1) Photodynamic therapy with topical 5 aminolevulinic acid is considered medically necessary and is covered for the treatment of:

Transcription

1 Medical Policy Title: Photodynamic Therapy ARBenefits Approval: 10/26/2011 for Dermatologic Conditions Effective Date: 01/01/2012 Document: ARB0282:02 Revision Date: 03/20/2013 Code(s): Photodynamic therapy by external application of light to destroy premalignant and/or malignant lesions of the skin and adjacent mucosa (eg, lip) by activation of photosensitive drug(s), each phototherapy exposure session J7308 Aminolevulinic acid HCl for topical administration, 20%, single unit dosage form (354 mg) J7309 Methyl aminolevulinate (mal) for topical administration, 16.8%, 1 gram Public Statement: Administered by: Photodynamic therapy refers to light activation of a photosensitizer to generate highly reactive oxygen intermediaries, which ultimately cause tissue injury and necrosis. This therapy is covered for treatment of actinic keratoses, superficial basal cell skin cancer and squamous cell carcinoma in situ (Bowen s disease). Any other use is considered investigational and experimental. Medical Policy Statement: 1) Photodynamic therapy with topical 5 aminolevulinic acid is considered medically necessary and is covered for the treatment of: o o o non-hyperkeratotic actinic keratosis. Treated lesions that have not completely resolved after 8 weeks may be treated a second time. Superficial basal cell skin cancer when surgery and radiation are contraindicated Bowen s disease (squamous cell carcinoma in situ) when surgery and radiation are contraindicated 2) Surgery or radiation is the preferred treatment for superficial basal cell cancer and Bowen s disease. If photodynamic therapy is selected for these indications because of contraindications to surgery or radiation, patients need to be aware that it may have a lower cure rated in comparison with surgery or radiation. Page 1 of 8

2 3) Photodynamic therapy for any other skin indication is considered investigational and is not covered. Background: When applied topically, the photosensitizing agent 5-aminolevulinic acid (5-ALA) or its methyl ester methyl aminolevulinate (MAL) passes readily through the abnormal keratin overlying the lesion and accumulates preferentially in dysplastic cells. 5-ALA and MAL are metabolized by the underlying cells to photosensitizing concentrations of porphyrins. Subsequent exposure to photoactivation (maximum absorption at nm and 635 nm) generates reactive oxygen species that are cytotoxic, ultimately destroying the lesion. PDT can cause erythema, burning, and pain. Healing occurs within 10 to 14 days, with generally acceptable cosmetic results. PDT with topical ALA has been investigated primarily as a treatment of actinic keratoses. It has also been investigated as a treatment of other superficial dermatologic lesions, such as Bowen s disease, acne vulgaris, mycoses, hidradenitis suppurativa, and superficial and nodular basal cell carcinoma. Potential cosmetic indications include skin rejuvenation and hair removal. Actinic keratoses are rough, scaly, or warty premalignant growths on sun-exposed skin that are very common in older individuals with fair complexions, with a prevalence of >80% in fair-skinned people over the age of 60. In some cases actinic keratosis may progress to squamous cell carcinoma. The available treatments for actinic keratoses can generally be divided into surgical and non-surgical methods. Surgical treatments used to treat one or a small number of dispersed individual lesions include excision, curettage (either alone or combined with electrodessication), and laser surgery. Nonsurgical treatments include cryotherapy, topical chemotherapy (5-fluorouracil [5-FU] or masoprocol creams), chemexfoliation (also known as chemical peels), and dermabrasion. Topical treatments are generally used in patients with multiple lesions and the involvement of extensive areas of skin. Under some circumstances, combinations of different treatment methods may be used. Non-melanoma skin cancers are the most common malignancies in the Caucasian population. Basal cell carcinoma (BCC) is most often found in light-skinned individuals and is the most common of the cutaneous malignancies. Although the tumors rarely metastasize, they can be locally invasive if left untreated, leading to significant local destruction and disfigurement. The most prevalent forms of BCC are nodular BCC and superficial BCC. Bowen s disease is a squamous cell carcinoma (SCC) in situ with the potential for significant lateral spread. Metastases are rare, with less than 5% of cases advancing to invasive SCC. Lesions may appear on sun-exposed or covered skin. Excision surgery is the preferred treatment for smaller non-melanoma skin lesions and those not in problematic areas, such as the face and digits. Other established treatments include topical 5-fluorouracil, imiquimod, and cryotherapy. Poor cosmesis resulting from surgical procedures and skin irritation induced by topical agents can be significant problems. Page 2 of 8

