PERSPECTIVES TIMELINE
Landmarks in erectile function recovery after radical prostatectomy Emmanuel Weyne, Fabio Castiglione, Frank Van der Aa, Trinity J. Bivalacqua and Maarten Albersen Abstract | The description of the nerve-sparing technique of radical prostatectomy by Walsh was one of the major breakthroughs in the surgical treatment of prostate cancer in the 20th century. However, despite this advance and consequent technological refinements to nerve-sparing surgery, a large proportion of men still suffer from erectile dysfunction (ED) as a complication of prostatectomy. A plethora of therapeutic approaches have been proposed to optimize erectile function recovery in these patients. Several preclinical and translational studies have shown benefits of therapies including PDE5 inhibitor (PDE5I) treatment, immunomodulation, neurotrophic factor administration, and regenerative techniques, such as stem cell therapy, in animal models. However, most of these approaches have either failed to translate to clinical use or have yet to be studied in human subjects. Penile rehabilitation with PDE5Is is currently the most commonly used clinical strategy, in spite of the absence of solid clinical evidence to support its use. Weyne, E. et al. Nat. Rev. Urol. advance online publication 14 April 2015; doi:10.1038/nrurol.2015.72
Introduction
Early accounts of prostatic surgery were first reported in the 19th century; however, most of these cases were performed on men with obstructive symptoms and the preferred route was transvesical. Billroth was one of the first surgeons reported to perform trans vesical partial prostatectomy,1 but McGill in Leeds and Belfield in Chicago performed the first total prostate enucleations around the 1880s. 2,3 This procedure was sub sequently popularized by Fuller in New York and Freyer in St Peter’s Hospital for Stone in London. However, it was 1905 before a series was published on the resection of the pros tate for prostate cancer by Young.4 In 1909, van Stockum published the first retropubic extravesical prostatectomy, but the approach did not become popular, perhaps owing to a lack of active pursuing by van Stockum himself.5 Retropubic extravesical prostatec tomy did not truly become popular until Terence Millin from London published his technique in 1945.6 The initial development and refinement of the surgical procedure to remove the prostate Competing interests The authors declare no competing interests.
in cases of malignancy is strongly associated with the James Buchanan Brady Urological Institute at Johns Hopkins University in Baltimore. The first transperineal radical prostatectomy for prostate cancer was performed in 1904, by Hugh H. Young, assisted by his chief, William S. Halsted, at Johns Hopkins (Box 1).4,7,8 In 1947, Terence Millin, who had not long before published his retropubic approach for benign prostatic hyperplasia (BPH),6 published a modified technique for suprapubic radical removal of the malignant prostate. He suggested the procedure as an alternative to radical trans perineal prostatectomy, on the grounds that patients often had pelvic lymph node metastases at diagnosis, and these should also be resected.9 However, until the 1980s, radical prostatectomy was rarely performed to treat prostate cancer, owing to the severe adverse effects: haemorrhage, incontinence and impotence—nowadays called erectile dysfunction (ED)—associated with the pro cedure. In 1979, Patrick C. Walsh at Johns Hopkins together with William Reiner described in detail the anatomy of the dorsal venous complex of the prostate, which led to the development of the ‘anatomical radical prostatectomy’ with early venous control
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and reduced blood loss, enhancing visu alisation and improving the outcomes of radical prostatectomy.10 This discovery paved the way to further exploration of potential surgical improvements in modern radical prostatectomy (Box 2). Before the introduction of the nervesparing radical prostatectomy (NSRP), all patients undergoing this procedure were rendered impotent owing to incomplete understanding of the anatomy of the caver nous nerves. In 1981, Patrick Walsh and Pieter Donker, who was at the time the chairman of Urology at Leiden University, first identified the anatomy of penile erec tile innervation by dissection of an infant cadaver (Figure 1).11 With this discovery and “by using the operating room as an anatomy laboratory,” Walsh performed the first purposeful nerve-sparing anatomical radical prostatectomy at Johns Hopkins in April 1982; the patient was fully potent 1 year later.12 This ground-breaking innovation repositioned radical prostatectomy as a firstline curative treatment for prostate cancer. In 1991, Schuessler performed the first laparoscopic radical prostatectomy,13 which gained popularity throughout the 1990s and early 2000s. However, research in robotic telepresence—mainly by US government agencies such as NASA and the US Army —was beginning to flourish at around the same time that laparoscopy was experienc ing limitations in more difficult procedures, leading to the development of surgical robots. In 2000, Binder performed the first robot-assisted laparoscopic radical prosta tectomy (RALRP) at the Johann-WolfgangGoethe University in Frankfurt am Main, Germany.14 Although they are associated with many technical advantages, robotic techniques have, however, not consistently shown better long-term functional outcomes compared to open radical prostatectomy.15
Post-prostatectomy erectile dysfunction The seminal discovery of the cavernous nerve anatomy and the subsequent develop ment of NSRP revolutionized the func tional outcomes of patients undergoing prostate cancer surgery. Today, radical prostatectomy—whether it is retropubic, laparoscopic, or robot-assisted—is regarded by many urologists as the gold-standard ADVANCE ONLINE PUBLICATION | 1
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PERSPECTIVES Box 1 | Hugh H. Young’s account of the circumstances surrounding the first prostatectomy 4 “I was struck by the fact that had the entire prostate gland been removed with its capsule, it would have been possible to cure both these patients. As a study of the literature revealed that no such radical operation had ever been attempted, I made careful sketches of what I thought would be necessary and showed them to my chief, Dr William S. Halsted, whose reputation was world-wide because of a very radical operation for cancer of the breast with which he had cured a large percentage of the patients brought to him. After examining the (first) patient, Dr Halsted carefully reviewed my sketches. He appeared greatly impressed, strongly advised me to carry out the operation, and said he would like to assist”.
Box 2 | Landmarks in radical prostatectomy 1904: First perineal radical prostatectomy for prostate cancer by Hugh H. Young, assisted by William Stewart Halsted at Johns Hopkins, Baltimore, which was the first radical operation carried out for carcinoma of the prostate with the intent of cure4 1945: First retropubic radical prostatectomy by Terence Millin in 1945 for BPH and in 1947 for prostate cancer6,9 1979: Reiner and Walsh describe the anatomy of the dorsal vein complex and its surgical control11 1981: Patrick C. Walsh and Pieter J. Donker determine the anatomy of the cavernous nerves in a stillborn male, followed in 1982 by the publication of their discoveries12 1991: Schuessler performs the first laparoscopic radical prostatectomy in Southeast Baptist Hospital, San Antonio13 2000: Binder performs the first robot-assisted laparoscopic radical prostatectomy at the Johann-Wolfgang-Goethe University in Frankfurt am Main, Germany14
treatment in men with localized prostate cancer and a good life expectancy.16 However, despite the introduction and the continuous optimization of the nerve sparing procedure, ED is still commonly reported after radical prostatectomy, with a prevalence ranging from 14% to 69%.15 Although erections can occur shortly after surgery, the majority of men lose their erectile function almost completely up to 3 months after surgery,17 and recovery can take 2 years or more. Recovery back to baseline is rare, especially when medically unassisted erec tile function is studied.18 Chances of recov ery are strongly influenced by age, vascular risk factors, and the quality of nerve sparing during surgery.18 Even when a surgically meticulous technique is employed to avoid direct injury to the cavernous nerves, ED can occur as a consequence of neuropraxia, caused by traction, compression and coagu lation. This injury initiates Wallerian degen eration of the nerves, and the subsequent denervation of the corpora cavernosa will lead to a loss in nocturnal erectile activity,19 penile hypoxia,20 fibrosis,20 and apoptosis, causing irreversible smooth-muscle cell loss in the penis.21 These events result in venoocclusive dysfunction, which precludes a recovery of normal erectile function.22 In some patients, an accessory puden dal artery (APA), arising from the femoral, obturator or vesical arteries, can be present
running parallel to the dorsal vascular complex. Ligation of this artery has been suggested to have a role in penile hypoxia independent from hypoxia as a result of denervation after neuropraxia.23 Reported prevalence rates of the presence of this APA vary between 4% and 75%, depending on whether cadaveric, angiographic or intra operative localization studies are used.23 In a large retrospective study analysing 835 patients undergoing open radical prosta tectomy at Johns Hopkins between 1987 and 1994, an APA was identified in 4% of patients.24 In their description of the sur gical technique to preserve the APA, the authors remark that this is often difficult owing to communications with the dorsal vein complex and, therefore, that preserva tion can be associated with extensive blood loss. 24 In a follow-up study, a trend was observed towards improved erectile func tion recovery in patients in whom the APA was preserved (67% versus 50%), but this difference was not statistically significant.25 Another study analysing the effect of sacri ficing APAs during RALRP found no cor relation with erectile function return, time to erectile function recovery and quality of erections assessed using the IIEF5 scores at 24 months.26 We can only conclude that the benefit of APA preservation during RP on erectile function recovery remains unclear based on the current data available.
