Proerectile pharmacological prophylaxis following nerve-sparing radical prostatectomy (NSRP)

Abstract

The importance of an early pharmacological prophylaxis for erectile function following nerve-sparing radical prostatectomy has been recently stressed by several authors. In spite of that, patient's compliance to erectile rehabilitation protocols seems to be low. The present review is an attempt to define the expected benefits of the currently proposed rehabilitative protocols in terms of cost-efficiency and quality of life. The conclusion is that current scientific evidence in support of an early postoperative use of erectile aids is based mainly on indirect proof of a cavernosal damage that may follow the temporary postoperative ‘erectile silence’. Intracavernosal injections or a vacuum device may represent the best first-line treatment option for the first few months from the procedure as their mechanism of action does not require intact neural tissue for erection. Thereafter oral phosphodiesterase 5 inhibitor therapy may be a reasonable choice for those patients who can achieve at least a partial erection. A phosphodiesterase 5 inhibitor may not be effective when spontaneous erections are absent. It is possible, since the rehabilitation of sexual function aims to prevent cavernosal tissue damage by providing oxygenation to the erectile tissue, the choice of a potentially ineffective treatment may jeopardize the results of a reasonable nerve-sparing procedure.

Introduction

Since the landmark study of Montorsi et al1 reporting a significantly higher recovery rate of spontaneous erections in patients who had undergone a nerve-sparing radical prostatectomy (NSRP) following early institution of postoperative PGE1 injections, urologists have increasingly advised some form of ‘erectile rehabilitation’ in order to maximise the return of normal sexual function. It has been hypothesised that the temporary erectile dysfunction that occurs even when the cavernosal nerves are scrupulously preserved may result in a hypoxia-induced fibrosis of the cavernosal tissue with subsequent permanent erectile dysfunction (ED). The importance of an early postoperative pharmacological prophylaxis has been recently stressed by the same author.2 In spite of that, patient's compliance to erectile rehabilitation protocols may be low as documented by the relatively high rates of postprostatectomy patients that discontinue treatment for sexual dysfunction.3 It seems appropriate therefore to attempt to define the expected benefits of the currently proposed rehabilitative protocols in terms of cost-efficiency and quality of life.

Patients bother for sexual function after NSRP

In one study, patients with ED after radical prostatectomy have been found to have better disease-specific quality of life than a matching group of ED patients with no history of prostate cancer.4 The former are probably more likely to accept with stoicism sexual dysfunction acquired after having received a potentially curative treatment for cancer. In another study, patients who were more bothered by sexual function after radical prostatectomy would not trade much of their current lifespan to regain sexual function.5 However, the fact that patients can live with their sexual dysfunction and would elect the same treatment for prostate cancer does not mean their quality of life is totally unaffected. By comparing sexual function after non-nerve-sparing and NS surgery, Gralnek et al6 reported that the latter had significantly better postoperative quality of life scores in regard to both sexual and physical function. More recent studies have explored the meaning of ‘sexual dysfunction’ after radical prostatectomy and noted several aspects of health-related quality of life being affected including sexual intimacy, everyday interaction with women and men's perception of their masculinity.7 The negative impact of sexual bother on quality of life may become even more marked at a longer time from the operation. In the study by Penson et al8 sexual dysfunction was an independent determinant of worse general health-related quality of life at 2 y from primary treatment for prostate cancer.

The current literature has shown a closer linkage between sexual dysfunction and quality of life in NSRP patients, making the recovery of sexual function an important issue for patients surgically treated for prostate cancer.

Has erectile rehabilitation improved overall potency rates of NSRP so far?

