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.

For individuals who have onychomycosis who receive treatment with laser therapy, the evidence includes small randomized controlled trials (RCTs). Relevant outcomes are symptoms, change in disease status, medication use and treatment-related morbidity. Some of the available RCTs have reported improvements in clinical outcomes with laser treatment, but these trials have mixed results and 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. The published evidence to date does not permit determining whether laser treatment improves health outcomes in patients with onychomycosis. Additional well-designed, adequately powered and well-conducted RCTs are needed. The evidence is insufficient to determine the effects of the technology on health outcomes.

Background
ONYCHOMYCOSIS
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.¹ 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 nondermatophytic 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. Also, various medical conditions increase the risk of comorbid onychomycosis. They 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 1 prospective study with diabetic patients found onychomycosis to be an independent predictor of foot ulcer.² Moreover, onychomycosis, especially more severe cases, may adversely impact the quality of life. Patients with onychomycosis have reported pain, uncomfortable nail pressure, embarrassment, and discomfort wearing shoes.^3,4  

Diagnosis
The diagnosis of onychomycosis can be confirmed by potassium hydroxide preparation, culture, or histology.

Treatment
Treatments for onychomycosis include topical antifungals such as nail paints containing ciclopirox (ciclopiroxolamine) or amorolfine and oral antifungals such as terbinafine and itraconazole. These have low-to-moderate efficacy and a high relapse rate. Topical antifungals and some long-available oral medications (e.g., 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 the 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, requires less long-term patient compliance. 

Laser treatment of onychomycosis uses the principle of selective photothermolysis. This is defined as the precise targeting of 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 for onychomycosis is to heat the nail bed to temperatures required to disrupt fungal growth (approximately 40º – 60º C) and at the same time avoid pain and necrosis to surrounding tissues.⁵ 

 Characteristics of laser systems used to treat onychomycosis are listed in Table 1.⁵  

Table 1. Characteristics of Lasers for Treating Onychomycosis

Regulatory Status 
Multiple Nd:YAG laser systems have been cleared by the U.S. Food and Drug Administration (FDA) for marketing for the temporary increase of clear nail in patients with onychomycosis. FDA determined that these devices were substantially equivalent to existing devices. Table 2 lists select approved laser systems.

Table 2. Select Laser Systems Approved for Temporary Increase of Clear Nail in Patients With Onychomycosis

Nd:YAG 1064-nm laser systems (FDA product code: GEX); dual wavelength Nd:YAG 1,064-nm and 532-nm laser system (FDA product code: PDX).

Policy:
Laser treatment of onychomycosis is investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY.

Policy Guidelines
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).

Benefit Application:
BlueCard^®/National Account Issues
State or federal mandates (e.g., FEP) may dictate that all devices approved by the U.S. Food and Drug Administration (FDA) may not be considered investigational. Therefore, FDA-approved devices may be assessed only on the basis of their medical necessity.

The approach to laser treatment of onychomycosis will depend on benefit language related to definitions of medically necessary, reconstructive and cosmetic services. Procedures are considered reconstructive when intended to address a significant variation from normal related to accidental injury, disease, trauma, treatment of a disease or congenital defect. Not all benefit contracts include benefits for reconstructive services. Benefit language supersedes this document.

Rationale 
Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the 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 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 technology, two domains are examined: the relevance, and 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 (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs 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.

Laser treatment for Onychomycosis
Clinical Context and Therapy Purpose
The purpose of laser treatment in patients who have onychomycosis is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of laser treatment improve the net health outcome compared with topical antifungal nail lacquer or oral antifungal therapy in patients who have onychomycosis?

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

Populations
The relevant population of interest is patients with onychomycosis.

Interventions
The therapy being considered is laser treatment. Laser treatment allows for precise targeting of the fungal areas with enough heat to disrupt growth while avoiding damage to surrounding tissues. Two types of lasers have been developed to treat onychomycosis: neodymium-doped:yttrium aluminum garnet (Nd:YAG) and diode lasers.

