Coverage Policy Manual
Policy #: 2013019
Category: Medicine
Initiated: June 2013
Last Review: June 2018
  Laser Treatment of Onychomycosis

Description:
Onychomycosis is a common fungal infection of the nail. Currently available treatments for onychomycosis, including systemic and topical antifungal medications, have relatively low efficacy and require a long course of treatment. Laser systems are proposed as another treatment option.
 
Onychomycosis is a common chronic fungal infection of the nail. It is estimated to cause up to 50% of all nail disease and 33% of cutaneous fungal infections (Rodgers, 2001). The condition can affect toenails or fingernails but is more frequently found in toenails. Primary infectious agents include dermatophytes (e.g., Trichophyton species), yeasts (e.g., Candida albicans) and non-dermatophytic molds. In temperate Western countries, infections are generally caused by dermatophytes.
 
Aging is the most common risk factor for onychomycosis, most likely due to decreased blood circulation, longer exposure to fungi, and slower nail growth. In addition, various medical conditions increase the risk of comorbid onychomycosis. These include diabetes, obesity, peripheral vascular disease, immunosuppression, and HIV infection. In certain populations, onychomycosis may lead to additional health problems. Although there is limited evidence of a causal link between onychomycosis and diabetic foot ulcers, at least one prospective study with diabetic patients found onychomycosis to be an independent predictor of foot ulcer (Boyko, 2006).  Moreover, onychomycosis, especially more severe cases, may adversely impact quality of life. Patients with onychomycosis have reported pain, discomfort wearing shoes, nail pressure, and embarrassment (Drake, 1998; Elewski, 2000).  
 
The diagnosis of onychomycosis can be confirmed by potassium hydroxide preparation, culture or histology. Treatments for onychomycosis include topical antifungals such as nail paints containing ciclopirox (ciclopiroxolamine) or amorolfine, and oral antifungals such as terbinafine and itraconazole. These generally have low to moderate efficacy and a high relapse rate. Topical antifungals and some long-available oral medications such as griseofulvin require a long course of treatment, which presents issues for patient compliance. Moreover, oral antifungal medications have been associated with adverse effects such as a risk of hepatotoxicity.
 
Several types of device-based therapies are under investigation for treatment of onychomycosis, including ultrasound, iontophoresis, photodynamic therapy and laser systems. A potential advantage of lasers is that they have greater tissue penetration than antifungal medication and thus may be more effective at treating infection embedded within the nail. Another potential advantage is that laser treatments are provided in a clinical setting in only one or several sessions and thus long-term patient compliance is less of an issue than with medications.
 
Laser treatment of onychomycosis uses the principle of selective photothermolysis. This is defined as the precise targeting of a tissue using a specific wavelength of light. The premise is that light is absorbed into the target area and heat generated by that energy is sufficient to damage the target area while sparing the surrounding area. The aim of laser treatment of onychomycosis is to heat the nail bed to temperatures required to disrupt fungal growth (approximately 40-60oC) and at the same time avoid pain and necrosis to surrounding tissues (Gupta, 2012).  
 
Characteristics of laser systems used to treat onychomycosis are as follows: (Gupta, 2012)
 
Wavelength: Lasers are single-wavelength light sources. There needs to be sufficient tissue penetration to adequately treat nail fungus. The near-infrared spectrum tends to be used because this is the part of the spectrum that has maximum tissue penetrance in the dermis and epidermis and the nail plate is similar to the epidermis. To date, most laser systems for treating onychomycosis have been Neodymium yttrium aluminum garnet (Nd:YAG) lasers that are typically operated at 1064nm; 940-1320nm and 1440nm wavelengths are also options.
 
Pulse duration: Pulses need to be short to avoid damage to the tissue surrounding the target area. For example, short-pulse systems have microsecond pulse durations and Q-switched lasers have nanosecond pulse durations.
 
Repetition rate (frequency of laser pulses, Hz): Selective photothermolysis requires that there be time between pulses to allow for dispersal of heat energy.
 
Spot size: This refers to the diameter of the laser beam. For treating onychomycosis, laser spot sizes range from 1 to 10 nm.
 
Fluence: This refers to the amount of energy delivered into the area and is measured in J/cm2).
 
