Exploratory Decision-Tree Modeling of Data from the Randomized REACTT Trial of Tadalafil Versus Placebo to Predict Recovery of Erectile Function After Bilateral Nerve-Sparing Radical Prostatectomy.

Understanding predictors for the recovery of erectile function (EF) after nerve-sparing radical prostatectomy (nsRP) might help clinicians and patients in preoperative counseling and expectation management of EF rehabilitation strategies. To describe the effect of potential predictors on EF recovery after nsRP by post hoc decision-tree modeling of data from A Study of Tadalafil After Radical Prostatectomy (REACTT). Randomized double-blind double-dummy placebo-controlled trial in 423 men aged <68 yr with adenocarcinoma of the prostate (Gleason ≤7, normal preoperative EF) who underwent nsRP at 50 centers from nine European countries and Canada. Postsurgery 1:1:1 randomization to 9-mo double-blind treatment with tadalafil 5mg once a day (OaD), tadalafil 20mg on demand, or placebo, followed by a 6-wk drug-free-washout, and a 3-mo open-label tadalafil OaD treatment. Three decision-tree models, using the International Index of Erectile Function-Erectile Function (IIEF-EF) domain score at the end of double-blind treatment, washout, and open-label treatment as response variable. Each model evaluated the association between potential predictors: presurgery IIEF domain and IIEF single-item scores, surgical approach, nerve-sparing score (NSS), and postsurgery randomized treatment group. The first decision-tree model (n=422, intention-to-treat population) identified high presurgery sexual desire (IIEF item 12: ≥3.5 and <3.5) as the key predictor for IIEF-EF at the end of double-blind treatment (mean IIEF-EF: 14.9 and 11.1), followed by high confidence to get and maintain an erection (IIEF item 15: ≥3.5 and <3.5; IIEF-EF: 15.4 and 7.1). For patients meeting these criteria, additional non-IIEF-related predictors included robot-assisted laparoscopic surgery (yes or no; IIEF-EF: 19.3 and 12.6), quality of nerve sparing (NSS: <2.5 and ≥2.5; IIEF-EF: 14.3 and 10.5), and treatment with tadalafil OaD (yes and no; IIEF-EF: 17.6 and 14.3). Additional analyses after washout and open-label treatment identified high presurgery intercourse satisfaction as the key predictor. Exploratory decision-tree analyses identified high presurgery sexual desire, confidence, and intercourse satisfaction as key predictors for EF recovery. Patients meeting these criteria might benefit the most from conserving surgery and early postsurgery EF rehabilitation. Strategies for improving EF after surgery should be discussed preoperatively with all patients; this information may support expectation management for functional recovery on an individual patient level. Understanding how patient characteristics and different treatment options affect the recovery of erectile function (EF) after radical surgery for prostate cancer might help physicians select the optimal treatment for their patients. This analysis of data from a clinical trial suggested that high presurgery sexual desire, sexual confidence, and intercourse satisfaction are key factors predicting EF recovery. Patients meeting these criteria might benefit the most from conserving surgery (robot-assisted surgery, perfect nerve sparing) and postsurgery medical rehabilitation of EF. ClinicalTrials.gov, NCT01026818.

Montorsi F ，Oelke M ，Henneges C ，Brock G ，Salonia A ，d'Anzeo G ，Rossi A ，Mulhall JP ，Büttner H ... -  《-》

Effects of tadalafil treatment on erectile function recovery following bilateral nerve-sparing radical prostatectomy: a randomised placebo-controlled study (REACTT).