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Since the acceptance of radical prostatec tomy as a first-line treatment for prostate cancer, urologists and basic researchers have been investigating strategies to inter vene in the ensuing pathological cascade and optimize functional outcome after surgery. These efforts have either specifi cally targeted the causative nerve injury— for example by improving nerve protection or stimulating nerve regeneration—or have aimed to preserve penile integrity while these nerves recover, thus preventing caver nosal fibrosis and smooth muscle apoptosis. At the same time, researchers have been working to promote stem cell therapies aimed at regeneration of either component, the nerves and the corpus cavernosum. In this Timeline Perspectives, we describe the landmarks in the treatment and develop ment of experimental therapies for erectile dysfunction after radical prostatectomy, from animal models all the way through to human studies and clinical application (Figure 2).27
The establishment of animal models
Research into penile innervation was active as early as 1863, when Eckhard elicited penile erection in an anaesthetized dog.28 Langworthy described penile innervation in cats,29 but the understanding of the caver nous nerve and its role in penile erection in animals was not properly advanced until the early 1980s, when Tom Lue published his seminal works on dogs and monkeys, in which he performed electrophysiologi cal and haemodynamic experiments. 30 Nowadays, the rat and mouse are the most widely used animal models in erectile function research, after Quinlan—under supervision of Patrick Walsh—developed a model for the study of penile erection using rats in 1989 (Box 3).31 Quinlan and Walsh identified the location of bilateral major pelvic ganglia, receiving pelvic and hypogastric innervation, and the cavernous nerves lateral to the prostate that innervate the corpora cavernosa.31 Electrical stimu lation of these nerves was straightforward and erectile responses were measured by changes in the intracavernosal pressure (ICP) induced by electrical stimulation of the cavernous nerves.31 Although rats are currently the standard translational model to study erectile physiology, one should keep in mind that the cavernous nerve anatomy in rats, one distinct nerve, is remarkably different from that in humans, in whom the cavernous nerve is a plexus instead of one single nerve. www.nature.com/nrurol
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PERSPECTIVES Efforts to re-establish neural integrity
In both animal and humans, the periph eral nervous system has a limited capacity to regenerate after injury, but this is often insufficient to prevent detrimental changes and functional failure of the end organ. Researchers have investigated strategies to enhance neuroregeneration or increase neuroprotection of the cavernous nerves in order to reduce the duration of corpora cavernosa denervation, such as immuno modulatory factors, neurotrophins, glial cell line-derived neurotrophic factors (GDNF), bone morphogenic proteins, immunophilin ligands, erythropoetin (EPO), and stem cells. Many of these strategies have shown benefi cial effects in animal models mimicking cav ernous nerve injury (CNI).32 Unfortunately, none of these strategies have yet found their way into clinical practice.
Immunomodulatory therapy Immediately after nerve injury—regardless of the severity and extent—a neuro inflammatory cascade is initiated, which is characteri zed by the production of a variety of proinflammatory cytokines and chemok ines, influx of macrophages and other inflammatory cells, and which ulti mately results in apoptosis of neurons and degeneration of axons in a process known as Wallerian degeneration. 33 Tempering this inflammatory reaction with immuno modulatory or immunosuppressant com pounds was hypothesized to improve nerve integrity and eventually enhance erectile function recovery (Box 4). The most studied immunomodulatory drugs are immunophilin ligands such as FK506 (tacrolimus), rapamycin and cyclo sporin, so named for their binding capacity on immunophilins, multifunctional proteins with a role in immunoregulation.34 These drugs have long been used to prevent allograft trans plant rejection. In 2001, a collaborative study by Burnett’s group and Sal Snyder showed in a landmark paper in Nature Medicine that FK506 treatment successfully improved erectile function recovery by significantly increasing the number of surviving unmyelin ated axons in a rat model of CNI.35 With this work, they showed the potent neuroprotective effects of FK506. Owing to concerns regard ing the administration of immunosuppressant compounds to patients with prostate cancer, it was not until several years later that a new class of nonimmunosuppressant immuno philin ligands—FK1706 and GPI1046—which had recently been developed, was studied for its neuroprotective properties in the
CNI rat model. Lue and colleagues studied the administration of FK1706 to rats with CNI, and concluded that long-term administra tion of high doses of FK1706 significantly improved erectile function recovery, associ ated with improved cavernous nerve archi tecture showed by immunohistochemical staining of neurofilament and neuromodulin (also known by the name of its gene, GAP43), a protein highly expressed in growth cones of regenerating nerves.36,37 Around the same time, GPI1046 was studied by Burnett’s lab, showing that treated rats maintained erectile function after cavernous-nerve-crush injury and that GPI1046 prevented axonal degen eration of nonmyelinated nerves, compared with controls.38 These promising preclinical results with immunophilin ligands prompted further investigation in clinical trials to investigate their translational value for use in men. In the first study, tacrolimus (FK506) treatment was not shown to significantly improve erec tile function recovery in patients who had undergone bilateral NSRP.39 In another clini cal trial, GPI1485, a nonimmunosuppressive analogue with high molecular similarity to GPI1046, was also unsuccessful at restor ing erectile function after bilateral NSRP.40 These conflicting results highlight the known translational differences between preclinical animal studies and human clinical trials. The investigators suggested that suboptimal scheduling or drug formulation could have been a factor explaining the failure when translated from rats to humans.34
Neurotrophic factor therapy The autonomic nervous system has a limited endogenous capacity to regenerate after injury, and this response is mediated by the secretion of neurotrophins in response to nerve injury. This process was illustrated by the early activation of genes involved in nerve repair and neuroprotection in a wholegenome microarray study following CNI.41 These neurotrophins are nerve-specific growth factors that regulate the survival, development and function of neurons and have been extensively studied in a preclinical setting as a strategy to optimize erectile func tion outcome after CNI.32 The neurotrophic factors studied that have shown interesting potential include brain-derived nerve growth factor (BDNF), 42,43 nerve growth factor (NGF),44 glial cell line-derived neurotropic factor (GDNF),45 neurotrophin 3 and 4 (NT3, NT4),46 neurturin (NTRN),47 growth differ entiation factor 5 (GDF5),48 and galanin,49 which in 2014 was identified as an important
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Figure 1 | Walsh and Nature Donker’s original| Urology notes Reviews regarding their identification of penile erectile innervation by dissection of an infant cadaver. Reprinted from J. Urol. 177, Walsh, P. C. The discovery of the cavernous nerves and development of nerve sparing radical retropubic prostatectomy, 1632–1635, © 2007, with permission from Elsevier.