A number of laser systems for treating onychomycosis have been cleared for marketing by the U.S. Food and Drug Administration (FDA). The FDA-cleared indications are for the temporary increase of clear nail; they are not cleared as a cure for onychomycosis.
 
Regulatory Status
A number of Nd:YAG laser systems have been cleared by the FDA for marketing for the temporary increase of clear nail in patients with onychomycosis. The FDA determined that these devices were substantially equivalent to existing devices. Cleared devices and year of FDA decision are as follows:
Nd:YAG 1064nm laser systems:
    • PinPointe FootLaser (PinPointe USA acquired by NuvoLase in 2011): 2010
    • GenesisPlus (Cutera): 2011
    • VARIABreeze (CoolTouch Inc.): 2011
    • JOULE ClearSense (Sciton): 2011
 
Dual wavelength Nd:YAG 1064nm and 532nm laser system:
    • Q-Clear (Light Age, Inc.): 2011
 
Coding
There is no specific CPT code for this treatment. It would likely be reported using an unlisted CPT code such as 17999 (Unlisted procedure, skin, mucous membrane and subcutaneous tissue) or 96999 (Unlisted special dermatological service or procedure).
 

Policy/
Coverage:
Laser treatment of onychomycosis does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, laser treatment of onychomycosis is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 

Rationale:
This policy was created with a search of the MEDLINE database through March 19, 2013. The main question for review is whether laser treatment is an efficacious treatment for onychomycosis, and whether it is at least as effective as alternatives.
 
In patients with onychomycosis, does laser treatment improve outcomes compared to alternative treatments?
 
Randomized, controlled trials with appropriate comparison groups are the best study design to answer this question. The most important outcome for this review is cure of onychomycosis, i.e., complete clearing without recurrence. Other useful outcomes would be symptoms and functional measures related to onychomycosis. Partial healing and accelerated nail growth are intermediate outcomes that may or may not be associated with reduction in symptoms, and/or cure of onychomycosis.
 
Randomized controlled trials (RCTs)
Findings of 2 RCTs evaluating laser treatment for onychomycosis have been published in peer-reviewed journals. One of the 2 studies used a laser system that has been cleared by the FDA for treating onychomycosis, the PinPointe Footlaser Nd: YAG 1064nm laser. This study, published in 2012 by Zhang and colleagues, was conducted in China and included 33 patients with clinical symptoms of onychomycosis and a diagnosis confirmed by mycological microscopic examination and fungal culture (Zhang, 2012). Patients were randomized to receive either 2 courses of laser treatment (n=15) or 1 course of laser treatment (n=18). Each session included 3 passes across the nail plate with 2-minute pauses between passes. A course of treatment consisted of 4 sessions, given on days 0, 7, 14, and 21, respectively. The group that received 2 courses of treatment underwent a total of 8 sessions. Patients were evaluated at weeks 8, 16 and 24.
 
The study’s primary efficacy outcome was the “effective rate”, i.e., the proportion of patients categorized as experiencing either “recovery” (full-grown new nail with a smooth plate, bright color and less than 5% defects) or “significant effect” (at least 60% newly grown nail). The unit of analysis was the number of treated nails (n=154) rather than number of patients assigned to that group. The investigators did not find a statistically significant difference in the effectiveness of treatment at any follow-up point between nails that received 2 courses compared to 1 course of treatment. For example, at week 24, treatment was determined to be effective in 40 of 78 nails (51%) that received 2 courses of treatment and 40 of 76 nails (53%) that received 1 course of treatment. No adverse events were reported.
 
The study has several methodological limitations that limit the ability to draw conclusions about the effect of laser treatment on outcomes in patients with onychomycosis. A key limitation is the lack of an appropriate comparison group. There was neither a control group who did not receive laser treatment, nor a comparison group that received standard treatment such as topical antifungals. Moreover, the authors did not discuss whether outcome assessment was blinded and this could have biased findings because the efficacy variable included a subjective component. In addition, randomization was done on a per patient basis but the analysis was done on a per nail basis, which can introduce bias because some patients contributed more than one nail and nails treated in the same individual cannot be considered independent units. A stronger study design when patients are the unit of randomization is to randomly select 1 eligible toe for inclusion in the study. Another option would be to include patients with 2 affected toes and randomize on a per toe basis, i.e., assign 1 toe to the treatment group and the other toe to the control group.
 
