Erectile Dysfunction

Erectile dysfunction is a common problem after radical prostatectomy. In particular, spontaneous erections are usually absent in men whose prostate cancer required bilateral resection of the neurovascular bundles as part of the radical prostatectomy procedure.

Treatment

A variety of noninvasive treatments are available, including vacuum constriction devices and intracavernosal injection therapy. However, spontaneous erectile activity is preferred by patients. Studies have reported results from bilateral and unilateral nerve grafts, the latter involving resection of 1 neurovascular bundle.

There has been interest in sural nerve grafting to replace cavernous nerves resection during prostatectomy. The sural nerve is considered expendable and has been extensively used in other nerve grafting procedures, such as brachial plexus and peripheral nerve injuries. As applied to prostatectomy, a portion of the sural nerve is harvested from 1 leg and then anastomosed to the divided ends of the cavernous nerve. Reports also indicate the use of other nerves (eg, genitofemoral nerve) for grafting.

Regulatory Status

A nerve graft with radical prostatectomy is a surgical procedure and, as such, is not subject to regulation by the U.S. Food and Drug Administration (FDA).

Several nerve cuff products have been cleared for marketing by FDA through the 510(k) process. FDA product code: JXI. An example of a human tissue nerve graft product, the Avance® nerve graft (AxoGen), is regulated by FDA under 21 CFR, Part 1271 regulations for Human Cellular and Tissue-based Products (HCT/P).

Related Policies

• None

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Clinical Context and Therapy Purpose

The purpose of nerve grafting in patients who have radical prostatectomy is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this policy is: Does nerve grafting improve the net health outcome in patients who have have radical prostatectomy with resection of neurovascular bundles?

The following PICO was used to select literature to inform this policy.

Patients

The relevant population of interest is men who have radical prostatectomy with resection of neurovascular bundles.

Interventions

The therapy being considered is nerve grafting in association with radical prostatectomy.

Comparators

The relevant comparator is prostatectomy without nerve grafting.

Outcomes

The outcomes of interest are functional outcomes, quality of life, and treatment-related morbidity.

Nerve Grafting

One randomized controlled trial evaluating nerve grafting to reduce the risk of erectile dysfunction has been published; findings were reported by Davis et al (2009). ^1, The trial included men age 65 years or younger with normal self-reported baseline erectile function selected for a unilateral nerve sparing radical prostatectomy with preservation of 1 neurovascular bundle. All patients had unilateral neurovascular bundle removal, and patients were randomized to receive or not sural nerve grafting after removal. The primary outcome was potency 2 years postsurgery, defined as the ability to have intercourse with or without erectile dysfunction medication. All patients received the same early erectile dysfunction therapy, including medication and mechanical devices. The investigators sought to detect an absolute difference of 20% between groups (graft, 60% potency rate vs no graft, 40% potency rate). A sample of 200 men was originally planned to provide 80% power. However, after 107 men were randomized, a preplanned interim analysis of evaluated patients found similar potency rates between groups. The data monitoring committee stopped the trial based on its estimate of less than a 5% chance that additional recruitment would result in a significant difference between groups. End point data were available for 66 patients. Potency was achieved in 32 (71%) of 45 sural nerve graft patients and 14 (67%) of 21 control patients (p=0.78). Trialists concluded that unilateral sural nerve graft did not result in an absolute improvement of 20% between groups, but that a smaller effect could not be ruled out. A limitation of the trial was that it was unblinded, which, because men knew the procedure they received, could have impacted self-report of potency.

The literature also includes 2 retrospective cohort studies and 3 case series.^2,3,4,5,6, The cohort studies are described below.

The cohort study by Kung et al (2015) included 38 patients who underwent nerve grafting after radical prostatectomy and a random sample of 53 control patients who had open prostatectomy without nerve grafting. Control patients had unilateral or bilateral nerve sparing prostatectomy or non-nerve sparing prostatectomy. Complete urinary incontinence, no erectile capacity at baseline, and follow-up data less than 12 months were study exclusion criteria. Unilateral nerve grafting (n=29) and unilateral nerve sparing (n=10) patients did not differ significantly between groups (p>0.05) on various outcomes, including urinary continence, erections sufficient for sex, spontaneous erections, and use of erectile dysfunction medications. Bilateral nerve grafting (n=9) and bilateral non-nerve sparing (n=10) patients had similar outcomes (p>0.05). This study lacked randomization and blinding, and subgroup analyses included small numbers of patients.

