Coverage Policy Manual
Policy #: 2004011
Category: Medicine
Initiated: March 2004
Last Review: January 2024
  Photodynamic Therapy for Dermatologic Conditions
Description:
Photodynamic therapy (PDT) refers to light activation of a photosensitizer to generate highly reactive intermediaries, which ultimately cause tissue injury and necrosis. Photosensitizing agents are being proposed for use with dermatologic conditions such as actinic keratoses (AKs) and nonmelanoma skin cancers. Two common photosensitizing agents are 5-aminolevulinic acid (ALA) and its methyl ester, methyl aminolevulinate. When applied topically, these agents pass readily through abnormal keratin overlying the lesion and accumulate preferentially in dysplastic cells. The agents ALA and methyl aminolevulinate are metabolized by underlying cells to photosensitizing concentrations of porphyrins. Subsequent exposure to photoactivation (maximum absorption at 404 to 420 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 (AKs).
  
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. Non-surgical 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.
 
Regulatory Status
In 1999, Levulan® Kerastick™, a topical preparation of ALA, in conjunction with illumination with the BLU-U™ Blue Light Photodynamic Therapy Illuminator, was approved by the U.S. Food and Drug Administration (FDA) for the treatment of nonhyperkeratotic AKs of the face and scalp. In 2018, the indication was expanded to include nonhyperkeratotic AKs of the upper extremities. The product is applied in the physician’s office.
 
FDA product code: MVF.
 
In 2016, the FDA approved Ameluz® (aminolevulinic acid hydrochloride) gel, 10% (BF-200 ALA; Biofrontera AG) in combination with PDT using BF-RhodoLED lamp, to be used for the lesion-directed and field-directed treatment of AKs of mild-to-moderate severity on the face and scalp. The treatment is to be administered by a healthcare provider.
 
AALApatch technology is available outside of the US through an agreement between Intendis (now Bayer HealthCare) and Photonamic. The ALA patch is not approved by the FDA.
 
Another variant of PDT for skin lesions is Metvixia® used with the Aktilite CL128 lamp, each of which received the FDA approval in 2004. Metvixia® (Galderma; Photocure) consists of the topical application of methyl aminolevulinate (in contrast to ALA used in the Kerastick procedure), followed by exposure with the Aktilite CL128 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 (FDA product code: ONF), pulsed dye lasers, and potassium-titanyl-phosphate lasers have also been used. Metvixia® is indicated for the treatment of nonhyperkeratotic AKs of the face and scalp in immunocompetent patients when used with lesion preparation (débridement using a sharp dermal curette) in the physician's office when other therapies are unacceptable or considered medically less appropriate.
 
FDA product codes: GEX and LNK.
 
Coding
In 2002, a new CPT code was introduced to specifically describe photodynamic therapy for actinic keratoses:
96567: Photodynamic therapy by external application of light to destroy premalignant and/or malignant lesions of the skin and adjacent mucosa (e.g., lip) by activation of photosensitive drug(s), each phototherapy exposure session.
 
In 2002, a HCPCS J code was also introduced to describe the 5-aminolevulinic acid, i.e., the drug component of the therapy:
J7308: Aminolevulinic acid HCl for topical administration, 20%, single unit dosage form (354 mg)
 
In 2011, a HCPCS J code was introduced for Metvixia®:
J7309: Methyl aminolevulinate (MAL) for topical administration, 16.8%, 1 gram
Policy/
Coverage:
Effective January 2024
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Photodynamic therapy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the treatment of:
 
    • non-hyperkeratotic actinic keratosis of the face, scalp, neck, forearms, and hands. Treated lesions that have not completely resolved after 8 weeks may be treated a second time.
    • Low-risk (i.e., superficial or nodular) basal cell carcinoma only when surgery and radiation are contraindicated.
    • Bowen’s disease (squamous cell carcinoma in situ) only when surgery and radiation are contraindicated.
 