The other RCT, an industry-sponsored study by Landsman and colleagues, used a dual-wavelength near-infrared diode laser that has not been cleared by the FDA for treatment of onychomycosis (Landsman, 2010). Patients were blinded to treatment group and outcome assessment was done by unblinded investigators who conducted clinical examinations as well as by an independent blinded expert panel that reviewed photographs. The study included 36 patients with mycologically confirmed onychomycosis. To be eligible for participation, patients had to have at least 1 great toe with distal/lateral or superficial white onychomycosis that did not have luminal involvement or extend beyond the eponychium. If patients had 2 great toes meeting these criteria, then both toes were considered eligible for inclusion in the study. If patients had only 1 great toe meeting the criteria, the other toe was treated as a “companion toe” and could be treated but not included in the primary study.
 
Patients were randomized to receive actual laser treatment (n=26) or sham treatment (n=10). A treatment session consisted of a 4-minute exposure using 870 and 930 nm wavelengths followed by a second exposure for 2 minutes at 930 nm only. A course of treatment included 4 sessions, 1 each on day 1, 14, 42, and 120. The sham treatment group received the same number of sessions, but the laser power was set to zero. A total of 34 of 36 patients (94%) completed the study. The 34 patients had a total of 59 toes treated with an active or sham laser. Thirty-seven of the toes met the clinical eligibility criteria described above (26 in the active treatment group and 11 in the control group).
 
The primary study outcomes were the proportion of patients that had at least 3 mm of clear nail growth and attainment of a negative mycological finding. As assessed by the blinded expert panel, at 180 days 17 of 26 toes (65%) in the active treatment group and 1 of 11 (9%) in the control group attained at least 3mm of clear lineal nail growth. The difference between groups was statistically significant, favoring the active treatment group, p=0.011. Moreover, 10 of 26 toes (39%) in the active treatment group and 1 of 11 (9%) in the control group had both a negative mycological culture and at least 3 mm of clear nail growth at 180 days; the difference between groups was not statistically significant (p=0.119).
 
In the subjective clinical visual assessment of improvement at 180 days, the investigators judged 5 of 26 (19%) toes in the active treatment group and 2 of 11 (18%) in the control group to be markedly improved. No toes were judged by the investigators to be completed cleared. Reviewing photographs, the expert panel judged 1 toe (4%) in the active treatment group and 2 toes (18%) in the control group to be markedly improved and 1 toe (4%) in the active treatment group to be completely cleared. (Statistical comparisons of the treatment vs. sham group were not reported for the visual assessment outcome.)
 
In 2012, Landsman and Robbins reported 270-day results in 36 of 40 treated toes (Landsman, 2012).  (This included clinically eligible toes as well as companion toes.) When photographs of 34 toes were evaluated, 35% were considered to have continued improvement, 38% were considered not to have changed since 180 days and 20% were considered to have worsened. The authors did not report 270-day findings in patients assigned to the sham control group.
 
While the Landsman et al. study did include an appropriate control group, it also has limitations. Some of the outcome measures used, such as 3 mm of clear lineal nail growth, are intermediate outcomes of uncertain clinical significance. In addition, like the Zhang et al. trial, the study randomized patients to the treatment and control group yet presented their findings on a per nail basis. Three of the 34 patients (9%) evaluated at 180 days contributed data from 2 toes to the analysis.
 
In addition to the 2 RCTs published in the peer-review literature, the 510(k) summary for the LightAge Q-Clear laser reported findings of an RCT with 100 participants with a clinically apparent diagnosis of onychomycosis (FDA, 2013). The FDA document stated that 95% of participants had significant apparent clearing and that the device demonstrated “substantially effective” clearance of toenails. Limitations of this report are that the document did not provide detail of the study methodology such as the comparison intervention, the treatment protocol and outcome variables, or a detailed description of study findings.
 