The second cohort study, published by Namiki et al (2007), included 113 patients: 19 had unilateral nerve sparing plus sural nerve graft, 60 patients had unilateral nerve sparing with no grafting, and 34 patients had bilateral nerve sparing surgery.^3, Function was assessed using validated questionnaires and, at 2 years, no difference in sexual function scores was found between the unilateral nerve graft and bilateral nerve sparing patients. At 3 years, similar percentages of patients in the unilateral nerve graft (25%) and bilateral nerve sparing (28%) groups considered their sexual function as fair or good. Urinary function returned to baseline continence in the unilateral nerve graft and bilateral nerve sparing groups at 6 months and in the unilateral nerve sparing group at 12 months. Baseline sexual function differed between groups, which could have biased study findings: the nerve grafted and bilateral nerve sparing patients reported higher baseline function than the unilateral nerve sparing group.

Summary of Evidence

For individuals who have radical prostatectomy with resection of neurovascular bundles who receive nerve grafting, the evidence includes a randomized controlled trial, cohort studies, and case series. Relevant outcomes are functional outcomes, quality of life, and treatment-related morbidity. The randomized controlled trial did not find that unilateral nerve grafting was associated with a statistically significant improvement in potency rates at 2 years postsurgery. Cohort studies also did not result in better outcomes with nerve grafting. The evidence is insufficient to determine the effects of the technology on health outcomes.

SUPPLEMENTAL INFORMATION
Clinical Input From Physician Specialty Societies and Academic Medical Centers

While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

In response to requests, input was received from 4 academic medical centers while this policy was under review in 2008; no input was received from physician specialty societies. Input from the 4 centers agreed that this procedure is considered investigational.

Practice Guidelines and Position Statements

The National Comprehensive Cancer Network guidelines on the treatment of prostate cancer (v.1.2020) states: “Replacement of resected nerves with nerve grafts has not been shown to be beneficial” for recovery of erectile function after radical prostatectomy.^7,

U.S. Preventive Services Task Force Recommendations

Not applicable.

Ongoing and Unpublished Clinical Trials

A currently unpublished trial that might influence this policy is shown in Table 1.

Table 1. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT01770340	Nerve Grafting With an Allograft During Radical Prostatectomy - Extended Follow-up in a Prospective Randomized Trial	30	Jul 2020

NCT: national clinical trial.]
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Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

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Index:
Nerve Graft with Radical Prostatectomy
Nerve Graft in Association with Radical Prostatectomy
Genitofemoral Nerve Graft in Association with Radical Prostatectomy
Prostatectomy, Nerve Graft in Association with
Sural Nerve Graft in Association with Radical Prostatectomy

References:
1. Davis JW, Chang DW, Chevray P, et al. Randomized phase II trial evaluation of erectile function after attempted unilateral cavernous nerve-sparing retropubic radical prostatectomy with versus without unilateral sural nerve grafting for clinically localized prostate cancer. Eur Urol. May 2009;55(5):1135-1143. PMID 18783876

2. Kung TA, Waljee JF, Curtin CM, et al. Interpositional nerve grafting of the prostatic plexus after radical prostatectomy. Plast Reconstr Surg Glob Open. Jul 2015;3(7):e452. PMID 26301141

3. Namiki S, Saito S, Nakagawa H, et al. Impact of unilateral sural nerve graft on recovery of potency and continence following radical prostatectomy: 3-year longitudinal study. J Urol. Jul 2007;178(1):212-216; discussion 216. PMID 17499797

4. Rabbani F, Ramasamy R, Patel MI, et al. Predictors of recovery of erectile function after unilateral cavernous nerve graft reconstruction at radical retropubic prostatectomy. J Sex Med. Jan 2010;7(1 Pt 1):166-181. PMID 19686422

5. Siddiqui KM, Billia M, Mazzola CR, et al. Three-year outcomes of recovery of erectile function after open radical prostatectomy with sural nerve grafting. J Sex Med. Aug 2014;11(8):2119-2124. PMID 24903070

6. Souza Trindade JC, Viterbo F, Petean Trindade A, et al. Long-term follow-up of treatment of erectile dysfunction after radical prostatectomy using nerve grafts and end-to-side somatic-autonomic neurorraphy: a new technique. BJU Int. Jun 2017;119(6):948-954. PMID 28093890

7. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer. Version 1.2020. https://www.nccn.org/professionals/physician_gls/PDF/prostate.pdf. Accessed March 2020.

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