Comparators
Current treatments for onychomycosis include topical antifungal nail lacquer and oral antifungal therapy. These treatments typically require long courses, which result in poor patient compliance and high relapse rates. Nail lacquers contain ciclopirox or amorolfine. Oral medications are terbinafine and itraconazole, which have been associated with a risk of hepatotoxicity.

Outcomes
The general outcomes of interest are symptom relief (e.g., clear nail growth), change in disease status (e.g., mycologic remission or Onychomycosis Severity Scale scores), reduction in medication use, and treatment-related morbidity.

Clinical response can be measured after laser treatment (3 – 6 months). To determine remission rates, follow-up may last a year or more.

Study Selection Criteria
To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.

Review of Evidence
Systematic Reviews
A systematic review by Bristow et al. (2014) identified 12 published studies on laser treatment for onychomycosis in a literature search conducted in June 2014.⁶ Two were RCTs, 4 were nonrandomized comparative studies with no placebo or control group, and 6 were case series. Bristow et al. (2014) did not pool study findings, concluding the evidence was limited and of poor methodologic quality.

Randomized Controlled Trials
Representative RCTs published after the systematic review, with the largest sample sizes, and comparing laser treatment with placebo or a different intervention are described next and in Tables 3 through 6.

Eight representative RCTs published after the systematic review compared laser treatment with placebo or a different intervention.^{7,8,9,10,11,12,13,14} These RCTs have generally compared laser therapy with either systemic or topical therapy, and often a combination laser and systemic/topical regimen. The primary outcomes evaluated in these trials have varied and generally were not uniformly or explicitly defined. Many trials report on clinical or mycological cure or improvement, the results of which have been conflicting. Moreover, follow-up duration has varied, ranging from 12 weeks in Kim et al. to 12 months in Karsai et al. and Nijenhuis-Rosien et al. (LASER-1: Laser Therapy for Onychomycosis in Patients With Diabetes at Risk for Diabetic Foot Complications).^10,12,11 Various methodologic limitations are also present. For example, Sabbah et al. (2019) did not recruit the prespecified sample required to be adequately powered, and reported outcomes only for the most severely affected greater toenail, which may not be representative of less severely affected nails.¹³ Additionally, Xu et al. (2014) reported outcomes on a per-nail basis, which did not account for correlated measurements.¹⁴ All trials employed laser therapy with 1064-nm Nd:YAG laser therapy.

Table 3. Characteristics of RCTs of Laser Treatment of Onychomycosis
 

RCT: randomized controlled trial; NR: not reported.

Table 4. Results of RCTs of Laser Treatment of Onychomycosis

CI: confidence interval; NS: not significant
1 At least 3 mm of clear nail growth and who attained a negative mycologic finding
2 ≤ 5% nail plate involvement in onychomycosis

Table 5. Study Relevance Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest.
c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 6. Study Design and Conduct Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Summary of Evidence
For individuals who have onychomycosis who receive treatment with laser therapy, the evidence includes small, randomized controlled trials. Relevant outcomes are symptoms, change in disease status, medication use, and treatment-related morbidity. The randomized controlled trials reported inconsistent results and had methodologic limitations. Clinical and mycologic outcomes differed across the trials, lacked consistent blinding of outcome assessments, and often reported outcomes on a per-nail basis without accounting for correlated measurements. The published evidence to date does not permit determining whether laser treatment improves health outcomes in patients with onychomycosis. Additionally, some registered clinical trials are completed without publication of results, indicating potential publication bias. Additional well-designed, adequately powered, and well-conducted randomized controlled trials are needed. The evidence is insufficient to determine that the technology results in an improvement in the net health outcomes.

The purpose of the remaining sections in Supplemental Information is to provide reference material regarding existing practice guidelines and position statements, U.S. Preventive Services Task Force Recommendations and Medicare National Coverage Decisions and registered, ongoing clinical trials. Inclusion in the Supplemental Information does not imply endorsement and information may not necessarily be used in formulating the evidence review conclusions.

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in Supplemental Information if they were issued by, or jointly by, a U.S. professional society, an international society with U.S. representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

No practice guidelines or position statements regarding issued by, or jointly by, a U.S. professional society, an international society with U.S. representation, or National Institute for Health and Care Excellence (NICE) were identified.

