Coverage Policy Manual
Policy #: 2001013
Category: Surgery
Initiated: May 2001
Last Review: October 2018
  Nerve Graft For Patients Undergoing Radical Non-Nerve-Sparing Prostatectomy

Description:
Erectile dysfunction is a common problem after radical prostatectomy. In particular, spontaneous erections are absent in patients whose extent of prostate cancer requires bilateral resection of the neurovascular bundles as part of the radical prostatectomy procedure. A variety of noninvasive treatments are available, including vacuum constriction devices and intracavernosal injection therapy. However, spontaneous erectile activity is clearly preferred by patients.
 
Recently, there has been interest in  nerve grafting to replace cavernous nerves resected at the time of prostatectomy. The sural nerve and the genitofemoral nerve are considered expendable and have been used extensively in other nerve grafting procedures, such as brachial plexus and peripheral nerve injuries. As applied to prostatectomy, a portion of the  nerve is harvested from 1 leg and then anastomosed to the divided ends of the cavernous nerve.
 
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 the FDA through the 510(k) process.
(FDA product code: JXI). An example of a human tissue nerve graft product, the AvanceĀ® nerve graft
(AxoGen, Inc.), is regulated by the FDA under the 21 CFR Part 1271 regulations for Human Cellular and Tissue-based Products (HCT/P).
  
There are no CPT codes specific to nerve graft replacement of the cavernous nerve.

Policy/
Coverage:
For member benefit contracts or Plans with Primary Coverage Criteria resection of one or both neurovascular bundles as part of a radical prostatectomy is not covered because it fails to meet the Primary Coverage Criteria ("The Criteria") of the applicable benefit certificate or health plan.  The Criteria require, among other things, that there be scientific evidence of effectiveness, as defined in the Criteria.  The Criteria exclude coverage of interventions if there is a lack of scientific evidence regarding the intervention, or if the available scientific evidence is in conflict or the subject of continuing debate.

For member benefit contracts or Plans with explicit exclusion language for experimental or investigational services, resection of one or both neurovascular bundles as part of a radical prostatectomy is not covered because it is considered experimental or investigational as defined in the applicable benefit contract or health plan, which excludes coverage of experimental or investigational treatment or services.

Rationale:
This policy originated from an Arkansas Blue Cross Blue Shield Technology Assessment in May 2001.
 
Limited data are published regarding the long-term outcomes of sural nerve grafting; the largest study reported is a case series of 23 men with a mean 23-month follow-up.  All men had clinically localized, but high-volume prostate cancer such that bilateral resection of the neurovascular bundles was considered necessary. Before surgery, all men reported spontaneous erection. Outcomes included assessment of erectile function based on:
    • the International Index of Erectile Function,
    • visual assessment, and
    • assessment by patient partners.
Patients were also encouraged to use a variety of erectile dysfunction treatments, including intracavernosal injections, vacuum constriction devices, or sildenafil citrate, as needed. The results were compared to a group of 12 men who were potent preoperatively and had undergone prostatectomy with bilateral nerve resection, but who declined nerve graft placement. Of the 23 men undergoing nerve graft, 6 (26%) had spontaneous, medically unassisted erection sufficient for sexual intercourse. An additional 6 men (26%) reported 40% to 60% spontaneous erection that was insufficient for intercourse; 4 of these patients were able to have intercourse using sildenafil. Therefore, a total of 10 of the 23 patients were able to have intercourse, either spontaneously or with pharmacologic therapy. A total of 11 men had no clinical response even with the use of sildenafil. Not unexpectedly, all outcomes were significantly better compared to the control group. Side effects of the sural nerve donor site, which included incisional pain and a sensory deficit along the lateral aspect of the foot, were considered tolerable. The authors noted improvement 8 to 12 months postoperatively and accelerated improvement at 12 to 18 months postoperatively. In addition there are reports from the same group of surgeons who reported in 2001 that some 220 sural nerve grafts had been performed at their institution.  Some surgeons have performed unilateral sural nerve grafts. However, without a controlled study in this population, it will be difficult to isolate the contribution of the sural nerve graft compared to the spontaneous recovery of erectile activity.
 