Ongoing clinical trials
Treatment of Onychomycosis Using a 0.65 Millisecond Pulsed Nd:YAG 1064 nm Laser (NCT01666002): This unblinded study is randomizing patients to receive 2 treatment sessions, 2 weeks apart, with a 1064nm Nd:YAG laser fitted with a special handpiece or to a no-treatment control group. The study aims to enroll 50 patients and the estimated date of study completion is November 2013.
 
Summary
The existing evidence on the efficacy of laser treatment consists of two small RCTs, only one of which included a comparison group that did not receive laser treatment. One of these studies reported improvements in intermediate outcomes such as lineal nail growth, but not in cure of onychomycosis. Moreover, both studies had the methodologic limitation of analyzing the data on a per toe basis, which does not account for correlated measurements. The published evidence to date is insufficient to determine whether laser treatment improves health outcomes in patients with onychomycosis. Additional RCTs are needed that use FDA-cleared devices and compare outcomes to those obtained with a sham control or an alternative treatment for onychomycosis and conduct appropriate statistical analyses.
 
Practice Guidelines and Position Statements
No relevant guidelines or position statements were identified.
 
2014 Update
A literature search conducted through April 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Several systematic reviews of literature on laser treatment, or laser and light treatment, of onychomycosis have been published (Gupta, 2013; Ledon, 2014; Ortiz, 2014). None of these identified any additional published RCTs and none conducted pooled analyses of study results.
 
As of March 2014, an identified study continues to recruit patients. Erbium-doped Yttrium Aluminium Garnet Laser (Er:Yag) Associated With Amorolfine Lacquer in the Treatment of Onychomycosis (NCT01528813) (Brasilia University Hospital): The unblinded RCT is assigning patients to drug treatment (amorolfine lacquer) plus a single session of ER:YAG laser treatment or drug treatment alone. Patients will receive weekly applications of the lacquer for six months. The estimated enrollment is 30 patients. In a preliminary report published in 2013, Morais et al report that early data show superior results in the group receiving laser treatment; detailed findings have not been reported (Morais, 2013).
 
2015 Update
A literature search conducted through May 2015 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Systematic Reviews
A 2014 systematic review by Bristow et al identified 12 published studies on laser treatment for
Onychomycosis (Bristow, 2014). Two were RCTs, 4 were nonrandomized comparative studies and the other 6 were case series. The authors did not pool study findings, but concluded that the evidence was limited and of poor methodologic quality. Representative RCTs with the largest sample sizes that compare laser treatment to placebo or to a different intervention are described next.
 
Randomized Controlled Trials
In 2015, El-Tatawy and colleagues in Egypt reported on 40 patients with toenail onychomycosis randomized to receive 4 sessions of treatment with a 1064nm Nd:YAG laser (n=20 ) or topical terbinafine twice daily for 6 months (n=20) (El-Tatawy. 2015). The laser was a Dualis SP device (Fontona, Slovenia). The clinical efficacy outcome measure categorized patients into those with marked improvement (>75%), moderate improvement (50% to 75%), mild improvement (25 to 50%) or no improvement (<25%). The authors did not state that outcome assessment was blinded. At the end of the 6 months, 100% of patients in the laser group and none in the medication group showed marked improvement (p<0.002). In the medication group, 8 patients had mild improvement, 2 had moderate improvement and 10 had no improvement. However, at the 6 month evaluation, none of the patients in either group had positive fungal cultures. Lack of blinding could have introduced bias in the clinical assessment of patients.
 
A 2014 trial by Xu and colleagues in China randomized 53 patients with toenail onychomycosis to 1 of 3 treatment groups: 250 mg daily oral terbinafine, weekly long-pulsed 1064nm Nd: YAG laser (Luminis One) or the combination of the two therapies (Xu, 2014). The medication only group included 16 patients with 30 infected nails, the laser group included 18 patients with 31 infected nails and the combination treatment group included 16 patients with 29 infected nails. Analysis was done on a per nail basis. All patients completed the 24 month follow-up. At this final evaluation point, the clinical clearance rate (defined as ≤5% nail plate involvement in onychomycosis) was 22 of 30 nails (73.3%) in the medication only group, 20 of 31 nails (64.5%) in the laser group and 28 of 29 nails (96.6%) in the combination treatment group. The rate was significantly higher in the combined treatment group compared to either treatment alone; clinical clearance in the medication versus laser group did not differ significantly. Findings were similar for the mycological clearance rate. A limitation of the study was reporting outcomes on a per nail basis which does not account for correlated measurements.
 