Note: Surgery or radiation is the preferred treatment for superficial and basal cell cancer and Bowen’s disease. If photodynamic therapy is selected for these indications because of contraindications to surgery or radiation, individuals need to be aware that it may have a lower cure rate in comparison with surgery or radiation.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Photodynamic therapy when performed for all other dermatologic applications including, but not limited to, acne vulgaris, non-superficial basal cell carcinoma, mycoses, or hidradenitis suppurativa does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, photodynamic therapy when performed for all other dermatologic applications including, but not limited to, acne vulgaris, non-superficial basal cell carcinoma, mycoses, or hidradenitis suppurativa is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Photodynamic therapy as a technique of skin rejuvenation, hair removal, or other cosmetic indications does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, photodynamic therapy as a technique of skin rejuvenation, hair removal, or other cosmetic indications is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective July 2011 – December 2023
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Photodynamic therapy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the treatment of:
 
        • non-hyperkeratotic actinic keratosis of the face, scalp, neck, forearms, and hands. Treated lesions that have not completely resolved after 8 weeks may be treated a second time.
        • Low-risk (ie superficial or nodular) basal cell carcinoma only when surgery and radiation are contraindicated.
        • Bowen’s disease (squamous cell carcinoma in situ) only when surgery and radiation are contraindicated.
 
Note: Surgery or radiation is the preferred treatment for superficial and 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.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Photodynamic therapy when performed for all other dermatologic applications including, but not limited to, acne vulgaris, non-superficial basal cell carcinoma, mycoses, or hidradenitis suppurativa does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, photodynamic therapy when performed for all other dermatologic applications including, but not limited to, acne vulgaris, non-superficial basal cell carcinoma, mycoses, or hidradenitis suppurativa is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective prior to July 2011
Photodynamic therapy with topical 5 aminolevulinic acid meets primary coverage criteria for effectiveness and is covered for the treatment of
    • non-hyperkeratotic actinic keratosis of the face, scalp, neck, forearms, and hands.  Treated lesions that have not completely resolved after 8 weeks may be treated a second time.
    • Superficial basal cell skin cancer only when surgery and radiation are contraindicated
    • Bowen’s disease (squamous cell carcinoma in situ) only when surgery and radiation are contraindicated
 
Surgery or radiation is the preferred treatment for superficial and 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.
 
Photodynamic therapy with topical 5 aminolevulinic acid when performed for all other dermatologic applications, including, but not limited to, acne vulgaris, non-superficial basal cell carcinoma, mycoses or hidradenitis suppurativa, is not covered  based on benefit certificate primary coverage criteria.
 
For members with  contracts without primary coverage criteria,  photodynamic therapy with topical 5 aminolevulinic acid when performed for other dermatologic applications, including but not limited to, acne vulgaris, non-superficial basal cell carcinoma, mycoses or hidradenitis suppurativa, is considered investigational.  Investigational services are an exclusion in the member certificate of coverage.
 
Photodynamic therapy with topical 5 aminolevulinic acid is considered medically necessary in the treatment of multiple (greater than 10 lesions) non-hyperkeratotic actinic keratosis of the face, scalp, neck, forearms, and hands. Treated lesions that have not completely resolved after 8 weeks may be treated a second time.
 
Photodynamic therapy with topical 5 aminolevulinic acid when performed for other dermatologic applications, including, but not limited to, squamous cell carcinoma, basal cell carcinoma or Bowen’s disease is not covered based on benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For contracts without primary coverage criteria,  photodynamic therapy with topical 5 aminolevulinic acid when performed for other dermatologic applications, including, but not limited to, squamous cell carcinoma, basal cell carcinoma or Bowen’s disease is considered investigational.  Investigational services are an exclusion in the member certificate of coverage.
Rationale:
The U.S. Food and Drug Administration (FDA) approval for Levulan® Kerastick™ represented the largest clinical trial at the time this policy was created.  As summarized in the package insert, 2 similarly designed studies randomized 243 patients with 4 to 15 non-hyperkeratotic actinic keratoses to receive Levulan® Kerastick™ plus blue light exposure or a vehicle solution plus blue light exposure. From 63% to 69% of patients in the active treatment group reported complete response at 8 weeks, compared to 13% to 14% in the placebo group. Patients who were not complete responders after 8 weeks had retreatment of the persistent lesions. Among these patients, 43% showed a complete response after a second treatment, compared to only 4% in the placebo group. This clinical trial has since been published in the peer-reviewed literature. (Piacquadio, 2004)
 