In summary, the data are insufficient to permit scientific conclusions regarding the long-term effectiveness of sural nerve grafting in men undergoing prostatectomy.
 
2004-2005 Update
A search of the literature did not identify any additional published articles that would alter the above conclusions; therefore, the policy statement is unchanged. Singh and colleagues investigated whether unilateral sural nerve graft would improve urinary function after radical prostatectomy.  Patients with and without a sural nerve graft were invited to complete a questionnaire. At 12 months after surgery, 94.7% of patients with a sural nerve graft reported complete urinary control compared to 58.3% without a sural nerve graft. The authors concluded that these preliminary results required validation in larger, multicenter, prospective randomized studies. No additional studies were identified that focused on the outcome of potency.
 
2007 Update
A search of the literature was conducted through February 2007. Secin and colleagues reported results on 44 consecutive patients who underwent bilateral nerve grafting from 1999 to 2004 at Memorial Sloan-Kettering Cancer Center.   The overall five-year recovery of erectile function was 34% and the rate of consistent function was 11%. None of a number of variables (e.g. age, type of nerve (sural, genitofemoral, ilioinguinal), comorbidities, etc.) were significantly associated with recovery of postoperative erectile function. The authors concluded that nerve grafts might be beneficial in select patients; but that a randomized controlled trial was needed.
 
Sim reported on two-year results in 41 patients who received unilateral sural nerve grafts following radical prostatectomy when one neurovascular bundle was resected.  In this series, recovery of erectile function was reported for 63% of patients (based on 24 of 38 patients). This paper also reported on erectile function on another group of patients who had unilateral resection at the same institution but without a nerve graft. In this group that was older and was not a matched on key characteristics to the group who received a nerve graft, the erectile function was 26.5% (13 of 49). Nelson reported on results of using genitofemoral nerve grafts in 27 patients (5 with bilateral grafts) with radical prostatectomy.  At a mean follow up of 14 months, 56% of patients reported erectile function sufficient for penetration. The authors noted uncertainly about whether their findings were a consequence of an effective unilateral nerve-sparing dissection or of the nerve grafting.
 
While these numerous studies demonstrate that unilateral or bilateral nerve grafting is feasible, whether or not this technique results in improved patient outcomes following radical prostatectomy requires further study in randomized controlled trials. Thus, the policy statement is unchanged.
 
2008 Update
A literature search was conducted using MEDLINE for February 2007 to April 2008. The studies identified were small, single-center cohort studies; some had non-grafted comparison groups. Several studies report on small numbers (3 to 6 patients) with bilateral grafting that are insufficient for making comparisons or conclusions.
 
Zorn et al (2008) reported the experience of 27 nerve grafted (23 unilateral, 4 bilateral) sural nerve grafts on sexual and urological function over a mean of 26 months.  Several comparisons were made using their prospectively collected database of non-grafted patients. At one year, continence rates were not different for the grafted and non-grafted but nerve(s) spared groups. Sexual function was defined using validated questionnaires, and 24 of 27 nerve grafted patients were potent preoperatively. No differences between unilateral nerve graft and unilateral nerve sparing with no grafting were noted with respect to return to baseline sexual function. At mean follow-up of 26 months, 47.8% of unilaterally grafted patients had regained potency, compared to 56% for age matched unilateral nerve sparing with no grafting.
 
Namiki et al (2007) published a 3-year study from Japan of the results of unilateral sural nerve graft on recovery of sexual and urological function. A total of 113 patients were compared: 19 patients with unilateral nerve sparing plus sural nerve graft, 60 patients with unilateral nerve sparing but no grafting, and 34 patients with bilateral nerve sparing surgery. Sexual function was assessed with validated questionnaires and at 2 years there was no difference between the nerve grafted and the bilateral nerve sparing patients with regard to sexual function scores. At 3 years, 25 and 28% of patients in the nerve grafted and bilateral nerve sparing patients respectively considered their sexual function as fair or good. Urinary function returned to baseline in the nerve grafted and bilateral nerve sparing groups at 6 months and in the unilateral nerve spring group at 12 months. Differences in sexual function were present at baseline with the nerve grafted and bilateral nerve sparing patients reporting higher baseline function than the unilateral nerve sparing group.
 