3 In 1999, Levulan Kerastick, a topical preparation of ALA, in conjunction with illumination with the BLU-U Blue Light Photodynamic Therapy Illuminator, received approval by the U.S. Food and Drug Administration (FDA) for the following indication: The Levulan Kerastick for topical solution plus blue light illumination using the BLU-U Blue Light Photodynamic Therapy Illuminator is indicated for the treatment of nonhyperkeratotic actinic keratoses of the face and scalp. As described in the package insert, the technique involves two steps starting with application of the ALA Topical Solution in the physician's office. The package insert recommends that the application should involve either face or scalp lesions but not both simultaneously. The patient is told to return in 14 to 18 hours, at which point the lesion is exposed to blue light for 17 minutes. During this period, the patient experiences sensations of tingling, stinging, or burning of the treated lesions. Treated lesions, that have not completely resolved after 8 weeks may be treated a second time. A 5-aminolevulinic acid patch technology (5-ALA Patch) is available outside of the U.S through an agreement between Intendis (part of Bayer HealthCare) and Photonamic GmbH and Co. KG. The 5-ALA patch is not approved by the FDA. Another variant of PDT for skin lesions is Metvixia and the Aktilite CL128 lamp, each of which received FDA approval in July Metvixia (Galderma, SA, Switzerland; PhotoCure ASA, Norway) consists of the topical application of methyl aminolevulinate (MAL) in contrast to ALA used in the Kerastick procedure, followed by exposure with the Aktilite CL 128 lamp, a red light source (in contrast to the blue light source in the Kerastick procedure). Broadband light sources (containing the appropriate wavelengths), intense pulsed light (IPL), pulsed dye lasers (PDL), and potassium titanyl phosphate (KTP) lasers have also been used. Metvixia is indicated for the treatment of non-hyperkeratotic actinic keratoses of the face and scalp in immunocompetent patients when used in conjunction with lesion preparation (debridement using a sharp dermal curette) in the physician's office when other therapies are unacceptable or considered medically less appropriate. PhotoCure also sought FDA approval of Metvixia for the treatment of BCCs. However, the indication for BCCs was not approved. In April 2009, HealthCanada approved Metvix (as it is called in Canada) for treatment of BCCs, as well as actinic keratoses. Metvixia is also marketed in Europe. Morton and colleagues (2006) conducted an industry-sponsored 25 center randomized left-right comparison of single photodynamic treatment and cryotherapy in 119 subjects. At 12-week follow-up, PDT resulted in a significantly larger rate of cured lesions compared with cryotherapy (86.9% vs. 76.2% cured). Lesions with a non-complete response were retreated after 12 weeks; a total of 108 of 725 lesions (14.9%) received a second PDT session; 191 of 714 lesions (26.8%) required a second cryotherapy treatment. At 24 weeks, the groups showed equivalent clearance (85.8% vs. 82.5%). Thus, approximately 12% more cryotherapy sessions were required to achieve comparable outcomes to PDT. Skin discomfort was reported to be greater with PDT than with cryotherapy. Investigator-rated cosmetic outcomes showed no difference in the percentage of subjects with poor cosmetic outcomes (0.3% vs. 0.5%), with more Page 3 of 8