U.S. Preventive Services Task Force Recommendations
Not applicable

Ongoing and Unpublished Clinical Trials
Some currently ongoing and unpublished trials that might influence this review are listed in Table 7.

Table 7. Summary of Key Trials

NCT: national clinical trial; Nd:YAG: neodymium yttrium aluminum garnet
a Denotes industry-sponsored or cosponsored trial
* No results published as of October 2020 

References 

1. Rodgers P, Bassler M. Treating onychomycosis. Am Fam Physician. Feb 15 2001; 63(4): 663-72, 677-8. PMID 11237081
2. Boyko EJ, Ahroni JH, Cohen V, et al. Prediction of diabetic foot ulcer occurrence using commonly available clinical information: the Seattle Diabetic Foot Study. Diabetes Care. Jun 2006; 29(6): 1202-7. PMID 16731996
3. Drake LA, Scher RK, Smith EB, et al. Effect of onychomycosis on quality of life. J Am Acad Dermatol. May 1998; 38(5 Pt 1): 702-4. PMID 9591814
4. Elewski BE. Onychomycosis. Treatment, quality of life, and economic issues. Am J Clin Dermatol. Jan-Feb 2000; 1(1): 19-26. PMID 11702301
5. Gupta A, Simpson F. Device-based therapies for onychomycosis treatment. Skin Therapy Lett. Oct 2012; 17(9): 4-9. PMID 23032936
6. Bristow IR. The effectiveness of lasers in the treatment of onychomycosis: a systematic review. J Foot Ankle Res. 2014; 7: 34. PMID 25104974
7. Bunyaratavej S, Wanitphakdeedecha R, Ungaksornpairote C, et al. Randomized controlled trial comparing long-pulsed 1064-Nm neodymium: Yttrium-aluminum-garnet laser alone, topical amorolfine nail lacquer alone, and a combination for nondermatophyte onychomycosis treatment. J Cosmet Dermatol. Sep 2020; 19(9): 2333-2338. PMID 31925917
8. El-Tatawy RA, Abd El-Naby NM, El-Hawary EE, et al. A comparative clinical and mycological study of Nd-YAG laser versus topical terbinafine in the treatment of onychomycosis. J Dermatolog Treat. Oct 2015; 26(5): 461-4. PMID 25669435
9. Hamed Khater M, Khattab FM. Combined long-pulsed Nd-Yag laser and itraconazole versus itraconazole alone in the treatment of onychomycosis nails. J Dermatolog Treat. Jun 2020; 31(4): 406-409. PMID 31157575
10. Karsai S, Jager M, Oesterhelt A, et al. Treating onychomycosis with the short-pulsed 1064-nm-Nd:YAG laser: results of a prospective randomized controlled trial. J Eur Acad Dermatol Venereol. Jan 2017; 31(1): 175-180. PMID 27521028
11. Kim TI, Shin MK, Jeong KH, et al. A randomised comparative study of 1064 nm Neodymium-doped yttrium aluminium garnet (Nd:YAG) laser and topical antifungal treatment of onychomycosis. Mycoses. Dec 2016; 59(12): 803-810. PMID 27402466
12. Nijenhuis-Rosien L, Kleefstra N, van Dijk PR, et al. Laser therapy for onychomycosis in patients with diabetes at risk for foot ulcers: a randomized, quadruple-blind, sham-controlled trial (LASER-1). J Eur Acad Dermatol Venereol. Nov 2019; 33(11): 2143-2150. PMID 30920059
13. Sabbah L, Gagnon C, Bernier FE, et al. A Randomized, Double-Blind, Controlled Trial Evaluating the Efficacy of Nd:YAG 1064 nm Short-Pulse Laser Compared With Placebo in the Treatment of Toenail Onychomycosis. J Cutan Med Surg. Sep/Oct 2019; 23(5): 507-512. PMID 31296045
14. Xu Y, Miao X, Zhou B, et al. 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): 1201-7. PMID 25322165

Coding Section

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.  

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

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History From 2024 Forward     

01/01/2024 NEW POLICY 

06/20/2024 Annual review, no change to policy intent.