Randomized trails are still warranted in order to discern the effects of nerve grafting and nerve sparing and to remove selection biases present in the current studies.  The impact of nerve grafting in association with radical prostatectomy on outcomes is unknown.  The statement of noncoverage remains.
 
2012 Update
This policy is being updated with a search of the MEDLINE database through July 2012.  There was no new information identified that would prompt a change in the coverage statement.
 
The first randomized controlled trial (RCT) that evaluated nerve grafting was published in 2009 by Davis and colleagues (Davis, 2009). Eligibility criteria included age 65 years or younger, normal self-report baseline erectile function, and scheduled for a unilateral nerve-sparing radical prostatectomy with preservation of one neurovascular bundle. All patients had the other neurovascular bundle removed, and patients were randomly assigned to receive or not receive sural nerve-grafting after its removal. The primary outcome was potency 2 years post-surgery, defined as the ability to have intercourse with or without erectile dysfunction medication. The investigators estimated that the control group would have a 40% potency rate and powered the study to detect an absolute difference of 20% between groups. All patients received the same early erectile dysfunction therapy including medication and mechanical devices. A sample size of 200 was originally planned to provide 80% power. However, after 107 patients were randomly assigned, a pre-planned interim analysis of evaluable patients found similar rates of potency in the 2 groups; the Data Monitoring Committee estimated that there was less than a 5% chance that there would be a significant difference between groups with additional recruitment and the trial was stopped early. When data collection ended, endpoint data were available for 66 patients who had either achieved potency or had been followed up for 2 years without potency. Potency was achieved in 32 of 45 (71%) sural nerve-graft patients and 14 of 21 (67%) control patients (p=0.78). The authors concluded that unilateral sural nerve-graft did not result in an absolute improvement of 20% in the rate of potency but that a smaller effect cannot be ruled out. A limitation of the study was that it was non-blinded, which could have impacted self-report of potency.
 
A recent case series reviewed the records of 131 men who had unilateral nerve grafts after radical prostatectomy with unilateral neurovascular bundle resection (Rabbani, 2010). Men who had prior radiation or hormonal treatment were excluded. Another eligibility criterion was satisfactory erections presurgery as assessed by a 5-point scale (1=full erections; 2=diminished erections, but routinely sufficient for sexual intercourse; 3=partial erections occasionally satisfactory for intercourse; 4=partial erections unsatisfactory for intercourse; and 5=no erections). A total of 49 men received sural nerve grafts, 79 received genitofemoral nerve grafts, and 3 received ilioinguinal nerve grafts. Recovery of erections was evaluated at each follow-up visit according to the 5-point scale (also called 5 levels). The median patient age was 58.7 years, and the median follow-up was 37 months. According to actuarial analysis, the 5-year probability of recovering erections of level 3 or better was 46%. The probability of recovering erections of at least level 2 or level 1 was 34% and 12%, respectively.
 
Practice Guidelines and Position Statements
The 2011 National Comprehensive Care Network (NCCN) prostate cancer guideline states that replacement of resected nerves has not been shown to be beneficial for recovery of erectile function after radical prostatectomy (NCCN, 2011).  
 
Summary
Only one randomized controlled trial that evaluated sural nerve-grafting with radical prostatectomy has been published, and this study did not find that unilateral nerve-grafting was associated with a statistically significant improvement in potency rates 2 years post-surgery. Due to the negative findings of this study, and the lack of other controlled studies evaluating unilateral or bilateral nerve grafting, there remains a lack of scientific evidence that this procedure improves health outcomes. The policy statement is unchanged.
 
2013 Update
 A search of the MEDLINE database did not reveal any new literature that would prompt a change in the coverage statement.
 
