience indicates that retrospective results in this area should be interpreted with caution. Careful evaluation in a controlled trial setting is necessary prior to routine clinical use to confirm efficacy of sometimes expensive therapies and to inform patients of potential adverse events. Other therapies with promise which did not hold up in randomized trials for recovery of erectile function after radical prostatectomy include sural nerve grafting and hyperbaric oxygen.^8,9 Future clinical studies of neurotrophic agents or targeted agents regulating neural and muscular function, which have been evaluated in preclinical nerve crush injury models,¹⁰ are needed.