While the above study demonstrates the treatment effectiveness of photodynamic therapy (PDT), few studies examined relative effectiveness of various different nonsurgical treatments. Kurwa and colleagues (1999) reported on a small study of 17 patients with lesions on the backs of both hands.  One hand was randomized to receive a 3-week course of topical fluorouracil applied twice per day, while the other hand underwent treatment with topical ALA followed 4 hours later by irradiation with red light. (Therefore, the photodynamic protocol differed from that described for Levulan® Kerastick™.) Patients were followed up at 1, 4, and 24 weeks after starting treatment. Results showed that no patients had complete lesional clearing with either treatment, although the decrease in total lesional area was similar in both groups. Both treatments cause mild pain and moderate erythema: PDT in the first 2 weeks after treatment; and 5-FU in the third and fourth weeks after treatment. The authors concluded that a single treatment with PDT appeared to be as effective and well tolerated as 3 weeks of twice daily topical 5-fluorouracil (5-FU).
 
Based on the available published data in 2001, PDT with ALA appeared to be an effective nonsurgical technique of treating actinic keratoses. However, limited data were available to evaluate whether treatment effectiveness was equivalent or superior to other widely available nonsurgical approaches (e.g. 5-FU, cryotherapy with liquid nitrogen). Cryotherapy has been used to treat patients with a small number of discrete lesions, and 5-FU has been used in patients with a large number of lesions (i.e., full face therapy). Data were inadequate regarding PDT of other dermatologic lesions, including basal cell carcinoma, squamous cell carcinoma, acne vulgaris, hidradenitis suppurativa, mycoses, or Bowen’s disease.
 
In July 2004, the FDA approved Metvixia (methyl aminolevulinate) for non-hyperkeratotic actinic keratoses of the face and scalp based on 2 clinical trials with a total of 130 patients.  Both studies consisted of lesion preparation by debridement, the application of MAL with an occlusive dressing, removal of the MAL cream after 2.5 to 4 hours, followed by red light dosimetry and illumination (CureLight Broadband). This process was repeated after 7 days for 2 treatment sessions. In the Australian study, 86% (76/88) of patients had 75% or more lesions clear and 81% (71/88) were complete responders at 3-month follow-up. In the United States study, 83% (35/42) of patients had 75% or more lesions clear, and 79% (33/42) were complete responders at 3-month follow-up. The FDA indicated data beyond the 3-month follow-up was not available. The FDA also noted that pretreatment debridement could be an essential component of the therapy and, therefore, is included in the labeling for Metvixia.
 
Several other reports were published on PDT with methyl aminolevulinate (MAL). In a randomized, placebo-controlled trial of 80 patients with actinic keratoses, Pariser and colleagues (2003) reported that the complete response rate for the MAL group was 89% compared to 38% in the placebo group. Freeman and colleagues (2003) conducted a trial that randomized 204 patients with actinic keratosis to undergo MAL-PDT or cryotherapy.  Those assigned to PDT were further randomized to an active or placebo group. In terms of response rate, the PDT group reported superior outcomes compared to cryotherapy or placebo. Rhodes and colleagues (2004) reported on the results of a trial that randomized 101 adults with previously untreated nodular basal cell carcinoma (BCC) to receive MAL therapy or surgery.  At 3 months, complete response rates did not differ between the 2 groups; however, at 12 months, the complete response rate had fallen from 91% to 83%, while in the surgery group the complete response rate had fallen from 98% to 96%. One additional study focused on PDT for Bowen’s disease.  Salim and colleagues (2003) published the results of a trial that randomized 40 patients with Bowen’s disease to undergo either topical 5-FU or MAL therapy.  A total of 29 of the 33 lesions in the photodynamic group cleared completely, as compared with 22 of 33 in the 5-FU group. In the 5-FU group, severe eczematous reactions developed around 7 lesions, ulceration in 3, and erosions in 2.  No such reactions were noted in the PDT group.
 
One small study using PDT for hidradenitis suppurativa (Gold, 2004) and small studies using PDT for patients with acne vulgaris and interdigital mycoses had been published. (Pollock, 2004; Calzavara-Pinton, 2004)  However, these studies were too small and limited in follow-up to draw conclusions. A study in 102 patients with basal cell cancer showed promising results; however, there was no comparative group. (Vinciullo, 2005)  Comparative trials for patients with acne vulgaris involved very few participants.
 