2014 Update
A literature search conducted through November 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
In 2014, Siddiqui et al reported 3-year follow-up on 66 men with clinically localized prostate cancer who had undergone sural nerve grafting during radical retropublic prostatectomy (Siddiqui, 2014). Forty-three (65%) were unilateral nerve grafts, and 23 (36%) were bilateral. All procedures were performed by a single surgeon. Recovery of potency was defined as a postoperative International Inventory of Erectile Function (IIEF) score greater than 22. Patients were permitted to use phosphodiesterase type 5 inhibitors) for erectile dysfunction. The mean preoperative IIEF score was 23.4 (SD 1.6), and postoperatively, 19 patients (28.8%) recovered potency ie, had an IIEF score greater than 22. When stratified by graft type, erectile function recovery rates were 28% after unilateral and 30% after bilateral nerve grafting.
 
2016 Update
A literature search conducted through November 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
A 2015 cohort study by Kung and colleagues 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 (Kung. 2015). 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 (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.
 
2017 Update
A literature search conducted through November 2017 did not reveal any new information that would prompt a change in the coverage statement.  
 
2018 Update
A literature search was conducted through September 2018.  There was no new information identified that would prompt a change in the coverage statement.  

CPT/HCPCS:
64999Unlisted procedure, nervous system

References: Canto EI, Nath RK, Slawin KM.(2001) Cavermap-assisted sural nerve interposition graft during radical prostatectomy. Urol Clin North Am, 2001; 28:839-48.

Davis JW, Chang DW, Chevray P et al.(2009) 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 2009; 55(5):1135-44.

Kim ED, Nath R, et al.(2001) Bilateral nerve grafting during radical retropubic prostatectomy: extended follow-up. Urology, 2001; 58:983-7.

Kim ED, Scardino PT, Hampel O, et al.(1999) Interposition of sural nerve restores function of cavernous nerves resected during radical prostatectomy. J Urol 1999; 161:188-19.

Kim ED, Scardino PT, Kadmon D, et ak,(2001) Interposition sural nerve grafting during radical retropubic prostatectomy. Urology 2001; 57:211-216.

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

Namiki S, Saito S, et al.(2007) Impact of unilateral sural nerve graft on recovery of potency and continence following radical prostatectoy: 3-year longitudinal study. J Urol, 2007; 178:212-6.

National Comprehensive Cancer Network.(2011) Clinical practice guidelines in oncology, v4.2011. Available online at: http://www.nccn.org/professionals/physician_gls/PDF/prostate.pdf. Last accessed October 2011.

Nelson BA, Chang SS, et al.(2006) Morbidity and efficacy of gentofemoral nerve grafts with radical retropubic prostatectomy. Urology, 2006; 67:789-92.

Rabbani F, Ramasamy R, Patel MI et al.(2010) Predictors of recovery of erectile function after unilateral cavernous nerve graft reconstruction at radical retropubic prostatectomy. J Sex Med 2010; 7(1 pt 1):166-81.

Secin FP, Koppie TM, et al.(2007) Bilateral cavernous nerve interposition grafting during radical retropubic prostatectomy: Memorial Sloan-Kettering Cancer Center experience. J Urol, 2007; 177:664-8.

Siddiqui KM, Billia M, Mazzola CR, et al.(2014) 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

Sim HG, Kliot M, et al.(2006) Two-year outcome of unilateral sural nerve interposition graft after radical prostatectomy. Urology, 2006; 68:1290-4.

Singh H, Karakiewicz P, et al.(2004) Impact of unilateral interposition sural nerve grafting on recovery of urinary function after radical prostatectomy. Urology, 2004; 63:1122-7.

Souza Trindade JC, Viterbo F, Petean Trindade A, et al.(2017) 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. Jan 17 2017. PMID 28093890

Zorn KC, Bernstein AJ, et al.(2008) Long-term functional and oncological outcomes of patients undergoing sural nerve interposition grafting during robot-assisted laparoscopic radical prostectomy. J Endourol, 2008;[epub ahead of print Apr 2008].


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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