Laser Treatment of Onychomycosis. Description

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Subject: Laser Treatment of Onychomycosis Page: 1 of 8 Last Review Status/Date: September 2014 Laser Treatment of Onychomycosis Description Onychomycosis is a common fungal infection of the nail.

1 Subject: Laser Treatment of Onychomycosis Page: 1 of 8 Last Review Status/Date: September 2014 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. Background 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 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. (2) 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. (3, 4) 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

2 Subject: Laser Treatment of Onychomycosis Page: 2 of 8 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. (5) Characteristics of laser systems used to treat onychomycosis are as follows: (6) 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; nm 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 (product code: GEX). 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, Inc.): 2010 GenesisPlus (Cutera): 2011

3 Subject: Laser Treatment of Onychomycosis Page: 3 of 8 VARIABreeze (CoolTouch Inc.): 2011 JOULE ClearSense (Sciton): 2011 Dual wavelength Nd: YAG 1064nm and 532nm laser system: Q-Clear (Light Age, Inc.): 2011 Related Policies Nonpharmacologic Treatment of Rosacea Laser Treatment of Port Wine Stains Policy *This policy statement applies to clinical review performed for pre-service (Prior Approval, Precertification, Advanced Benefit Determination, etc.) and/or post-service claims. Laser treatment of onychomycosis is considered not medically necessary. Rationale Literature Review 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 peerreviewed 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. (7) 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.

4 Subject: Laser Treatment of Onychomycosis Page: 4 of 8 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. (8) 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

5 Subject: Laser Treatment of Onychomycosis Page: 5 of 8 active treatment group, p= 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. (9) (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. (10) 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. Systematic reviews Several systematic reviews of literature on laser treatment, or laser and light treatment, of onychomycosis have been published. (11-13) None of these identified any additional published RCTs and none conducted pooled analyses of study results. Clinical Trials Treatment of Onychomycosis Using a 0.65 Millisecond Pulsed Nd:YAG 1064 nm Laser (NCT ) (14): 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 As of March 2014 this study continues to recruit patients.

6 Subject: Laser Treatment of Onychomycosis Page: 6 of 8 Erbium-doped Yttrium Aluminium Garnet Laser (Er:Yag) Associated With Amorolfine Lacquer in the Treatment of Onychomycosis (NCT ) (15): 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. As of March 2014, the study continues to recruit 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. (16) Evaluation Study for the Efficacy and Safety of PinPointe FootLaser in Treatment for Onychomycosis (NCT ) (17): This is a single-blind sham-controlled RCT evaluating the PinPointe laser for treatment of onychomycosis. Patients will be followed for 2 years; the primary outcomes will be assessed after 1 year. The estimated enrollment is 30 patients. As of March 2014, the study continues to recruit patients. Practice Guidelines and Position Statements No relevant guidelines or position statements were identified. 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. Thus, laser treatment for onychomycosis is considered not medically necessary. Medicare National Coverage There is no national coverage determination. References 1. Rodgers P, Bassler M. Treating onychomycosis. Am Fam Physician 2001; 63(4):663-72, 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 2006; 29(6): Drake LA, Scher RK, Smith EB et al. Effect of onychomycosis on quality of life. J Am Acad Dermatol 1998; 38(5 Pt 1): Elewski BE. Onychomycosis. Treatment, quality of life, and economic issues. Am J Clin Dermatol 2000; 1(1):19-26.

7 Subject: Laser Treatment of Onychomycosis Page: 7 of 8 5. Gupta A, Simpson F. Device-based therapies for onychomycosis treatment. Skin Therapy Lett 2012; 17(9): Gupta AK, Simpson FC. Medical devices for the treatment of onychomycosis. Dermatol Ther 2012; 25(6): Zhang RN, Wang DK, Zhuo FL et al. Long-pulse Nd:YAG 1064-nm laser treatment for onychomycosis. Chin Med J (Engl) 2012; 125(18): Landsman AS, Robbins AH, Angelini PF et al. Treatment of mild, moderate, and severe onychomycosis using 870- and 930-nm light exposure. J Am Podiatr Med Assoc 2010; 100(3): Landsman AS, Robbins AH. 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): Food and Drug Administration (FDA). 510(k) Summary: Light Age, Inc. Q-ClearM Nd:YAG Laser (K110370). Available online at: Last accessed April 29, Gupta AK, Simpson FC. Laser therapy for onychomycosis. J Cutan Med Surg 2013; 17(5): Ledon JA, Savas J, Franca K et al. Laser and light therapy for onychomycosis: a systematic review. Lasers Med Sci 2014; 29(2): Ortiz AE, Avram MM, Wanner MA. A review of lasers and light for the treatment of onychomycosis. Lasers Surg Med 2014; 46(2): Sponsored by Stanford University. Treatment of Onychomycosis Using a 0.65 Millisecond Pulsed Nd:YAG 1064 nm Laser (NCT ). Available online at: Last accessed April 29, Sponsored by Brasilia University Hospital. Erbium-doped Yttrium Aluminium Garnet Laser(Er:Yag)Associated With Amorolfine Lacquer in the Treatment of Onychomycosis (NCT ) Available online at: Last accessed March Morais OO, Costa IM, Gomes CM. The use of the Er:YAG 2940nm laser associated with amorolfine lacquer in the treatment of onychomycosis. An Bras Dermatol 2013; 88(5): Sponsored by Cambridge Health Alliance. Evaluation Study for the Efficacy and Safety of PinPointe FootLaser in Treatment for Onychomycosis (NCT ) Available online at: Last accessed April 29, Policy History Date Action Reason September 2013 New Policy September 2014 Update Policy Policy updated with literature review through March 18, Policy statement unchanged. References and added. Keywords Onychomycosis, laser treatment

8 Subject: Laser Treatment of Onychomycosis Page: 8 of 8 This policy was approved by the FEP Pharmacy and Medical Policy Committee on September 12, 2014 and is effective October 15, Signature on File Deborah M. Smith, MD, MPH

Corporate Medical Policy

Corporate Medical Policy Laser Treatment of Onychomycosis File Name: Origination: Last CAP Review: Next CAP Review: Last Review: laser_treatment_of_onychomycosis 5/2013 11/2017 11/2018 11/2017 Description