4 subjects rated as having excellent outcomes at 24 weeks after PDT (77.2% vs. 49.7%). With PDT, 22.5% had cosmetic ratings of fair or good compared to 49.9% for cryotherapy. Subjects perceived PDT to have better efficacy and cosmetic outcome. Together with the randomized trial described above (Freeman, 2003), the data suggest that PDT may have improved efficacy and cosmetic outcomes compared with cryotherapy. Tschen and colleagues (2006) reported 12-month follow-up from an industry sponsored phase IV multicenter clinical trial of PDT for actinic keratosis. Of 110 patients enrolled, 98 (89%) completed the study. The percentage of cleared lesions was 86% at 4 months and 78% at 12 months, with a recurrence rate of 19% for histologically confirmed actinic keratosis lesions. Per patient analysis showed that 60% of the patients required a second treatment. In a small randomized study with 29 patients, Wiegel and colleagues (2008) reported that MAL with daylight was as effective (79% reduction in lesions) and less painful than using red light-emitting diodes (71% reduction in lesions). Basal and Squamous Cell Carcinoma An updated Cochrane review (2007) evaluated surgical, destructive (including PDT), and chemical interventions for basal cell carcinoma. The authors concluded that surgery and radiotherapy appeared to be the most effective treatments, with the best results being obtained with surgery. In comparison with cryotherapy, PDT was shown to have greater participant tolerability and cosmetic outcomes. The authors concluded that current efficacy data does not support the introduction of PDT for the treatment of BCC. However, this review did not distinguish between BCC subtypes. The literature on PDT and superficial BCC, which consists primarily of uncontrolled trials, suggests high initial clearance rates for lesions on the face, trunk, and extremities (Braathen, 2007). An industry sponsored multicenter open trial compared MAL-PDT with surgery for small (8-20 mm) superficial basal cell carcinoma in 196 patients. (Szeimies, 2008) At 3 months after treatment, 92% of lesions treated with MAL-PDT showed clinical response, compared with 99% of lesions treated with surgery (per protocol analysis). At 12-month follow-up, no lesions had recurred in the surgery group and 9% of lesions had recurred with MAL-PDT. About 10% of patients discontinued MAL-PDT due to an incomplete response or adverse event, compared with 5% of patients in the surgery group. Cosmetic outcomes were rated by the investigators as good to excellent in 94% of lesions treated with MAL-PDT in comparison with 60% following surgery. In uncontrolled trials, recurrence rates for PDT-treated superficial BCC lesions have been reported in the range of 18% to 22% at 48 months. (Braathen, 2007) This can be compared with rates around 1% reported at 48 months following surgical excision. (Bath-Hextall, 2007) A study that compared PDT with cryotherapy for superficial BCC has been published in abstract form. (Basset-Seguin, 2005) Lesion recurrence rates were reported to be similar after 48 months (22% for PDT vs. 19% for cryotherapy). Overall cosmetic outcome at 48 months was rated as excellent or good for 88% of patients in the PDT group and 62% of patients in the cryotherapy group. Page 4 of 8