peptide in the neuroregenerative reponse to injury, being 180-fold upregulated in the first week after crush injury of the cavern ous nerves and present in the nNOS-positive nerves innervating the corpora cavernosa.49 NGF was the first neurotrophic factor to be discovered, in 1951 by Nobel prize winners Rita Levi-Montalcini and Stanley Cohen (Box 5).50 NGF was also the first neurotrophin investigated in the field of urology, with a documented neuroprotective effect in vitro on major pelvic ganglion (MPG) neurons.51 After cavernous nerve ablation, NGF treatment minimally increased erectile function, and the combination of nerve grafts with NGF restored erectile function in vivo.44 In 2014, researchers showed that blockade of neuro trophic tyrosine kinase receptor type 1, NGF’s preferred receptor, using a monoclonal anti body, had a positive effect on erectile function recovery in cavernous-nerve-crushed rats, as a result of preferential parasympathetic over sympathetic nerve regeneration.52 For NTRN, another glial-derived neurotrophic factor, a similar selective neurotrophic effect was seen, with in vitro treatment stimulating outgrowth preferentially in parasympathetic but not sympathetic pelvic neurons.53 In 2003, Tom Lue’s lab reported the development of an explant nerve culture model of the MPG to elegantly study the neurotrophic properties of different growth factors and peptides, showing that vascular endothelial growth factor (VEGF), NT3, NT4 and BDNF significantly increased nerve outgrowth.46 Intracavernosal injec tion of BDNF as a neurotrophic factor 54 or as gene therapy via an adenoviral vector 43 both enhanced erectile function recovery in CNI rats and improved regeneration of the nNOS‑containing nerves. ADVANCE ONLINE PUBLICATION | 3
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PERSPECTIVES Walsh performs first purposeful nerve-sparing radical prostatectomy
Rita Levi-Montalcini and Stanley Cohen discover NGF for which they will later receive the Nobel Prize in Physiology or Medicine
First perineal radical prostatectomy for prostate cancer, carried out with the intent to cure by H. H. Young
1904
1947
Schuessler performs the first laparoscopic radical prostatectomy
Reiner and Walsh describe the anatomy of the dorsal vein complex and its surgical control
1951
1979
Binder performs first RALP
Proof of interposition nerve grafting after cavernous nerve resection in rats
1981
First retropubic radical prostatectomy for prostate cancer by T. Millin Advances in Advances in Advances in Advances in Advances in Advances in Preclinical Clinical
Viagra® (sildenafil citrate) is the first PDE5I approved by the FDA for the treatment of ED
anatomy and surgery cavernous nerve grafting and identification growth factors penile oxygenation strategies stem cells immunomodulation
1982
1989
1991
1996
1998
2000
Kim introduces a technique of sural nerve grafting to restore erectile function
Quinlan first describes a rat animal model of CNI to study penile erection
Walsh and Donker discover the anatomy of the cavernous nerves in a stillborn male infant
1999
2001
FK506 is shown to have a neuroprotective effect in cavernous nerve-crushed rats
Early postoperative administration of alprostadil injections shown to increase the recovery rate of spontaneous erections after radical prostatectomy
Figure 2 | Landmarks in erectile function recovery after radical prostatectomy. Abbreviations: CNI, cavernous nerve injury; ED, erectile dysfunction; MSC, mesenchymal stem cels; NGF, nerve growth factor; PDE5I, phosphodiesterase-5 inhibitor; RALP, robot-assisted radical prostatectomy.
Concerns remain regarding the use of neurotrophic factors in patients who have recently undergone prostatectomy for onco logical purposes. Besides this concern, the pharmacokinetic properties of these neuro trophic factors are an important reason why the promising preclinical results of neurotrophic factor therapy have, so far, not been investigated in clinical studies. Neurotrophins have a poor permeability over biological barriers such as the intestinal mucosa and undergo presystemic enzymatic degradation.55 Incorporating neurotrophic factors into a hydrogel for intraoperative topical application on the neurovascular bundle could be an alternative to oral admin istration, and could, potentially, be used to optimize erectile function recovery after radical prostatectomy.56
Cavernous nerve identification
In the late 1990s, a device was designed to improve the intraoperative identification of the cavernous nerve and reduce injury to this vital structure. Cavermap® (UroMed, Boston, MA), a commercially available nerve stimulator and tumescence-detecting
device, was developed to facilitate neuro vascular bundle preservation (Box 3).57 The widespread use of this device was, however, prevented by the high false-positive detec tion rates58 and the inability to significantly improve postoperative erectile function in clinical studies.59 In patients at risk for extracapsular exten sion of their tumour, one or both cavernous nerves must be sacrificed to achieve local cancer control. To bridge the resulting gap between both nerve ends, reconstruction of the nerve using an interposition nerve graft has been performed.60 The proof of principle was provided in a study by Quinlan et al.61 in 1991, in which they showed that rats treated with an interposition genitofemoral nerve graft had significantly better erectile function than nongrafted rats after cavernous nerve ablation. In 1999, Kim et al.62 first reported the use of bilateral sural nerve interposition after wide resection of the neurovascular bundle, which enabled one-quarter of patients to have medically unassisted sexual intercourse and a further 43% to have medi cally assisted intercourse.63 Several groups have since reported their own results with the
Box 3 | Landmarks in cavernous nerve grafting and identification 1989: Quinlan first describes a rat model of CNI to study penile erection31 1991: Proof of interposition nerve grafting after cavernous nerve resection in rats by Quinlan 61 1998: Introduction of Cavermap®for intraoperative identification of the cavernous nerves57,58 1999: Kim introduces a technique of sural nerve grafting to restore erectile function after non‑nerve-sparing radical prostatectomy62 2009: A large randomized clinical trial shows no significant benefit in erectile function recovery 2 years after unilateral sural graft interposition66 Abbreviation: CNI, cavernous nerve injury.
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use of sural or genitofemoral grafts, in series including up to 107 patients.60,64,65 However, despite the promising results of these initial series, a well-designed randomized multi centre phase II trial, published in 2009, demonstrated no difference in erectile func tion recovery between patients undergoing unilateral NSRP with or without sural nerve graft interposition.66 These disappointing results decreased the general popularity and use of nerve interposition grafting, owing to the unclear added benefit in terms of erec tile function recovery, and the technique has now been abandoned (Box 3).
Preserving cavernosal integrity
The denervation occurring after radical prostatectomy results in a decrease of the rate and quality of both daily and nocturnal erections, rendering the penis in a persistent state of hypoxia.67 In vitro and in vivo studies support the theory that penile hypoxia results in collagen accumulation, smooth muscle apoptosis, and fibrosis.67,68 Eventually, this penile damage can result in permanent ED, even if normal function of the nerves is restored.67 The concept of penile rehabilita tion is based on the use of any therapy able to preserve erectile function via an improve ment in cavernosal oxygenation, in order to preserve endothelial function and to prevent smooth muscle fibrosis. Montorsi and colleagues69 were the first group to clinically test the concept of post prostatectomy penile rehabilitation, when in 1997 they published a pioneering clinical study on the effects of intracavernosal injec tions of alprostadil early after NSRP (Box 6). www.nature.com/nrurol
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PERSPECTIVES Mulhall describes an erectogenic pharmacotherapy regimen combining assessment of PDE5I response with intracavernous injections in case of PDE5I-nonreponders
Raina et al. describe the use of regular application of the vacuum erection device for the recovery of erectile function after radical prostatectomy
A large double-blind prospective randomized trial (REINVENT) fails to show the effectiveness of daily administration of vardenafil as a treatment for ED after nerve-sparing radical prostatectomy
A large double-blind prospective randomized trial (REACTT) fails to show the effectiveness of daily administration of tadalafil as a treatment for ED after nerve-sparing radical prostatectomy when compared with on-demand use and placebo
FK506 and GPI-1046 fail to show proven benefit in erectile function recovery after nerve-sparing radical prostatectomy in humans