With guidelines from the National Comprehensive Cancer Network (NCCN) and the International Society for Photodynamic Therapy in Dermatology published in 2007, literature search updates through June 2008 focused on the use of PDT for low-risk non-melanoma skin cancers, including superficial basal cell carcinoma (BCC) and Bowen’s disease. Additional papers published prior to 2006 were identified from citations in review articles. Also reviewed were studies comparing PDT with other treatments for actinic keratosis.
 
Actinic Keratosis
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 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.
 
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.
 
Acne
Literature on the use of PDT for acne consists of a several small (n = 30 or fewer per group) randomized controlled trials from outside of the United States. Results from these initial studies suggest a reduction in lesion count but significant adverse effects of MAL treatment. In 1 study 30% of subjects dropped out of the MAL group due to pain. (Wiegell, 2006)  An evidence-based review of PDT for the treatment of acne identified 5 randomized controlled trials (RCTs) with a total of 114 patients. (Haedersdal, 2008)  PDT was reported to be superior to untreated controls and to placebo PDT, with about 60% reduction of inflammatory lesions. Erythema, pustular eruptions and epithelial exfoliation were more severe in ALA than MAL treated sides. No studies were identified that compared PDT with other available treatments. Due to the small number of patients studied and high incidence of adverse effects, PDT for acne is considered investigational.
 
Professional Society Guidelines and Position Statements
Current practice guidelines from the National Comprehensive Cancer Network (NCCN) state that, “Surgical approaches often offer the most effective and efficient means for accomplishing cure, but considerations of function, cosmesis, and patient preference may lead to choosing radiation therapy as primary treatment in order to achieve optimal overall results.” (2007)  In patients with superficial BCC or Bowen’s disease for whom surgery or radiation is contraindicated or impractical, “topical therapies such as 5-fluorourcil, imiquimod, photodynamic therapy (e.g., porfimer sodium, topical amino levulinic acid (ALA)), or vigorous cryotherapy may be considered, even though the cure rate may be lower.”
 
The International Society for Photodynamic Therapy in Dermatology published consensus-based guidelines on the use of PDT for non-melanoma skin cancer. Braathen, 2004)  Based on both efficacy and cosmetic outcome, they recommended PDT as a first-line therapy for actinic keratosis. The guideline authors considered ALA to not have sufficient tissue penetration for nodular basal cell carcinoma. Based on 2 randomized-controlled and 3 open-label studies, it was concluded that MAL-PDT can be effective for nodular basal cell carcinoma lesions less than 2 mm in depth if debulked. The guideline recommended PDT for superficial basal cell carcinoma as “a viable alternative when surgery would be inappropriate or the patient or physician wishes to maintain normal skin appearance.” The report concluded that PDT is at least as effective as cryotherapy or 5-FU for Bowen’s disease, but that there is insufficient evidence to support the routine use of topical PDT for squamous cell carcinoma.
 
2011 Update
The policy was updated with a search of the MEDLINE database. The key new studies are summarized below.
 
There was one new RCT that evaluated PDT for treating acne. This study, published in 2010 by Orringer and colleagues, was a single-blind split-face study and included 44 patients with facial acne (Orringer, 2010).   A randomly selected side of the face received topical 5-ALA and pulsed dye laser (VBeam) therapy and the other side of the face remained untreated. Patients received up to 3 treatments at intervals of approximately 2 weeks. Twenty-nine patients (66%) completed the 16-week study. For most outcomes, there were no statistically significant differences between the treated and untreated sides of the face. This included change from baseline to 16 weeks in the mean number of inflammatory papules, pustules, cysts, closed comedones or open comedones. There was a significantly greater reduction in erythematous macules on the treated compared to the untreated side of the face (a mean reduction of 5.9 and 2.5, respectively; p=0.04). In addition, the improvement in mean Leed acne severity score was significantly greater on the treated side of the face (-1.07) than the untreated side (-0.52); p=0.001. There were few adverse effects, and they tended to be mild. A limitation of the study was the high drop-out rate.
 