The proportion of individuals who experience complete recovery of erectile function following bilateral anatomical preservation of neurovascular bundles during NSRP remains a matter of debate, but probably does not occur in more than 50% or so of patients overall. A further 25% reduction is expected if only one neurovascular bundle can be spared at the time of surgery. Age and preoperative sexual functioning are also independent predictors of postoperative ED.9 Outstanding postoperative potency rates varying from 86 to 62% seem to be confined to few centres of excellence.10, 11 The success rate of the procedure drops to 44% in a large retrospective survey of nonspecialists12 and fall to 21% in a single institutional prospective series assessing preoperative and postoperative outcomes with validated questionnaires.13 Differences in surgical technique, outcome measurements and follow-up duration have been advocated to explain these discrepancies, but none of the reported studies mentions whether the patients had undergone specific erectile rehabilitation treatment during the follow-up. It is of note, however, that the only series where patients were counselled to start a pharmacological erectile treatment as early as the second postoperative month gave the best results of potency recover at 24 months.10

The most recent series have concentrated on the results of nerve preservation following laparoscopic radical prostatectomy showing success rates comparable to open surgery.14 In the study by Katz et al15 patients were deliberately asked not to undertake any postoperative erectile rehabilitation and despite that a high potency preservation rate was observed.15

As yet data on the efficacy of early postoperative erectile treatment rely on few randomised trials. In the study of Montorsi et al1 recovery of spontaneous erection occurred at 6 months in 67% of 12 patients who self-injected with PGE vs 20% of 15 patients who did not. More recently, 27% of 51 preoperatively potent patients taking sildenafil at bedtime for 9 months regained potency 1 y after surgery vs only 4% in the control group.16 As the natural recovery of erectile function has been reported to take as long as 24 months,17 it is possible that the erectile rehabilitation may simply bring forward the natural ‘healing’ time of the erectile function rather than saving patients from a permanent erectile failure. Larger randomised trials with a minimum 2-y follow-up are required before a definite conclusion on the true efficacy of sexual therapy in this context can be drawn.

Is there scientific evidence to support early rehabilitation of erectile function?

Spontaneous erectile function is absent for the majority of NSRP patients in the early postoperative period but a progressive return is observed over a 2-y period in a variable proportion of cases. This observation has led to the hypothesis of the so-called ‘neuropraxia’ phenomenon, that is a temporary deficit of the cavernous nerves, which would abolish any form of erection. The low oxygen tensions in a constantly flaccid penis may switch on severe fibrotic changes in the cavernosal tissue. In a recent experimental model, penile tissue from rats undergone bilateral incision of cavernosal nerves 3 months earlier showed a significant overexpression of hypoxia-related substances like TGF-beta and collagen I and III compared with the same tissue from a control group.18 Using a similar neurogenic ED model, User et al19 documented a significant apoptosis in the subalbugineal smooth muscle cells following bilateral neurotomy of the rat penis. Histomorphometric studies have shown that when a high proportion of trabecular smooth muscles is replaced by collagen, the caverno-occlusive mechanism is lost with subsequent venogenic ED. The reduction in penile length that occurs in a significant proportion of postradical prostatectomy men has also been linked to the corporeal fibrosis.20

A penile hemodynamic study on NSRP patients who had no pharmacological support in the initial 12 months after surgery revealed a progressive incidence of venous leakage varying from 14% at 4 months to 50% at more than 12 months.21 Similarly, in the study of Montorsi et al1 53% of patients who did not self-inject with alprostadil in the first 4 months after surgery had a colour Doppler diagnosis of venous leakage vs only 17% of the treatment group. Schwarts et al22 evaluated the cavernosal smooth muscle content in 40 patients before undergoing NSRP and after 6 months of postoperative treatment with sildenafil. A statistical significant increase in mean smooth muscle content was observed in the group of patients receiving 100 mg sildenafil compared with those treated with 50 mg sildenafil. These findings corroborate the hypothesis that erectile rehabilitation prevents the occurrence of vasculogenic ED during the process of nerve healing after NSRP, probably by reducing the postoperative hypoxia-induced cavernosal fibrosis. In this respect, early postoperative use of erectile aids may also prove effective in reducing penile shortening.

What is currently the most effective rehabilitative therapy?

Early rehabilitative treatment may turn out to be necessary in the long-term therapy for a significant proportion of patients who had unintentional severe neurovascular damage.23 However, many men may not be willing to undergo ongoing sexual therapy. In the series of Gralnek et al,6 a large number of men chose not to use any erectile aid for post-NSRP ED and the few patients who did, had only modestly better outcomes than those not employing therapy for erectile failure. The ideal treatment designed to ameliorate the restoration of erectile function following NSRP should combine a proven efficacy with an acceptable tolerability.