First phase I safety data for penile injection of bone-marrow mononucleated cells in humans
A large randomized clinical trial shows no significant benefit of unilateral sural graft interposition on erectile function 2003
2004
A randomized, placebo-controlled study is published, examining the benefits of nightly administration of sildenafil for the return of erectile function after bilateral nerve-sparing radical prostatectomy
2005
2006
2007
First report of neural embryonic stem cells preserving the erectile function in a rat model of CNI An uncontrolled trial demonstrates that early, regular sildenafil citrate administration after nerve-sparing radical retropubic prostatectomy preserves, or even increases, intracorporal smooth muscle content
In this study, 30 patients were randomized to receive either alprostadil injections three times per week for 12 weeks (n = 15) or obser vation alone (n = 15); participants were then evaluated 3 months later. In the treatment group, 12 of 15 men completed treatment. Of these, eight (67%) reported the recovery of spontaneous erection sufficient for satis factory sexual intercourse, compared with only three patients (20%) in the observation arm.69 The authors concluded that early use of alprostadil injections significantly increased the recovery rate of spontaneous erections after NSRP. Notable limitations were that preoperative parameters of erec tile function were not assessed, and that this study was performed before the routine use of validated questionnaires. Additionally, the short follow-up duration limited the drawing of any conclusions regarding long‑term effects of therapy.69 Considering the flaws in the study design, especially regarding the delayed start of rehabiliatation after surgery, it is somewhat surprising that this study, and the general concept of penile rehabilitation, has influ enced not only the clinical trials but also the basic science studies in this field for almost 20 years.70 The optimal rehabilitation sched ule is based on two key points: the first is that the therapy should be started as soon as possible after the iatrogenic damage, and the second that it should be administered as a continuous treatment and not as an on-demand therapy.70 Since Montorsi and coauthors’ 1997 study, several rehabilita tion strategies have been proposed, includ ing neuromodulatory agents, Medicated Urethral System for Erection (MUSE®, Vivus, USA), oral PDE5I therapy and vacuum erection devices (VEDs) (Box 6).71
2008
2009
2010
2012
2013
2014
Confirmation of the beneficial effect of MSC in a CNI rat model
Non-immunosuppressive immunophilin ligands show benefit in erectile function preservation in CNI rat models
PDE5 inhibitors Since the introduction of sildenafil in 1998, penile rehabilitation with PDE5I therapy has garnered further interest within the inter national urological community. Several well designed preclinical studies using rodent models have investigated the role of PDE5Is in penile rehabilitation.68 In 2006, Vignozzi et al.72 demonstrated that the daily admin istration of tadalafil reduced penile hypoxia, smooth muscle apoptosis, and fibrosis induced by cavernous neurotomy in rats. In the same year Ferrini and coauthors73 showed that daily vardenafil treatment prevented veno-occlusive dysfunction after bilateral cavernous nerve resection in rats. Then, in 2008, Mulhall and colleagues74 demonstrated the beneficial effect of daily administration of sildenafil in a rat model of cavernous nerve crush injury, which mimics the nerve injury occurring during NSRP. Their study showed that daily sildenafil administration improved the penile smooth muscle:collagen ratio, increased penile smooth muscle replication, reduced penile apoptotic index and preserved penile endothelial function shown by eNOS expression preservation.74 Furthermore, in 2011, Ferrini and colleagues showed that PDE5I rehabilitation has a beneficial effect, not only on the penile tissue, but also on the MPG, where it attenuates the upregulation
Adminstration of SVF shown to increase erectile function recovery in a rat model of CNI
A large double-blind prospective randomized trial fails to show the effectiveness of daily administration of sildenafil as a treatment for ED after nerve-sparing radical prostatectomy
Nature Reviews | Urology of profibrotic factors such as TGFβ and connective tissue growth factor (CTFG), and upregulates the expression of beneficial factors such as the angiogenic factor VEGF after CNI.75,76 Based on these results, PDE5Is might prove able to ameliorate neuro pathic pain, promote neuroprotection, and favour nerve regeneration, providing for the first time a justification for their use as a neuroprotective agent after NSRP.75,77 Surprisingly, the majority of these basic studies were conducted and published after PDE5I rehabilitation had already found its way into clinical practice. In 2004, Schwartz and colleagues demonstrated that early, regular (every other night) use of silde nafil after nerve-sparing radical retropubic prostatectomy preserves, or even increases, intracorporeal smooth muscle content in humans, although it is important to note that this study did not include a control group.78 Padma-Nathan and colleagues79 reported the results of a randomized, placebo- controlled study examining the benefits of nightly administration of sildenafil during the postoperative period following bilateral nerve-sparing prostatectomy in 2008. The study included 76 men with normal pre operative erectile function, and 27% of those receiving sildenafil self-reported a return of spontaneous erectile function at 48 weeks
Box 4 | Landmarks in immunomodulatory therapy 2001: The neuromodulatory drug FK506 is shown to have a neuroprotective effect in cavernous-nerve-crushed rats35 2007: Non-immunosuppressive immunophilin ligands FK1706 and GPI1046 show benefit in erectile function preservation in a CNI rat model37,38 2008: FK506 and GPI1485 fail to show proven benefit in erectile function recovery after nerve‑sparing radical prostatectomy39,40 Abbreviation: CNI, cavernous nerve injury.
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PERSPECTIVES Box 5 | Landmarks in neurotrophic factor therapy 1951: Rita Levi-Montalcini and Stanley Cohen discover NGF, for which they will later receive the Nobel Prize in Physiology or Medicine50 1992: First use of NGF in a preclinical study in urology; NGF shown to support survival of MPG neurons51 2003: MPG explant nerve culture used to screen for neurotrophic effects of different peptides 46 2006: BDNF shown to stimulate neurite outgrowth through JAK-STAT signalling102 Abbreviations: BDNF, brain-derived neurotrophic factor; JAK-STAT, janus kinase–signal transducer and activator of transcription; MPG, major pelvic ganglion; NGF, nerve growth factor.
Box 6 | Landmarks in penile rehabilitation 1996: Montorsi et al.69 show that the early postoperative administration of alprostadil injections significantly increases the recovery rate of spontaneous erections after radical prostatectomy 1998: Viagra®(Pfizer, New York) is the first PDE5I approved by the FDA for the treatment of erectile dysfunction103 2003: Padma-Nathan and colleagues report the results of a randomized, placebo-controlled study examining the benefits of nightly administration of sildenafil during the postoperative period for the return of normal function at 48 weeks following a bilateral nerve-sparing radical prostatectomy79 2004: Schwartz and colleagues show in an uncontrolled trial that early, regular use of sildenafil after nerve-sparing radical retropubic prostatectomy preserves, or even increases, intracorporal smooth muscle content78 2005: Mulhall describes an erectogenic pharmacotherapy regimen combining assessment of PDE5I response with intracavernous injections in case of PDE5I-nonresponders, and shows benefit of this approach in a nonrandomized trial104 2006: First preclinical evidence for beneficial effect of daily administration of tadalafil in rats after bilateral cavernous neurotomy72 2006: Raina et al.88 report on the use of regular application of the vacuum erection device for the recovery of erectile function after radical prostatectomy 2008: Montorsi et al.81 fail to show the effectiveness of daily administration of vardenafil as a treatment for ED after nerve-sparing radical prostatectomy in a large double-blind prospective randomized trial, when compared with on-demand use and placebo 2013: Pavlovich et al.83 fail to show the effectiveness of daily administration of sildenafil as a treatment for ED after nerve-sparing radical prostatectomy in a large double-blind prospective randomized trial when compared with on-demand use and placebo 2014: Montorsi et al.84 fail to show the effectiveness of daily administration of tadalafil as a treatment for ED after nerve-sparing radical prostatectomy in a large double-blind prospective randomized trial when compared with on-demand use and placebo Abbreviations: ED, erectile dysfunction; PDE5I, phosphodiesterase type 5 inhibitor.