In 2010, Foley and colleagues reported on a pair of industry-sponsored single-blind RCTs evaluating MAL-PDT for treating primary nodular basal cell carcinoma (BCC) (5 mm or less in depth); one study was conducted in Australia and the other in the United States (Foley, 2009).  The studies used the same design and procedures. Patients were randomly assigned to receive treatment with PDT using MAL 160 mg/g or placebo cream. The initial treatment cycle consisted of 2 PDT sessions a week apart. Patients whose lesions showed a partial response at the 3-month follow-up underwent a second treatment cycle. Clinical response was categorized as complete response ([CR] disappearance of lesion), partial response ([PR] at least 50% reduction in the longest diameter of the lesion), no response (less than 50% reduction in the longest diameter) or progression (at least 20% increase in the longest diameter). Combining the 2 studies, 131 patients with 160 lesions were enrolled (there were 66 patients in the Australian study and 65 patients in the U.S. study). Sixty-six patients were assigned to the MAL-PDT group and 65 to the placebo group. After randomization, 10 lesions were excluded because they were found histologically not to be nodular BCCs, leaving 150 lesions (75 per group). A total of 117 of 150 lesions (78%) received 1 complete treatment cycle, and 31 of 150 (21%) received 2 complete treatment cycles. The remaining 2 lesions received only a partial treatment cycle.
 
The rate of any local adverse event was 49 of 66 (74%) in the MAL-PDT group and 30 of 65 (46%) in the placebo group. The most common local event was a burning sensation of the skin, which was reported by 19 patients (29%) in the MAL-PDT group and 8 patients (12%) in the treatment group. In addition, 9 serious adverse events were reported by 6 patients, 2 treated with MAL-PDT and 4 treated with placebo. None of the serious adverse effects were determined to be related to the study treatment. The study is limited by a lack of statistical reporting and a comparison only to placebo, not surgery.
 
A second study identified in the updated literature search addressed MAL-PDT for treating nodular BCC. Fantini and colleagues published a retrospective analysis of data from Italy on 194 BCCs in 135 patients (Fantini, 2010). There was a significantly higher rate of CR in superficial BCCs 95 of 116, 82%), compared to nodular BCCs (26 of 78, 33%); p<0.001.
 
The 2010 practice guideline from the National Comprehensive Cancer Network (NCCN) states that, “surgical approaches often offer the most effective and efficient means for accomplishing cure, but considerations of function, cosmesis, and patient preference may lead to choosing radiation therapy as primary treatment in order to achieve optimal overall results.”  “In patients with low-risk superficial basal cell skin cancer, where surgery or radiation is contraindicated or impractical, topical therapies such as 5-fluorourcil, imiquimod, photodynamic therapy (e.g., porfimer sodium, topical amino levulinic acid [ALA]), or vigorous cryotherapy may be considered, even though the cure rate may be lower.”
 
The evidence to date suggests that the net health outcome is better with surgery than with PDT for treating  basal cell carcinoma and that photodynamic therapy  for superficial basal cell carcinoma has a similar efficacy to cryotherapy and better cosmetic outcomes. There is insufficient evidence that photodynamic therapy improves the net health outcome for nodular basal cell carcinoma compared to accepted treatments. New evidence on acne is insufficient to change conclusions about the ability of photodynamic thearpy to improve health outcomes for this indication. Thus, the policy statements are unchanged.
 
2012 Update
A search of the MEDLINE database was conducted through September 2012.  There was no new information identified that would prompt a change in the coverage statement. The following is a summary of the key identified literature.
 
An uncontrolled retrospective study evaluating recurrence of BCC after treatment with PDT was published in 2011 (Lindberg-Larsen, 2011).   A total of 90 patients with 157 lesions (n=111 superficial BCC, n=40 nodular BCC and n=6 unknown) were initially treated with MAL-PDT. Each lesion was treated twice, with 1 week between treatments. The authors did not report the initial rate of clinical response. Recurrence was defined as reappearance of a histologically-verified BCC in a previously affected area. The estimated recurrence rate was 11% at 6 months, 16% at 12 months, and 19% at 24 months. There was a significantly higher rate of recurrence for nodular BCC than superficial BCC (e.g., at 12 months, the recurrence rates were 28% and 13%, respectively, p=0.008). Study findings suggest the use of PDT with superficial BCC and not with nodular BCC. However, there may be confounding factors. For example, the authors noted that nodular BCCs were more frequently located on patients with fewer tumors and that patients with more tumors had a lower risk of recurrence.
 