5 A multicenter randomized trial with 225 patients (from 40 hospital outpatient dermatology clinics in 11 European countries) compared MAL with cryotherapy or 5-FU for the treatment of Bowen s disease (squamous cell carcinoma in situ) with lesions on the face or scalp (23%), neck or trunk (12%), or extremities (65%). (Morton, 2006) Unblinded assessment of lesion clearance found PDT to be non-inferior to cryotherapy and 5-FU (93%, 86%, 83%, respectively) at 3 months, and superior to cryotherapy and 5-FU (80%, 67%, 69%, respectively) at 12 months. Cosmetic outcome at 3 months was rated higher for PDT than the standard non-surgical treatments by both investigators and blinded evaluators, with investigators rating cosmetic outcome as good or excellent in 94% of patients treated with MAL-PDT, 66% of patients treated with cryotherapy, and 76% of those treated with 5-FU. A randomized study by Salim and colleagues (2003), which found greater clearing and fewer adverse eczematous reactions with PDT as compared with 5-FU for treatment of Bowen s disease, was described above. Rhodes et al., published 5-year follow-up of an industry sponsored multicenter randomized study comparing MAL-PDT to surgery for nodular basal cell carcinoma. (2004, 2007) Out of 97 patients in the per protocol population, 66 (68%) were available for 5-year follow-up; 16 (32%) discontinued in the MAL-PDT group due to treatment failure or adverse events vs. 6 (13%) in the surgery group. A time-to-event analysis of lesion response over time estimated a sustained lesion response rate of 76% for MAL- PDT and 96% for excision surgery. Cosmetic outcomes were rated as good to excellent in 87% of the MAL-PDT patients and 54% of the surgery patients. Thus, although cosmetic outcomes may be improved, PDT does not seem to be as effective as surgery in terms of the more important clinical outcomes of treatment completion and lesion recurrence. References: Basset-Seguin N, Ibbotosn S, et al.(2005) MAL-PDT vs. cryotherapy in primary sbcc:results of 48-month follow up. J Eur Acad Dermatol Venereol 2005; 19(suppl 2):237. Bath-Hextall FJ, Perkins W, et al.(2007) Interventions for basal cell carcinoma of the skin. Cochrane Database Syst Rev. 2007; (1):CD Braathen LR, Szeimies RM, et al.(2007) Guidelines on the use of photodynamic therapy for nonmelanoma skin cancer: an international consensus. International Society for Photodynamic Therapy in Dermatology, J Am Acad Dermatol, 2007; 56: Calzavara-Pinton PG, Venturini M, et al.(2004) Photodynamic therapy of interdigital mycoses of the feet with topical application of 5-aminolevulinic acid. Photodermatol Photoimmunol Photomed 2004; 20(3): Fantini F, Greco A, Del Giovane C et al.(2010) Photodynamic therapy for basal cell carcinoma: clinical and pathological determinants of response. J Eur Acad Dermatol Page 5 of 8

6 Venereol 2010 [Epub before print]. Feldman SR, Fleischer AB, et al.(1999) Destructive procedures are the standard of care for treatment of actinic keratoses. J Am Acad Derm 1999; 40(1. Foley P, Freeman M, Menter A et al.(2009) Photodynamic therapy with methylaminolevulinate for primary basal cell carcinoma: results of two randomized studies. Int J Dermatol 2009; 48(11): Freeman M, Vinciullo C, et al.(2003) A comparison of photodynamic therapy using topical methyl aminolevulinate (Metvix) with single cycle cryotherapy in patients with actinic keratosis: a prospective, randomized study. J Dermatol, 2003; 14: Gold M, Bridges TM, et al.(2004) ALA-PDT and blue light therapy for hidradenitis suppurativa. J Drugs Dermatol, 2004; 3(1suppl):S32-5. Jeffes EW, McCullough JL, et al.(1997) Photodynamic therapy of actinic keratosis with topical 5-aminolevulinic acid; a pilot dose-ranging study. Arch Derm 1997; 133: Jeffes EW, McCullough JL, et al.(2001) Photodynamic therapy of actinic keratoses with topical aminolevulinic acid hydrochloride and fluorescent blue light. J Am Acad Derm 2001; 45: Kurwa, HA, Yong-Gee SA, et al.(1999) A randomized paired comparison of photodynamic therapy and topical 5-fluorouracil in the treatment of actinic keratosis. J Am Acad Derm 1999; 41: Morton C, Campbell S, Gupta G et al; AKtion Investigators.(2006) Intraindividual, rightleft comparison of topical methyl aminolaevulinate-photodynamic therapy and cryotherapy in subjects with actinic keratoses: a multicentre, randomized controlled study. Br J Dermatol, 2006; 155: Morton C, Horn M, et al.(2006) Comparison of topical methyl aminolevulinate photodynamic therapy with cryotherapy or Fluorouracil for treatment of squamous cell carcinoma in situ: Results of a multicenter randomized trial. Arch Dermatol, 2006; 142: National Comprehensive Cancer Network. Practice Guidelines in Oncology- v Basal Cell and Squamous Cell Skin Cancers. Available online at: Last accessed January Ormond D, Jarvis B.(2000) Aminolevulinic acid HCL photodynamic therapy. Am J Clin Derm 2000; 1 (2): Orringer JS, Sachs DL, Bailey E et al.(2010) Photodynamic therapy for acne vulgaris: a randomized, controlled, split-face clinical trial of topical aminolevulinic acid and pulsed Page 6 of 8