after surgery, compared with only 4% in the placebo group.80 Although this study has been criticized for the seemingly low per centage of men considered responders in the placebo arm, the criteria for being consid ered a responder in this study were stringent, and it represents the first placebo-controlled trial suggesting a benefit of oral PDE5I therapy in improving the return of spon taneous erections. In a subanalysis of data from this study, the self-reported results were corroborated by nocturnal penile tumes cence data. A rapid and profound reduction in nocturnal erectile function was noted in all groups after surgery, but a gradual dosedependent improvement in base and tip rigidity was predominantly observed in the sildenafil groups, with little improvement in the placebo group.80
More recently, well conducted, well designed, prospective, large randomized clinical trials have challenged the belief that regular dosing of a PDE5I following radical prostatectomy can prevent the deterioration of erectile function. The REINVENT trial, which included 628 men, failed to show the effectiveness of daily administration of vardenafil from an early postoperative stage.81 A 2010 randomized, prospective trial compared the effectiveness of nightly administration of intraurethral alprostadil (MUSE®) and sildenafil to rehabilitate erec tile function after radical prostatectomy, but no differences in IIEF-EF score were found between groups at 11 months after surgery.82 Pavlovich and co-workers investi gated the benefits of nightly administration of sildenafil during the postoperative period
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following bilateral NSRP in a double- dummy designed trial published in 2013.83 This study included a total of 100 pre operatively potent men, aged
Landmarks in erectile function recovery after radical prostatectomy Emmanuel Weyne, Fabio Castiglione, Frank Van der Aa, Trinity J. Bivalacqua and Maarten Albersen Abstract | The description of the nerve-sparing technique of radical prostatectomy by Walsh was one of the major breakthroughs in the surgical treatment of prostate cancer in the 20th century. However, despite this advance and consequent technological refinements to nerve-sparing surgery, a large proportion of men still suffer from erectile dysfunction (ED) as a complication of prostatectomy. A plethora of therapeutic approaches have been proposed to optimize erectile function recovery in these patients. Several preclinical and translational studies have shown benefits of therapies including PDE5 inhibitor (PDE5I) treatment, immunomodulation, neurotrophic factor administration, and regenerative techniques, such as stem cell therapy, in animal models. However, most of these approaches have either failed to translate to clinical use or have yet to be studied in human subjects. Penile rehabilitation with PDE5Is is currently the most commonly used clinical strategy, in spite of the absence of solid clinical evidence to support its use. Weyne, E. et al. Nat. Rev. Urol. advance online publication 14 April 2015; doi:10.1038/nrurol.2015.72
Introduction
Early accounts of prostatic surgery were first reported in the 19th century; however, most of these cases were performed on men with obstructive symptoms and the preferred route was transvesical. Billroth was one of the first surgeons reported to perform trans vesical partial prostatectomy,1 but McGill in Leeds and Belfield in Chicago performed the first total prostate enucleations around the 1880s. 2,3 This procedure was sub sequently popularized by Fuller in New York and Freyer in St Peter’s Hospital for Stone in London. However, it was 1905 before a series was published on the resection of the pros tate for prostate cancer by Young.4 In 1909, van Stockum published the first retropubic extravesical prostatectomy, but the approach did not become popular, perhaps owing to a lack of active pursuing by van Stockum himself.5 Retropubic extravesical prostatec tomy did not truly become popular until Terence Millin from London published his technique in 1945.6 The initial development and refinement of the surgical procedure to remove the prostate Competing interests The authors declare no competing interests.
in cases of malignancy is strongly associated with the James Buchanan Brady Urological Institute at Johns Hopkins University in Baltimore. The first transperineal radical prostatectomy for prostate cancer was performed in 1904, by Hugh H. Young, assisted by his chief, William S. Halsted, at Johns Hopkins (Box 1).4,7,8 In 1947, Terence Millin, who had not long before published his retropubic approach for benign prostatic hyperplasia (BPH),6 published a modified technique for suprapubic radical removal of the malignant prostate. He suggested the procedure as an alternative to radical trans perineal prostatectomy, on the grounds that patients often had pelvic lymph node metastases at diagnosis, and these should also be resected.9 However, until the 1980s, radical prostatectomy was rarely performed to treat prostate cancer, owing to the severe adverse effects: haemorrhage, incontinence and impotence—nowadays called erectile dysfunction (ED)—associated with the pro cedure. In 1979, Patrick C. Walsh at Johns Hopkins together with William Reiner described in detail the anatomy of the dorsal venous complex of the prostate, which led to the development of the ‘anatomical radical prostatectomy’ with early venous control
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and reduced blood loss, enhancing visu alisation and improving the outcomes of radical prostatectomy.10 This discovery paved the way to further exploration of potential surgical improvements in modern radical prostatectomy (Box 2). Before the introduction of the nervesparing radical prostatectomy (NSRP), all patients undergoing this procedure were rendered impotent owing to incomplete understanding of the anatomy of the caver nous nerves. In 1981, Patrick Walsh and Pieter Donker, who was at the time the chairman of Urology at Leiden University, first identified the anatomy of penile erec tile innervation by dissection of an infant cadaver (Figure 1).11 With this discovery and “by using the operating room as an anatomy laboratory,” Walsh performed the first purposeful nerve-sparing anatomical radical prostatectomy at Johns Hopkins in April 1982; the patient was fully potent 1 year later.12 This ground-breaking innovation repositioned radical prostatectomy as a firstline curative treatment for prostate cancer. In 1991, Schuessler performed the first laparoscopic radical prostatectomy,13 which gained popularity throughout the 1990s and early 2000s. However, research in robotic telepresence—mainly by US government agencies such as NASA and the US Army —was beginning to flourish at around the same time that laparoscopy was experienc ing limitations in more difficult procedures, leading to the development of surgical robots. In 2000, Binder performed the first robot-assisted laparoscopic radical prosta tectomy (RALRP) at the Johann-WolfgangGoethe University in Frankfurt am Main, Germany.14 Although they are associated with many technical advantages, robotic techniques have, however, not consistently shown better long-term functional outcomes compared to open radical prostatectomy.15
Post-prostatectomy erectile dysfunction The seminal discovery of the cavernous nerve anatomy and the subsequent develop ment of NSRP revolutionized the func tional outcomes of patients undergoing prostate cancer surgery. Today, radical prostatectomy—whether it is retropubic, laparoscopic, or robot-assisted—is regarded by many urologists as the gold-standard ADVANCE ONLINE PUBLICATION | 1
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PERSPECTIVES Box 1 | Hugh H. Young’s account of the circumstances surrounding the first prostatectomy 4 “I was struck by the fact that had the entire prostate gland been removed with its capsule, it would have been possible to cure both these patients. As a study of the literature revealed that no such radical operation had ever been attempted, I made careful sketches of what I thought would be necessary and showed them to my chief, Dr William S. Halsted, whose reputation was world-wide because of a very radical operation for cancer of the breast with which he had cured a large percentage of the patients brought to him. After examining the (first) patient, Dr Halsted carefully reviewed my sketches. He appeared greatly impressed, strongly advised me to carry out the operation, and said he would like to assist”.
Box 2 | Landmarks in radical prostatectomy 1904: First perineal radical prostatectomy for prostate cancer by Hugh H. Young, assisted by William Stewart Halsted at Johns Hopkins, Baltimore, which was the first radical operation carried out for carcinoma of the prostate with the intent of cure4 1945: First retropubic radical prostatectomy by Terence Millin in 1945 for BPH and in 1947 for prostate cancer6,9 1979: Reiner and Walsh describe the anatomy of the dorsal vein complex and its surgical control11 1981: Patrick C. Walsh and Pieter J. Donker determine the anatomy of the cavernous nerves in a stillborn male, followed in 1982 by the publication of their discoveries12 1991: Schuessler performs the first laparoscopic radical prostatectomy in Southeast Baptist Hospital, San Antonio13 2000: Binder performs the first robot-assisted laparoscopic radical prostatectomy at the Johann-Wolfgang-Goethe University in Frankfurt am Main, Germany14
treatment in men with localized prostate cancer and a good life expectancy.16 However, despite the introduction and the continuous optimization of the nerve sparing procedure, ED is still commonly reported after radical prostatectomy, with a prevalence ranging from 14% to 69%.15 Although erections can occur shortly after surgery, the majority of men lose their erectile function almost completely up to 3 months after surgery,17 and recovery can take 2 years or more. Recovery back to baseline is rare, especially when medically unassisted erec tile function is studied.18 Chances of recov ery are strongly influenced by age, vascular risk factors, and the quality of nerve sparing during surgery.18 Even when a surgically meticulous technique is employed to avoid direct injury to the cavernous nerves, ED can occur as a consequence of neuropraxia, caused by traction, compression and coagu lation. This injury initiates Wallerian degen eration of the nerves, and the subsequent denervation of the corpora cavernosa will lead to a loss in nocturnal erectile activity,19 penile hypoxia,20 fibrosis,20 and apoptosis, causing irreversible smooth-muscle cell loss in the penis.21 These events result in venoocclusive dysfunction, which precludes a recovery of normal erectile function.22 In some patients, an accessory puden dal artery (APA), arising from the femoral, obturator or vesical arteries, can be present
running parallel to the dorsal vascular complex. Ligation of this artery has been suggested to have a role in penile hypoxia independent from hypoxia as a result of denervation after neuropraxia.23 Reported prevalence rates of the presence of this APA vary between 4% and 75%, depending on whether cadaveric, angiographic or intra operative localization studies are used.23 In a large retrospective study analysing 835 patients undergoing open radical prosta tectomy at Johns Hopkins between 1987 and 1994, an APA was identified in 4% of patients.24 In their description of the sur gical technique to preserve the APA, the authors remark that this is often difficult owing to communications with the dorsal vein complex and, therefore, that preserva tion can be associated with extensive blood loss. 24 In a follow-up study, a trend was observed towards improved erectile func tion recovery in patients in whom the APA was preserved (67% versus 50%), but this difference was not statistically significant.25 Another study analysing the effect of sacri ficing APAs during RALRP found no cor relation with erectile function return, time to erectile function recovery and quality of erections assessed using the IIEF5 scores at 24 months.26 We can only conclude that the benefit of APA preservation during RP on erectile function recovery remains unclear based on the current data available.