Nocturnal penile tumescence is still severely impaired after 8 months from an NSRP.24 Early intake of the phosphodiesterase type 5 inhibitor sildenafil at bedtime has been advocated with the aim to potentiate nocturnal erections. In the preliminary study from Padma-Nathan et al16 patients who were potent preoperatively were randomised after NSRP to sildenafil or placebo for 36 weeks. Those who regained sexual function after 9 months of treatment (27%) had also better nocturnal erections recorded a year after the operation. Unfortunately, the study does not address the prevalence of nocturnal erections over the 9 months for all the patients in the treatment arm compared with those in the placebo arm. It is possible that sildenafil as well as the other currently available phosphodiesterase type 5 inhibitors, such as vardenafil and tadalafil, may not be such effective in the early phase of nerve healing as documented by the clinical inefficacy of sildenafil in the first 9 months after the NSRP.25 Notably, Schwarts et al22 reported a 20% dropout rate due to pharmacological side effects in postradical prostatectomy patients enrolled in a trial on daily sildenafil 50 and 100 mg, respectively, for 6 months. This observation raises issues about patients' compliance with the required schedule of sildenafil prophylaxis.

Three monthly intracavernous injections with prostaglandin E1 starting the first postoperative month significantly enhanced subsequent response to sildenafil as compared with sildenafil alone started at the fourth postoperative month. At 6-month follow-up, 82% of patients in the combination arm responded to subsequent sildenafil vs only 52% in the sildenafil only arm.26 Intracavernosal therapy has been found to produce a high erectile response in non-nerve-sparing patients and therefore it may be the treatment of choice in the early postoperative period following the NS procedure. Similarly, the use of vacuum constrictor device may facilitate early sexual intercourse and potentially early return of natural erections, although no controlled study has been carried out to test this hypothesis. From the point of view of patient's tolerability a trend favouring ICI treatment over vacuum was reported in a randomised trial on men with ED due to other causes.27

Conclusions

ED may significantly impact on the quality of life of patients who have undergone a radical prostatectomy with a nerve-sparing intent and effort should be made to improve sexual outcomes of NS procedures. Sexual rehabilitation involves the regular early postoperative use of an erectile aid to be carried out until spontaneous erectile activity is regained, which may be as long as 2 y from surgery. The current scientific evidence in support of that concept is at present based mainly on indirect proof of a cavernosal damage that may follow the temporary postoperative ‘erectile silence’.

Based on the few data available, either intracavernosal injections or a vacuum device should be offered as a first-line option for the first few months from the procedure as their mechanism of action does not require intact neural tissue for erection. Thereafter sildenafil, or equivalent phosphodiesterase inhibitor therapy, may be a reasonable choice for those patients who can achieve at least a partial erection. A phosphodiesterase 5 inhibitor may not be effective when spontaneous erections are absent. It is possible, since the rehabilitation of sexual function aims to prevent cavernosal tissue damage by providing oxygenation to the erectile tissue, the choice of a potentially ineffective treatment may jeopardise the results of a reasonable NS procedure.

We conclude that rehabilitative treatment should be offered to all patients undergoing NSRP, particularly if at higher risk to develop permanent erectile failure, namely those who had a resection of one neurovascular bundle and those over 60 y. Ultimately, patients should be counselled on the current level of knowledge about the potential efficacy of rehabilitative protocols rather than steered in the direction of expensive treatments that may in the end not be effective.

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Gontero, P., Kirby, R. Proerectile pharmacological prophylaxis following nerve-sparing radical prostatectomy (NSRP). Prostate Cancer Prostatic Dis 7, 223–226 (2004). https://doi.org/10.1038/sj.pcan.4500737

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Keywords

  • radical prostatectomy
  • nerve-sparing
  • erectile dysfunction
  • treatment
  • rehabilitation

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