7 dye laser. J Cosmet Dermatol 2010; 9(1): Pariser DM, Lowe NJ, et al.(2003) Photodynamic therapy with topical methyl aminolevulinate for actinic keratosis: results of a prospective randomized multicenter trial. J Am Acad Dermatol, 2003;48: Pfenninger JL, Fowler GC.(1994) Procedures for primary care physicians. Mosby-Year Book, Inc Piacquadio DJ, Chen DM, et al.(2004) Photodynamic therapy with aminolevulinic acid topical solution and visible blue light in the treatment of multiple actinic keratoses of the face and scalp: investigator-blinded, phase 3, multicenter trials. Arch Dermatol 2004;140:41-6. Practice Guidelines in Oncology v Basal Cell and Squamous Cell Skin Cancers. Product Insert: Levulan Kerastick Rhodes LE, de Rie M, et al.(2004) Photodynamic therapy using topical methyl aminolevulinate vs surgery for nodular basal cell carcinoma: results of a multicenter randomized prospective trial. Arch Dernatol, 2004; 140: rhodes LE, de Rie MA, et al.(2007) Five-year follow-up of a randomized, prospective trial of topical methyl aminolevulinate photodynamic therapy vs surgery for nodular basal cell carcinoma. Arch Dermatol, 2007; 143: Salim A, Leman JA, et al.(2003) Randomized comparison of photodynamic therapy with topical 5-fluorouracil in Bowen's disease. Br J Dermatol, 2003; 148: Sxeimies RM, Karrer S, et al.(1996) Photodynamic therapy with topical application of 5 aminolevulinic acid in the treatment of actinic keratoses: an initial clinical study. Derm 1996; 192: Szeimies R, Ibbotson S, et al; on behalf of the Excilight Study Group.(2008) A clinical study comparing methyl aminolevulinate photodynamic therapy and surgery in small superficial basal cell carcinoma (8-20 mm), with a 12-month follow-up. J Eur Acad Dermatol Venereol 2008 Jul 2 [Epub ahead of print]. Tschen EH, Wong DS, et al.(2006) Phase IV ALA-PDT Actinic Keratosis Study Group. Photodynamic therapy using aminolaevulinic acid for patients with nonhyperkeratotic actinic keratoses of the face and scalp: phase IV multicentre clinical trial with 12-month follow up. Br J Dermatol, 2007; 155: Vinciullo C, Elliott T, Francis D, et al.(2005) Photodynamic therapy with topical methyl Page 7 of 8

8 aminolaevulinate for 'difficult-to-treat' basal cell carcinoma. Br J Dermatol, 2005; 152: Wiegell SR, Haedersdal M, et al.(2008) Continuous activation of PpIX by daylight is as effective as and less painful than conventional photodynamic therapy for actinic keratoses; a randomized, controlled, single-blinded study. Br J Dermatol, 2008; 158: Wiegell SR, Wulf HC.(2006) Photodynamic therapy of acne vulgaris using methyl aminolaevulinate: a blinded, randomized, controlled trial. Br J Dermatol, 2006; 154: Application to Products This policy applies to ARBenefits. Consult ARBenefits Summary Plan Description (SPD) for additional information. Last modified by: SCS Date: 03/19/2013 Page 8 of 8