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Since the acceptance of radical prostatec tomy as a first-line treatment for prostate cancer, urologists and basic researchers have been investigating strategies to inter vene in the ensuing pathological cascade and optimize functional outcome after surgery. These efforts have either specifi cally targeted the causative nerve injury— for example by improving nerve protection or stimulating nerve regeneration—or have aimed to preserve penile integrity while these nerves recover, thus preventing caver nosal fibrosis and smooth muscle apoptosis. At the same time, researchers have been working to promote stem cell therapies aimed at regeneration of either component, the nerves and the corpus cavernosum. In this Timeline Perspectives, we describe the landmarks in the treatment and develop ment of experimental therapies for erectile dysfunction after radical prostatectomy, from animal models all the way through to human studies and clinical application (Figure 2).27
The establishment of animal models
Research into penile innervation was active as early as 1863, when Eckhard elicited penile erection in an anaesthetized dog.28 Langworthy described penile innervation in cats,29 but the understanding of the caver nous nerve and its role in penile erection in animals was not properly advanced until the early 1980s, when Tom Lue published his seminal works on dogs and monkeys, in which he performed electrophysiologi cal and haemodynamic experiments. 30 Nowadays, the rat and mouse are the most widely used animal models in erectile function research, after Quinlan—under supervision of Patrick Walsh—developed a model for the study of penile erection using rats in 1989 (Box 3).31 Quinlan and Walsh identified the location of bilateral major pelvic ganglia, receiving pelvic and hypogastric innervation, and the cavernous nerves lateral to the prostate that innervate the corpora cavernosa.31 Electrical stimu lation of these nerves was straightforward and erectile responses were measured by changes in the intracavernosal pressure (ICP) induced by electrical stimulation of the cavernous nerves.31 Although rats are currently the standard translational model to study erectile physiology, one should keep in mind that the cavernous nerve anatomy in rats, one distinct nerve, is remarkably different from that in humans, in whom the cavernous nerve is a plexus instead of one single nerve. www.nature.com/nrurol
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PERSPECTIVES Efforts to re-establish neural integrity
In both animal and humans, the periph eral nervous system has a limited capacity to regenerate after injury, but this is often insufficient to prevent detrimental changes and functional failure of the end organ. Researchers have investigated strategies to enhance neuroregeneration or increase neuroprotection of the cavernous nerves in order to reduce the duration of corpora cavernosa denervation, such as immuno modulatory factors, neurotrophins, glial cell line-derived neurotrophic factors (GDNF), bone morphogenic proteins, immunophilin ligands, erythropoetin (EPO), and stem cells. Many of these strategies have shown benefi cial effects in animal models mimicking cav ernous nerve injury (CNI).32 Unfortunately, none of these strategies have yet found their way into clinical practice.
Immunomodulatory therapy Immediately after nerve injury—regardless of the severity and extent—a neuro inflammatory cascade is initiated, which is characteri zed by the production of a variety of proinflammatory cytokines and chemok ines, influx of macrophages and other inflammatory cells, and which ulti mately results in apoptosis of neurons and degeneration of axons in a process known as Wallerian degeneration. 33 Tempering this inflammatory reaction with immuno modulatory or immunosuppressant com pounds was hypothesized to improve nerve integrity and eventually enhance erectile function recovery (Box 4). The most studied immunomodulatory drugs are immunophilin ligands such as FK506 (tacrolimus), rapamycin and cyclo sporin, so named for their binding capacity on immunophilins, multifunctional proteins with a role in immunoregulation.34 These drugs have long been used to prevent allograft trans plant rejection. In 2001, a collaborative study by Burnett’s group and Sal Snyder showed in a landmark paper in Nature Medicine that FK506 treatment successfully improved erectile function recovery by significantly increasing the number of surviving unmyelin ated axons in a rat model of CNI.35 With this work, they showed the potent neuroprotective effects of FK506. Owing to concerns regard ing the administration of immunosuppressant compounds to patients with prostate cancer, it was not until several years later that a new class of nonimmunosuppressant immuno philin ligands—FK1706 and GPI1046—which had recently been developed, was studied for its neuroprotective properties in the
CNI rat model. Lue and colleagues studied the administration of FK1706 to rats with CNI, and concluded that long-term administra tion of high doses of FK1706 significantly improved erectile function recovery, associ ated with improved cavernous nerve archi tecture showed by immunohistochemical staining of neurofilament and neuromodulin (also known by the name of its gene, GAP43), a protein highly expressed in growth cones of regenerating nerves.36,37 Around the same time, GPI1046 was studied by Burnett’s lab, showing that treated rats maintained erectile function after cavernous-nerve-crush injury and that GPI1046 prevented axonal degen eration of nonmyelinated nerves, compared with controls.38 These promising preclinical results with immunophilin ligands prompted further investigation in clinical trials to investigate their translational value for use in men. In the first study, tacrolimus (FK506) treatment was not shown to significantly improve erec tile function recovery in patients who had undergone bilateral NSRP.39 In another clini cal trial, GPI1485, a nonimmunosuppressive analogue with high molecular similarity to GPI1046, was also unsuccessful at restor ing erectile function after bilateral NSRP.40 These conflicting results highlight the known translational differences between preclinical animal studies and human clinical trials. The investigators suggested that suboptimal scheduling or drug formulation could have been a factor explaining the failure when translated from rats to humans.34
Neurotrophic factor therapy The autonomic nervous system has a limited endogenous capacity to regenerate after injury, and this response is mediated by the secretion of neurotrophins in response to nerve injury. This process was illustrated by the early activation of genes involved in nerve repair and neuroprotection in a wholegenome microarray study following CNI.41 These neurotrophins are nerve-specific growth factors that regulate the survival, development and function of neurons and have been extensively studied in a preclinical setting as a strategy to optimize erectile func tion outcome after CNI.32 The neurotrophic factors studied that have shown interesting potential include brain-derived nerve growth factor (BDNF), 42,43 nerve growth factor (NGF),44 glial cell line-derived neurotropic factor (GDNF),45 neurotrophin 3 and 4 (NT3, NT4),46 neurturin (NTRN),47 growth differ entiation factor 5 (GDF5),48 and galanin,49 which in 2014 was identified as an important
NATURE REVIEWS | UROLOGY
Figure 1 | Walsh and Nature Donker’s original| Urology notes Reviews regarding their identification of penile erectile innervation by dissection of an infant cadaver. Reprinted from J. Urol. 177, Walsh, P. C. The discovery of the cavernous nerves and development of nerve sparing radical retropubic prostatectomy, 1632–1635, © 2007, with permission from Elsevier.