The published evidence to date is insufficient to determine whether laser treatment improves health outcomes in patients with onychomycosis. A few small RCTs report improvements in clinical outcomes with laser treatment, but the available trials have methodologic limitations. Clinical and mycological outcomes sometimes differed in the trials, which may be due in part to lack of consistent blinding of outcome assessment. Additional well-designed and conducted RCTs are needed that include sufficient numbers of patients and follow patients for an adequate amount of time. Thus, laser treatment for onychomycosis is considered investigational.
 
2017 Update
A literature search conducted through May 2017 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Randomized Controlled Trials
Karsai and colleagues reported on a prospective randomized pilot study with blinded outcome assessment comparing laser treatment (short-pulsed 1064-nm-ND:YAG laser) with control (no laser treatment) in 20 patients with 82 mycotic toenails (Karsai, 2016). All patients received treatment with amorolofine cream over the soles of the feet, their intertriginous areas, and the skin directly surrounding the nails. Patients in the laser group received a total of 4 treatments at intervals of 4-6 weeks. The study’s primary endpoint, the proportion of nails with mycological remission, was not achieved in either group after 12 months. The study’s secondary endpoint was the clinical appearance of the nails using the Onychomycosis Severity Index (OSI) which was assessed by 2 independent blinded investigators. There were no differences in OSI scores at baseline or at 12 month follow-up. The OSI score worsened by a mean 2.0 points in the treatment group, compared with 3.6 points in the control group (between group change: 1.6 points not significant, 95% CI -0.7 to 3.9, P=0.5531).
 
Kim and colleagues reported on a RCT comparing 1064-nm Nd:YAG laser alone (n=19) to laser with topical antifungal therapy (n=18) and topical antifungal therapy (n=19) among 56 patients (in the final group; original N enrolled not specified) (Kim, 2016). Topical antifungal therapy included naftifine spray. Laser sessions were repeated at 4 week intervals for 12 weeks. Clinical response rates at 12 weeks were 70.9% in the laser only group, 73.2% in the laser/topical group, and 14.9% in the topical group (P<0.05 for difference between the topical only group). Cure rates at 24 weeks were 15.2% in the laser only group, 22.5% of the laser/topical group, and 4.5% of the topical group (P<0.05 for difference between the topical only group). There was no mention of blinded outcome assessment.
 
ONGOING AND UNPUBLISHED CLINICAL TRIALS
Some currently ongoing and unpublished trials that might influence this review are listed below:
 
Ongoing
(NCT02019446) Laser Treatment for Onychomycosis in Diabetes; planned enrollment 60; projected completion date January 2017
 
(NCT02812043) Comparison Between Lon-pulsed Nd:YAG, Amorolfine and Combination Treatment in Treating Non-dermatophyte Onychomycosis; planned enrollment 60; projected completion date April 2017
 
(NCT01996995) Laser Therapy for Onychomycosis in Patient with Diabetes at Risk for Diabetic Food Complications (LASER-12); planned enrollment 64; projected completion date July 2017
 
Unpublished
(NCT01915355) Pulsed Dye Laser Treatment on Onychomycosis; planned enrollment 11; completion date July 2015
 
(NCT02588599) an industry-sponsored or cosponsored trial. A Retrospective Analysis of the Effect of Low Level Laser Therapy on Toenail Onychomycosis; planned enrollment 54; completion date October 2015
 
2018 Update
A literature search conducted using the MEDLINE database through May 2018 did not reveal any new information that would prompt a change in the coverage statement.

