Effects of tadalafil treatment after bilateral nerve-sparing radical prostatectomy: quality of life, psychosocial outcomes, and treatment satisfaction results from a randomized, placebo-controlled phase IV study

Any major surgery is expected to reduce overall patient QoL during the initial stages of healing and rehabilitation, this is enhanced by the psychosocial impact of a cancer diagnosis. Patients after nsRP face additional challenges, namely impaired EF and urinary continence, which may continue to affect their QoL long after the initial healing phase is complete [ 17, 18]. This can be particularly difficult for younger patients who may be more sexually active than the elderly population. Patients are faced with a long period of time during which sexual and urinary function is not entirely regained, substantially impacting QoL not only for the patients recovering from nsRP but also for their partners [ 19].

As reported previously, 9 months of DBT with tadalafil OaD, but not tadalafil PRN, significantly increased and accelerated EF recovery when compared with placebo [ 9, 20]; improvements in IIEF-EF and SEP-3 exceeded the minimum clinically relevant difference (MCID) [ 9]. Treatment with tadalafil OaD treatment was well tolerated; no new safety signals were detected in the prostate cancer patient population [ 9]. This analysis evaluated if tadalafil treatment affected the patients’ perceived QoL in terms of sexual function and urinary incontinence, as assessed by the respective EPIC domain scores. During DBT, IIEF-EF, EPIC sexual domain score, and EDITS score improved with tadalafil OaD versus placebo but not with tadalafil PRN (Figure  2). This may be due to chronic (daily) tadalafil dosing that would lead to steady-state PDE5-inhibition [ 21] and may be associated with prolonged (continuous) periods of increased tissue oxygenation during the post-operative regenerative process.

During DBT, patient-rated EPIC sexual domain scores improved in all 3 treatment groups by 27.5% with tadalafil OaD, 20.7% with tadalafil PRN, and 18.0% with placebo. As for IIEF-EF and SEP-3 [ 9], the improvement was statistically significant versus placebo (p = 0.004) in the tadalafil OaD group only.

The LS mean difference in EPIC sexual domain score changes between tadalafil OaD and placebo was 3.2 points; there is currently no general consensus on how to define the MCID for EPIC domain scores. During the 3 months of additional OLT with tadalafil OaD, EPIC sexual domain scores continued to improve, with overall improvements of more than 30% from baseline to the end of OLT in all 3 groups. The significant treatment group differences from DBT were not maintained as all groups received active tadalafil OaD during OLT.

A significant age group-by-treatment interaction (p = 0.084) indicated that in older patients only (61–68 years of age), EPIC urinary incontinence scores also significantly improved with tadalafil OaD compared with placebo (no significant effect with PRN). The effect was not observed in younger patients (<61 years of age), potentially because they were less affected by urinary incontinence symptoms. There are currently competing hypotheses for the etiology of post-prostatectomy incontinence [ 22]. Apart from the experience of the surgeon and the surgical technique employed, the most relevant pre-operative predictors of urinary incontinence following robot-assisted nsRP as identified by a meta-analysis included age, body mass index (BMI), comorbidity index, lower urinary tract symptoms, and prostate volume [ 23]. Urinary incontinence after nsRP is known to be a long-term complication. In the prostate cancer outcome study, 8.4% of all patients were incontinent at ≥18 months after nsRP, even more (14%) had urinary incontinence symptoms after 5 years [ 12, 17]. In a recent study by Nam et al. approximately 5% of patients required incontinence surgery within 15 years post-nsRP [ 24]. In both studies, the risk for late urinary complications post-nsRP also increased with age [ 17, 24]. In the elderly patients, a fair correlation between EPIC urinary and sexual domain scores (highest at baseline: r = 0.39) was observed in the current study.

Several clinical trials show that PDE5 inhibitors, including tadalafil OaD, can reduce lower urinary tract symptoms in patients with benign prostate hyperplasia [ 25- 27]. A positive effect for PDE5 inhibitors on urinary continence following nsRP was initially observed in a retrospective study by Gandaglia et al. [ 28]. More recently, Gacci et al. reported significantly improved urinary continence in patients using vardenafil (nightly) compared with placebo in a prospective 12-month study (39 patients) [ 29].

It is not fully understood how PDE5 inhibitors might act to improve bladder function, although improvements in sphincteric and/or pelvic floor blood supply could be responsible for this effect [ 28, 29]. Moreover, the human bladder expresses high levels of PDE5, inhibition of which can modulate bladder contractility through induction of cyclic guanosine monophosphate [ 29, 30]. The correlation between EPIC urinary incontinence and sexual domain scores decreased over time, potentially due to a differential improvement of sexual and urinary scores.

The perception of the partner during couples’ sexual recovery after nsRP has not been extensively studied, although partners’ needs should be addressed as legitimate aspect of patient care [ 31]. In this study, only 33.2% of patients’ partners completed the EPIC questionnaire, no clear pattern of patient-partner agreement could be derived. Findings in other studies have indicated that partner QoL can be negatively impacted for at least as long as a patient’s QoL following prostate cancer treatment [ 19, 32].

Although significant improvements in the EPIC sexual and urinary incontinence domains were only observed for tadalafil OaD treatment, treatment satisfaction at the end of DBT, as measured by the EDITS questionnaire, was significantly improved following both tadalafil OaD and PRN administration relative to placebo. However, at the end of OLT, improvement in treatment satisfaction was only significant for tadalafil OaD versus placebo.

There were several potential limitations of the current study. One important consideration is that the patient group selected may not have been ideal for observing an effect on EF or urinary incontinence with chronic tadalafil administration. Patients were on average relatively young (58 years of age), sexually active, and had few comorbidities, thus possibly representing a population of patients who might have shown improvement of EF and urinary continence rates after nsRP without treatment [ 33]. This could result in dilution of an effect of tadalafil on QoL, and might explain why tadalafil OaD administration significantly improved EPIC urinary incontinence domain scores versus placebo in the elderly population (61 to 68 years) only. Thus, future studies with different patient populations (older, less fit) could help clarify the effect of tadalafil OaD treatment on QoL in post-nsRP patients.

Additional limitations were imposed by the study design. First, the 9-month DBT period may have been too short for optimal assessment of EF recovery, sexual function, urinary incontinence, and associated QoL. After 9 months of DBT, low EF recovery rates of 25.2%, 19.7%, and 14.2% for tadalafil OaD, tadalafil PRN, and placebo, respectively, were observed [ 9]. In contrast, a retrospective study from Briganti et al. found 3-year EF recovery rates following nsRP of 72% in patients receiving PDE5 inhibitors versus 38% in patients receiving placebo [ 1], and a recent sildenafil study found recovery rates of around 40% following 12 months of treatment [ 34]. Second, EPIC scores were not assessed at the end of the drug-free washout period, but only at the end of DBT and OLT. Thus, sexual function and urinary incontinence after treatment cessation could not be assessed. Also, no valid conclusions are possible regarding the patient-partner agreement for EPIC domain scores since only one-third of the partners completed the questionnaire. Finally, the only source for the data on urinary incontinence was the respective EPIC domain score. EPIC data were collected to evaluate patients’ disease-specific QoL; standard instruments for assessment of urinary function, such as the International Prostate Symptom Score might be better suited to evaluate the impact of PDE5 inhibitor treatment on urinary function.