peptide in the neuroregenerative reponse to injury, being 180-fold upregulated in the first week after crush injury of the cavern ous nerves and present in the nNOS-positive nerves innervating the corpora cavernosa.49 NGF was the first neurotrophic factor to be discovered, in 1951 by Nobel prize winners Rita Levi-Montalcini and Stanley Cohen (Box 5).50 NGF was also the first neurotrophin investigated in the field of urology, with a documented neuroprotective effect in vitro on major pelvic ganglion (MPG) neurons.51 After cavernous nerve ablation, NGF treatment minimally increased erectile function, and the combination of nerve grafts with NGF restored erectile function in vivo.44 In 2014, researchers showed that blockade of neuro trophic tyrosine kinase receptor type 1, NGF’s preferred receptor, using a monoclonal anti body, had a positive effect on erectile function recovery in cavernous-nerve-crushed rats, as a result of preferential parasympathetic over sympathetic nerve regeneration.52 For NTRN, another glial-derived neurotrophic factor, a similar selective neurotrophic effect was seen, with in vitro treatment stimulating outgrowth preferentially in parasympathetic but not sympathetic pelvic neurons.53 In 2003, Tom Lue’s lab reported the development of an explant nerve culture model of the MPG to elegantly study the neurotrophic properties of different growth factors and peptides, showing that vascular endothelial growth factor (VEGF), NT3, NT4 and BDNF significantly increased nerve outgrowth.46 Intracavernosal injec tion of BDNF as a neurotrophic factor 54 or as gene therapy via an adenoviral vector 43 both enhanced erectile function recovery in CNI rats and improved regeneration of the nNOS‑containing nerves. ADVANCE ONLINE PUBLICATION | 3
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PERSPECTIVES Walsh performs first purposeful nerve-sparing radical prostatectomy
Rita Levi-Montalcini and Stanley Cohen discover NGF for which they will later receive the Nobel Prize in Physiology or Medicine
First perineal radical prostatectomy for prostate cancer, carried out with the intent to cure by H. H. Young
1904
1947
Schuessler performs the first laparoscopic radical prostatectomy
Reiner and Walsh describe the anatomy of the dorsal vein complex and its surgical control
1951
1979
Binder performs first RALP
Proof of interposition nerve grafting after cavernous nerve resection in rats
1981
First retropubic radical prostatectomy for prostate cancer by T. Millin Advances in Advances in Advances in Advances in Advances in Advances in Preclinical Clinical
Viagra® (sildenafil citrate) is the first PDE5I approved by the FDA for the treatment of ED
anatomy and surgery cavernous nerve grafting and identification growth factors penile oxygenation strategies stem cells immunomodulation
1982
1989
1991
1996
1998
2000
Kim introduces a technique of sural nerve grafting to restore erectile function
Quinlan first describes a rat animal model of CNI to study penile erection
Walsh and Donker discover the anatomy of the cavernous nerves in a stillborn male infant
1999
2001
FK506 is shown to have a neuroprotective effect in cavernous nerve-crushed rats
Early postoperative administration of alprostadil injections shown to increase the recovery rate of spontaneous erections after radical prostatectomy
Figure 2 | Landmarks in erectile function recovery after radical prostatectomy. Abbreviations: CNI, cavernous nerve injury; ED, erectile dysfunction; MSC, mesenchymal stem cels; NGF, nerve growth factor; PDE5I, phosphodiesterase-5 inhibitor; RALP, robot-assisted radical prostatectomy.
Concerns remain regarding the use of neurotrophic factors in patients who have recently undergone prostatectomy for onco logical purposes. Besides this concern, the pharmacokinetic properties of these neuro trophic factors are an important reason why the promising preclinical results of neurotrophic factor therapy have, so far, not been investigated in clinical studies. Neurotrophins have a poor permeability over biological barriers such as the intestinal mucosa and undergo presystemic enzymatic degradation.55 Incorporating neurotrophic factors into a hydrogel for intraoperative topical application on the neurovascular bundle could be an alternative to oral admin istration, and could, potentially, be used to optimize erectile function recovery after radical prostatectomy.56
Cavernous nerve identification
In the late 1990s, a device was designed to improve the intraoperative identification of the cavernous nerve and reduce injury to this vital structure. Cavermap® (UroMed, Boston, MA), a commercially available nerve stimulator and tumescence-detecting
device, was developed to facilitate neuro vascular bundle preservation (Box 3).57 The widespread use of this device was, however, prevented by the high false-positive detec tion rates58 and the inability to significantly improve postoperative erectile function in clinical studies.59 In patients at risk for extracapsular exten sion of their tumour, one or both cavernous nerves must be sacrificed to achieve local cancer control. To bridge the resulting gap between both nerve ends, reconstruction of the nerve using an interposition nerve graft has been performed.60 The proof of principle was provided in a study by Quinlan et al.61 in 1991, in which they showed that rats treated with an interposition genitofemoral nerve graft had significantly better erectile function than nongrafted rats after cavernous nerve ablation. In 1999, Kim et al.62 first reported the use of bilateral sural nerve interposition after wide resection of the neurovascular bundle, which enabled one-quarter of patients to have medically unassisted sexual intercourse and a further 43% to have medi cally assisted intercourse.63 Several groups have since reported their own results with the
Box 3 | Landmarks in cavernous nerve grafting and identification 1989: Quinlan first describes a rat model of CNI to study penile erection31 1991: Proof of interposition nerve grafting after cavernous nerve resection in rats by Quinlan 61 1998: Introduction of Cavermap®for intraoperative identification of the cavernous nerves57,58 1999: Kim introduces a technique of sural nerve grafting to restore erectile function after non‑nerve-sparing radical prostatectomy62 2009: A large randomized clinical trial shows no significant benefit in erectile function recovery 2 years after unilateral sural graft interposition66 Abbreviation: CNI, cavernous nerve injury.
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use of sural or genitofemoral grafts, in series including up to 107 patients.60,64,65 However, despite the promising results of these initial series, a well-designed randomized multi centre phase II trial, published in 2009, demonstrated no difference in erectile func tion recovery between patients undergoing unilateral NSRP with or without sural nerve graft interposition.66 These disappointing results decreased the general popularity and use of nerve interposition grafting, owing to the unclear added benefit in terms of erec tile function recovery, and the technique has now been abandoned (Box 3).
Preserving cavernosal integrity
The denervation occurring after radical prostatectomy results in a decrease of the rate and quality of both daily and nocturnal erections, rendering the penis in a persistent state of hypoxia.67 In vitro and in vivo studies support the theory that penile hypoxia results in collagen accumulation, smooth muscle apoptosis, and fibrosis.67,68 Eventually, this penile damage can result in permanent ED, even if normal function of the nerves is restored.67 The concept of penile rehabilita tion is based on the use of any therapy able to preserve erectile function via an improve ment in cavernosal oxygenation, in order to preserve endothelial function and to prevent smooth muscle fibrosis. Montorsi and colleagues69 were the first group to clinically test the concept of post prostatectomy penile rehabilitation, when in 1997 they published a pioneering clinical study on the effects of intracavernosal injec tions of alprostadil early after NSRP (Box 6). www.nature.com/nrurol
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PERSPECTIVES Mulhall describes an erectogenic pharmacotherapy regimen combining assessment of PDE5I response with intracavernous injections in case of PDE5I-nonreponders
Raina et al. describe the use of regular application of the vacuum erection device for the recovery of erectile function after radical prostatectomy
A large double-blind prospective randomized trial (REINVENT) fails to show the effectiveness of daily administration of vardenafil as a treatment for ED after nerve-sparing radical prostatectomy
A large double-blind prospective randomized trial (REACTT) fails to show the effectiveness of daily administration of tadalafil as a treatment for ED after nerve-sparing radical prostatectomy when compared with on-demand use and placebo
FK506 and GPI-1046 fail to show proven benefit in erectile function recovery after nerve-sparing radical prostatectomy in humans
First phase I safety data for penile injection of bone-marrow mononucleated cells in humans
A large randomized clinical trial shows no significant benefit of unilateral sural graft interposition on erectile function 2003
2004
A randomized, placebo-controlled study is published, examining the benefits of nightly administration of sildenafil for the return of erectile function after bilateral nerve-sparing radical prostatectomy
2005
2006
2007
First report of neural embryonic stem cells preserving the erectile function in a rat model of CNI An uncontrolled trial demonstrates that early, regular sildenafil citrate administration after nerve-sparing radical retropubic prostatectomy preserves, or even increases, intracorporal smooth muscle content