CPT/HCPCS:
17999Unlisted procedure, skin, mucous membrane and subcutaneous tissue
96999Unlisted special dermatological service or procedure

References: Xu Y, Miao X, Zhou B, et al(2014) Combined oral terbinafine and long-pulsed 1,064-nm Nd: YAG laser treatment is more effective for onychomycosis than either treatment alone. Dermatol Surg. Nov 2014;40(11):1201-1207. PMID 25322165

Ameen M, Lear JT, Madan V, et al.(2014) British Association of Dermatologists' guidelines for the management of onychomycosis 2014. Br J Dermatol. Nov 2014;171(5):937-958. PMID 25409999

Boyko EJ, Ahroni JH, Cohen V et al.(2006) Prediction of diabetic foot ulcer occurrence using commonly available clinical information: the Seattle Diabetic Foot Study. Diabetes Care 2006; 29(6):1202-7.

Bristow IR.(2014) The effectiveness of lasers in the treatment of onychomycosis: a systematic review. J Foot Ankle Res. 2014;7:34. PMID 25104974

Drake LA, Scher RK, Smith EB et al.(1998) Effect of onychomycosis on quality of life. J Am Acad Dermatol 1998; 38(5 Pt 1):702-4.

El-Tatawy RA, Abd El-Naby NM, El-Hawary EE, et al.(2015) A comparative clinical and mycological study of Nd-YAG laser versus topical terbinafine in the treatment of onychomycosis. J Dermatolog Treat. Feb 11 2015:1-4. PMID 25669435

Elewski BE.(2000) Onychomycosis. Treatment, quality of life, and economic issues. Am J Clin Dermatol 2000; 1(1):19-26.

Food and Drug Administration (FDA). 510(k) Summary: Light Age, Inc. Q-ClearM Nd:YAG Laser (K110370). Available online at: http://www.accessdata.fda.gov/cdrh_docs/pdf11/K110370.pdf. Last accessed April, 2013.

Gupta A, Simpson F.(2012) Device-based therapies for onychomycosis treatment. Skin Therapy Lett 2012; 17(9):4-9.

Gupta AK, Simpson FC.(2012) Medical devices for the treatment of onychomycosis. Dermatol Ther 2012; 25(6):574-81.

Gupta AK, Simpson FC.(2013) Laser therapy for onychomycosis. J Cutan Med Surg 2013; 17(5):301-7.

Karsai S, Jager M, Oesterhelt A, et al.(2016) Treating onychomycosis with the short-pulsed 1064-nm-Nd:YAG laser: results of a prospective randomized controlled trial. J Eur Acad Dermatol Venereol. Aug 13 2016. PMID 27521028

Kim TI, Shin MK, Jeong KH, et al.(2016) A randomised comparative study of 1064 nm Neodymium-doped yttrium aluminium garnet (Nd:YAG) laser and topical antifungal treatment of onychomycosis. Mycoses. Jul 12 2016. PMID 27402466

Landsman AS, Robbins AH, Angelini PF et al.(2010) Treatment of mild, moderate, and severe onychomycosis using 870- and 930-nm light exposure. J Am Podiatr Med Assoc 2010; 100(3):166-77.

Landsman AS, Robbins AH.(2012) Treatment of mild, moderate, and severe onychomycosis using 870- and 930-nm light exposure: some follow-up observations at 270 days. J Am Podiatr Med Assoc 2012; 102(2):169-71.

Ledon JA, Savas J, Franca K et al.(2014) Laser and light therapy for onychomycosis: a systematic review. Lasers Med Sci 2014; 29(2):823-9.

Morais OO, Costa IM, Gomes CM et al.(2013) The use of the Er:YAG 2940nm laser associated with amorolfine lacquer in the treatment of onychomycosis. An Bras Dermatol 2013; 88(5):847-9.

NCT01666002. Sponsored by Stanford University. Treatment of Onychomycosis Using a 0.65 Millisecond Pulsed Nd:YAG 1064 nm Laser. Available online at: www.clinicaltrials.gov. Last accessed April, 2013.

Ortiz AE, Avram MM, Wanner MA.(2014) A review of lasers and light for the treatment of onychomycosis. Lasers Surg Med 2014; 46(2):117-24.

Rodgers P, Bassler M.(2001) Treating onychomycosis. Am Fam Physician 2001; 63(4):663-72, 77-8.

Zhang RN, Wang DK, Zhuo FL et al.(2012) Long-pulse Nd:YAG 1064-nm laser treatment for onychomycosis. Chin Med J (Engl) 2012; 125(18):3288-91.


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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