The potential rehabilitative and protective effect of phosphodiesterase type 5 inhibitors (PDE5-Is) on penile function after nerve-sparing radical prostatectomy (NSRP) remains unclear. The primary objective was to compare the efficacy of tadalafil 5mg once daily and tadalafil 20mg on demand versus placebo taken over 9 mo in improving unassisted erectile function (EF) following NSRP, as measured by the proportion of patients achieving an International Index of Erectile Function-Erectile Function domain (IIEF-EF) score ≥ 22 after 6-wk drug-free washout (DFW). Secondary measures included IIEF-EF, Sexual Encounter Profile question 3 (SEP-3), and penile length. Randomised, double-blind, double-dummy, placebo-controlled trial in men ≤ 68 yr of age with adenocarcinoma of the prostate (Gleason ≤ 7) and normal preoperative EF who underwent NSRP at 50 centres from nine European countries and Canada. 1:1:1 randomisation to 9 mo of treatment with tadalafil 5mg once daily, tadalafil 20mg on demand, or placebo followed by a 6-wk DFW and 3-mo open-label tadalafil once daily (all patients). Logistic regression, mixed-effects model for repeated measures, and analysis of covariance, adjusting for treatment, age, and country, were applied to IIEF-EF scores ≥ 22, SEP-3, and penile length. Four hundred twenty-three patients were randomised to tadalafil once daily (n=139), on demand (n=143), and placebo (n=141). The mean age was 57.9 yr of age (standard deviation: 5.58 yr); 20.9%, 16.9%, and 19.1% of patients in the tadalafil once daily, on demand, and placebo groups, respectively, achieved IIEF EF scores ≥ 22 after DFW; odds ratios for tadalafil once daily and on demand versus placebo were 1.1 (95% confidence interval [CI], 0.6-2.1; p=0.675) and 0.9 (95% CI, 0.5-1.7; p=0.704). At the end of double-blind treatment (EDT), least squares (LS) mean IIEF-EF score improvement significantly exceeded the minimally clinically important difference (MCID: ΔIIEF-EF ≥ 4) in both tadalafil groups; for SEP-3 (MCID ≥ 23%), this was the case for tadalafil once daily only. Treatment effects versus placebo were significant for tadalafil once daily only (IIEF-EF: p=0.016; SEP-3: p=0.019). In all groups, IIEF-EF and SEP-3 decreased during DFW but continued to improve during open-label treatment. At month 9 (EDT), penile length loss was significantly reduced versus placebo in the tadalafil once daily group only (LS mean difference 4.1mm; 95% CI, 0.4-7.8; p=0.032). Tadalafil once daily was most effective on drug-assisted EF in men with erectile dysfunction following NSRP, and data suggest a potential role for tadalafil once daily provided early after surgery in contributing to the recovery of EF after prostatectomy and possibly protecting from penile structural changes. Unassisted EF was not improved after cessation of active therapy for 9 mo. ClinicalTrials.gov identifier NCT01026818.

Montorsi F ，Brock G ，Stolzenburg JU ，Mulhall J ，Moncada I ，Patel HR ，Chevallier D ，Krajka K ，Henneges C ，Dickson R ，Büttner H ... -  《-》

Effects of Tadalafil Once-Daily or On-Demand vs Placebo on Return to Baseline Erectile Function After Bilateral Nerve-Sparing Radical Prostatectomy--Results from a Randomized Controlled Trial (REACTT).

The multicenter, randomized, double-blind, double-dummy, placebo-controlled REACTT trial suggested that treatment with tadalafil once daily (OaD) started early after bilateral nerve-sparing radical prostatectomy (nsRP) for prostate cancer may contribute to erectile function (EF)-recovery, which was predefined as achieving an International Index of Erectile Function (IIEF)-EF score ≥22. Here, we report descriptive post-hoc analyses, using the more strict definition for EF-recovery of returning back to the pre-surgery IIEF-EF-level ("back-to-baseline analysis"). REACTT included 422 men <68 years with adenocarcinoma of the prostate and preoperative IIEF-EF ≥22 who underwent nsRP at 50 centers from 9 European countries and Canada. Patients were randomized post-nsRP 1:1:1 to 9-month double-blind treatment (DBT) with tadalafil 5 mg OaD (n = 139), tadalafil 20 mg on-demand (pro-re-nata, PRN; n = 142), or placebo (n = 141), followed by 6-week drug-free washout (DFW) and 3-month open-label tadalafil OaD treatment (OLT). Proportion of patients returning to their preoperative IIEF-EF category (22-25 or ≥26) at the end of DBT, DFW, and OLT. Overall, 92.4% of patients had pre-surgery (baseline) IIEF-EF scores ≥26 (tadalafil OaD 94.2%, PRN 91.6%, placebo 91.5%), 7.4% had IIEF-EF 22-25. At the end of DBT, 22.3% of patients on tadalafil OaD had achieved "back-to-baseline" IIEF-EF, compared with 11.3% on tadalafil PRN and 7.8% on placebo. Of all 58 patients "back-to-baseline" at the end of DBT, only 1 PRN-group patient had started from a baseline IIEF-EF <26. The treatment-group difference at the end of DBT was not maintained after DFW. After 3 months of OLT with tadalafil OaD, the proportion of patients with "back-to-baseline" IIEF-EF had almost doubled in all 3 groups. Changing the definition for EF-recovery from IIEF-EF ≥22 to the more strict definition of "returning back-to-baseline IIEF-EF" had no major impact. Tadalafil OaD started early after nsRP improved drug-assisted EF, but had no effect on unassisted EF following treatment cessation after 9 months.

Mulhall JP ，Brock G ，Oelke M ，Fode M ，Probst KA ，Henneges C ，d'Anzeo G ，Rossi A ，Büttner H ... -  《-》

Effect of surgical approach on erectile function recovery following bilateral nerve-sparing radical prostatectomy: an evaluation utilising data from a randomised, double-blind, double-dummy multicentre trial of tadalafil vs placebo.