In this study, 30 patients were randomized to receive either alprostadil injections three times per week for 12 weeks (n = 15) or obser vation alone (n = 15); participants were then evaluated 3 months later. In the treatment group, 12 of 15 men completed treatment. Of these, eight (67%) reported the recovery of spontaneous erection sufficient for satis factory sexual intercourse, compared with only three patients (20%) in the observation arm.69 The authors concluded that early use of alprostadil injections significantly increased the recovery rate of spontaneous erections after NSRP. Notable limitations were that preoperative parameters of erec tile function were not assessed, and that this study was performed before the routine use of validated questionnaires. Additionally, the short follow-up duration limited the drawing of any conclusions regarding long‑term effects of therapy.69 Considering the flaws in the study design, especially regarding the delayed start of rehabiliatation after surgery, it is somewhat surprising that this study, and the general concept of penile rehabilitation, has influ enced not only the clinical trials but also the basic science studies in this field for almost 20 years.70 The optimal rehabilitation sched ule is based on two key points: the first is that the therapy should be started as soon as possible after the iatrogenic damage, and the second that it should be administered as a continuous treatment and not as an on-demand therapy.70 Since Montorsi and coauthors’ 1997 study, several rehabilita tion strategies have been proposed, includ ing neuromodulatory agents, Medicated Urethral System for Erection (MUSE®, Vivus, USA), oral PDE5I therapy and vacuum erection devices (VEDs) (Box 6).71
2008
2009
2010
2012
2013
2014
Confirmation of the beneficial effect of MSC in a CNI rat model
Non-immunosuppressive immunophilin ligands show benefit in erectile function preservation in CNI rat models
PDE5 inhibitors Since the introduction of sildenafil in 1998, penile rehabilitation with PDE5I therapy has garnered further interest within the inter national urological community. Several well designed preclinical studies using rodent models have investigated the role of PDE5Is in penile rehabilitation.68 In 2006, Vignozzi et al.72 demonstrated that the daily admin istration of tadalafil reduced penile hypoxia, smooth muscle apoptosis, and fibrosis induced by cavernous neurotomy in rats. In the same year Ferrini and coauthors73 showed that daily vardenafil treatment prevented veno-occlusive dysfunction after bilateral cavernous nerve resection in rats. Then, in 2008, Mulhall and colleagues74 demonstrated the beneficial effect of daily administration of sildenafil in a rat model of cavernous nerve crush injury, which mimics the nerve injury occurring during NSRP. Their study showed that daily sildenafil administration improved the penile smooth muscle:collagen ratio, increased penile smooth muscle replication, reduced penile apoptotic index and preserved penile endothelial function shown by eNOS expression preservation.74 Furthermore, in 2011, Ferrini and colleagues showed that PDE5I rehabilitation has a beneficial effect, not only on the penile tissue, but also on the MPG, where it attenuates the upregulation
Adminstration of SVF shown to increase erectile function recovery in a rat model of CNI
A large double-blind prospective randomized trial fails to show the effectiveness of daily administration of sildenafil as a treatment for ED after nerve-sparing radical prostatectomy
Nature Reviews | Urology of profibrotic factors such as TGFβ and connective tissue growth factor (CTFG), and upregulates the expression of beneficial factors such as the angiogenic factor VEGF after CNI.75,76 Based on these results, PDE5Is might prove able to ameliorate neuro pathic pain, promote neuroprotection, and favour nerve regeneration, providing for the first time a justification for their use as a neuroprotective agent after NSRP.75,77 Surprisingly, the majority of these basic studies were conducted and published after PDE5I rehabilitation had already found its way into clinical practice. In 2004, Schwartz and colleagues demonstrated that early, regular (every other night) use of silde nafil after nerve-sparing radical retropubic prostatectomy preserves, or even increases, intracorporeal smooth muscle content in humans, although it is important to note that this study did not include a control group.78 Padma-Nathan and colleagues79 reported the results of a randomized, placebo- controlled study examining the benefits of nightly administration of sildenafil during the postoperative period following bilateral nerve-sparing prostatectomy in 2008. The study included 76 men with normal pre operative erectile function, and 27% of those receiving sildenafil self-reported a return of spontaneous erectile function at 48 weeks
Box 4 | Landmarks in immunomodulatory therapy 2001: The neuromodulatory drug FK506 is shown to have a neuroprotective effect in cavernous-nerve-crushed rats35 2007: Non-immunosuppressive immunophilin ligands FK1706 and GPI1046 show benefit in erectile function preservation in a CNI rat model37,38 2008: FK506 and GPI1485 fail to show proven benefit in erectile function recovery after nerve‑sparing radical prostatectomy39,40 Abbreviation: CNI, cavernous nerve injury.
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PERSPECTIVES Box 5 | Landmarks in neurotrophic factor therapy 1951: Rita Levi-Montalcini and Stanley Cohen discover NGF, for which they will later receive the Nobel Prize in Physiology or Medicine50 1992: First use of NGF in a preclinical study in urology; NGF shown to support survival of MPG neurons51 2003: MPG explant nerve culture used to screen for neurotrophic effects of different peptides 46 2006: BDNF shown to stimulate neurite outgrowth through JAK-STAT signalling102 Abbreviations: BDNF, brain-derived neurotrophic factor; JAK-STAT, janus kinase–signal transducer and activator of transcription; MPG, major pelvic ganglion; NGF, nerve growth factor.
Box 6 | Landmarks in penile rehabilitation 1996: Montorsi et al.69 show that the early postoperative administration of alprostadil injections significantly increases the recovery rate of spontaneous erections after radical prostatectomy 1998: Viagra®(Pfizer, New York) is the first PDE5I approved by the FDA for the treatment of erectile dysfunction103 2003: Padma-Nathan and colleagues report the results of a randomized, placebo-controlled study examining the benefits of nightly administration of sildenafil during the postoperative period for the return of normal function at 48 weeks following a bilateral nerve-sparing radical prostatectomy79 2004: Schwartz and colleagues show in an uncontrolled trial that early, regular use of sildenafil after nerve-sparing radical retropubic prostatectomy preserves, or even increases, intracorporal smooth muscle content78 2005: Mulhall describes an erectogenic pharmacotherapy regimen combining assessment of PDE5I response with intracavernous injections in case of PDE5I-nonresponders, and shows benefit of this approach in a nonrandomized trial104 2006: First preclinical evidence for beneficial effect of daily administration of tadalafil in rats after bilateral cavernous neurotomy72 2006: Raina et al.88 report on the use of regular application of the vacuum erection device for the recovery of erectile function after radical prostatectomy 2008: Montorsi et al.81 fail to show the effectiveness of daily administration of vardenafil as a treatment for ED after nerve-sparing radical prostatectomy in a large double-blind prospective randomized trial, when compared with on-demand use and placebo 2013: Pavlovich et al.83 fail to show the effectiveness of daily administration of sildenafil as a treatment for ED after nerve-sparing radical prostatectomy in a large double-blind prospective randomized trial when compared with on-demand use and placebo 2014: Montorsi et al.84 fail to show the effectiveness of daily administration of tadalafil as a treatment for ED after nerve-sparing radical prostatectomy in a large double-blind prospective randomized trial when compared with on-demand use and placebo Abbreviations: ED, erectile dysfunction; PDE5I, phosphodiesterase type 5 inhibitor.
after surgery, compared with only 4% in the placebo group.80 Although this study has been criticized for the seemingly low per centage of men considered responders in the placebo arm, the criteria for being consid ered a responder in this study were stringent, and it represents the first placebo-controlled trial suggesting a benefit of oral PDE5I therapy in improving the return of spon taneous erections. In a subanalysis of data from this study, the self-reported results were corroborated by nocturnal penile tumes cence data. A rapid and profound reduction in nocturnal erectile function was noted in all groups after surgery, but a gradual dosedependent improvement in base and tip rigidity was predominantly observed in the sildenafil groups, with little improvement in the placebo group.80
More recently, well conducted, well designed, prospective, large randomized clinical trials have challenged the belief that regular dosing of a PDE5I following radical prostatectomy can prevent the deterioration of erectile function. The REINVENT trial, which included 628 men, failed to show the effectiveness of daily administration of vardenafil from an early postoperative stage.81 A 2010 randomized, prospective trial compared the effectiveness of nightly administration of intraurethral alprostadil (MUSE®) and sildenafil to rehabilitate erec tile function after radical prostatectomy, but no differences in IIEF-EF score were found between groups at 11 months after surgery.82 Pavlovich and co-workers investi gated the benefits of nightly administration of sildenafil during the postoperative period
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following bilateral NSRP in a double- dummy designed trial published in 2013.83 This study included a total of 100 pre operatively potent men, aged