To report pre-specified and exploratory results on the effect of different surgical approaches on erectile function (EF) after nerve-sparing radical prostatectomy (nsRP) obtained from the multicentre, randomised, double-blind, double-dummy REACTT trial of tadalafil (once a day [OaD] or on-demand [pro-re-nata, PRN]) vs placebo. Patients aged <68 years with normal preoperative EF who underwent nsRP for localised prostate cancer (Gleason ≤7, prostate-specific antigen [PSA] <10 ng/mL) were randomised after nsRP 1:1:1 to 9-month double-blind treatment with tadalafil 5 mg OaD, tadalafil 20 mg PRN, or placebo, followed by 6-week drug-free washout, and 3-month open-label OaD treatment (all patients). Recovery of EF was defined as an International Index of Erectile Function (IIEF)-EF domain score of ≥22 and normal orgasmic function was defined based on IIEF Question 10. Both parameters were analysed at the end of washout using logistic regression including terms for treatment, country, visit, visit-by-treatment interaction, age group, nerve-sparing score (perfect = 2, non-perfect >2), and surgical approach (open surgery, robot-assisted laparoscopy, conventional laparoscopy, other). Time to EF recovery was analysed post hoc with a Cox proportional-hazards model including terms for treatment, age-group, country, surgical approach and surgery-by-treatment interaction. Of 422 patients treated, 189 underwent open surgery, 115 robot-assisted laparoscopy, 88 conventional laparoscopy and 30 surgery classified as 'other'. The odds of achieving EF recovery at the end of drug-free washout were about twice as high for the robot-assisted laparoscopy group compared with the open surgery group (odds ratio 2.42; 95% confidence interval [CI] 1.24, 4.72; P = 0.029). Patients who underwent robot-assisted laparoscopy were significantly more likely to recover during double-blind treatment compared with patients who underwent open surgery (hazard ratio 1.92; 95% CI 1.17, 3.15; P = 0.010). No favourable effect of conventional laparoscopy compared with open surgery could be seen. These results may provide further insights into the role of surgery on EF recovery after nsRP. However, the trial was not designed for these analyses and further prospective studies are needed.

Stolzenburg JU ，Graefen M ，Kriegel C ，Michl U ，Martin Morales A ，Pommerville PJ ，Manning M ，Büttner H ，Henneges C ，Schostak M ... -  《-》

Nightly vs on-demand sildenafil for penile rehabilitation after minimally invasive nerve-sparing radical prostatectomy: results of a randomized double-blind trial with placebo.

To clarify the role of phosphodiesterase type 5 (PDE5) inhibitors in post-prostatectomy penile rehabilitation (PPPR). To compare nightly and on-demand use of PDE5 inhibitors after nerve-sparing minimally invasive radical prostatectomy (RP). We conducted a single-institution, double-blind, randomized controlled trial of nightly vs on-demand 50-mg sildenafil citrate after nerve-sparing minimally invasive RP. A total of 100 preoperatively potent men, aged <65 years, with scores on the Erectile Function domain of the International Index of Erectile Function (IIEF-EF) ≥26, underwent nerve-sparing surgery. The patients were randomized to either nightly sildenafil and on-demand placebo (nightly sildenafil group), or on-demand sildenafil and nightly placebo (on-demand sildenafil group; maximum on-demand dose six tablets/month) for 12 months. Patients then underwent a 1-month washout period. Validated measures of erectile function (IIEF-EF score and the Expanded Prostate Cancer Index Composite [EPIC]) were compared between treatment groups over the entire 13-month time course, using multivariable mixed linear regression models. The treatment groups were well matched preoperatively (mean age 54.3 vs 54.6 years, baseline IIEF-EF score 29.4 vs 29.3, for the nightly vs the on-demand sildenafil groups, respectively). No significant differences were found in erectile function between treatments (nightly vs on-demand sildenafil) at any single timepoint after RP, after adjusting for potential confounding factors. When evaluated over all timepoints simultaneously, no significant effects of treatment group (nightly vs on-demand sildenafil) were found on recovery of potency, as assessed by absolute IIEF-EF scores (P = 0.765), on percentage of men returning to an IIEF-EF score >21 (P = 0.830), or on IIEF-EF score recovery to a percentage of baseline value (P = 0.778). When evaluated over all timepoints simultaneously, no significant effects of treatment group were found on secondary endpoints such as assessment of potency (including EPIC item 59 response 'erections firm enough for intercourse'), attempted intercourse frequency or confidence. Erectile recovery up to 1 year after RP does not differ between previously potent men who use sildenafil nightly compared to on-demand. This trial does not support chronic nightly sildenafil as being any better than on-demand sildenafil for use in penile rehabilitation after nerve-sparing minimally invasive RP.

Pavlovich CP ，Levinson AW ，Su LM ，Mettee LZ ，Feng Z ，Bivalacqua TJ ，Trock BJ ... -  《-》