The 2012 clinical practice guideline on basal cell skin cancers from the National Comprehensive Cancer Network (NCCN) states: “In patients with low-risk shallow cancers, such as SCC in situ (Bowen’s disease) or low-risk superficial BCC, topical therapies such as 5-fluorourcil, imiquimod, photodynamic therapy (e.g., methyl aminolevulinate [MAL], amino levulinic acid [ALA]), porfimer sodium), or vigorous cryotherapy may be considered, even though the cure rate may be lower” (NCCN, 2.2012).
 
2013 Update
A search of the MEDLINE database was conducted through September 2013. There was no new information identified that would prompt a change in the coverage statement. The following is a summary of the key identified literature.
 
Actinic Keratoses
A 2012 randomized pilot study from Spain compared PDT using methyl aminolevulinate (MAL) alone, imiquimod alone, and the combination of the 2 treatments (Serra, 2012).  Patients with non-hyperkeratonic actinic keratoses were randomly assigned to 1 of 3 groups: 1) 1 session of PDT with MAL (n=40): 2) self-administered imiquimod 5% cream for 4 weeks (n=33); or 3) PDT, as above, followed by 4 weeks of imiquimod cream (n=32). Follow-up occurred 1 month after PDT (group 1) or 1 month after the end of treatment with imiquimod (groups 2 and 3). The primary outcome measure, complete clinical response, was defined as the total absence of actinic keratoses by visual evaluation and palpation. Complete clinical response was achieved by 4 (10%) of patients in group 1, 9 (27%) of patients in group 2, and 12 (37.5%) of patients in group 3. There was a statistically significantly higher rate of complete response in the PDT plus imiquimod group compared to PDT only (p=0.004). A limitation of the study was that the PDT-only group was followed for a shorter amount of time, which could at least partially explain the lower rate of complete response.
 
Superficial Basal Cell Carcinoma
A 2012 systematic review by Roozeboom and colleagues examined randomized and non-randomized trials evaluating treatments for superficial basal cell carcinoma (Roozeboom, 2012).  A total of 16 studies were identified that evaluated PDT for treating BCC; 6 of the studies were RCTs. There was significant heterogeneity among studies (p<0.0001). A pooled estimate of complete response after treatment with PDT in 13 studies (PDT arms only) was 79% (95% confidence interval [CI]: 71% to 87%). In 3 studies that compared illumination regimens, only 1 arm was included, and in 2 studies that compared PDT agents, both arms were included.
 
Acne
In 2012, Shaaban and colleagues in Egypt conducted a split-face study that included 30 patients with inflammatory and nodulocystic acne (Schweiger, 2011).  In each patient, the right side was treated with a monthly session of ALA-PDT plus intense pulsed-light (IPL) treatment, and the left side was treated with IPL only. From baseline to the 1-month follow-up, the mean count of facial acne lesions decreased from 9.55 (standard deviation [SD]: 1.1) to 2.1 (SD: 1.68) in the combined treatment group and from 9.8 (SD: 4.8) to 5.01 (SD: 1.7) in the IPL-only group. The difference in lesion count between groups was statistically significant. Limitations of the study were that it was not randomized and did not include a group that received PDT as the sole intervention.
 
NCCN
The 2012 clinical practice guideline on basal cell skin cancers from the National Comprehensive Cancer Network (NCCN) states: “Since cure rates may be lower, superficial therapies should be reserved for those patients where surgery or radiation is contraindicated or impractical…In patients with low-risk shallow cancers, such as SCC in situ (Bowen’s disease) or low-risk superficial BCC, topical therapies such as 5-fluorouracil, imiquimod, PDT (MAL, porfimer sodium or topical amino levulinic acid) or vigorous cryotherapy may be considered even though the cure rate may be lower” (NCCN, V2.2012).
 
2014 Update
A literature search conducted through September 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
In 2012, Scola et al in Germany published findings from a randomized split-area comparison of 5-ALA PDT and carbon dioxide laser ablation in 21 patients with multiple actinic keratoses (Scola, 2012). Seventeen of the 21 patients had lesions located on the face or scalp and, in the other 4 patients, lesions were on the back of the hand or forearms. The primary efficacy outcome was the reduction in the number of actinic keratoses. At baseline, the median number of actinic keratoses was 6 (range, 4-28) in the PDT group and 8 (range, 3-34) in the laser ablation group. The median number of actinic keratoses in the PDT was 0 (range, 0-12) at the end of the 4-week treatment period and one (range, 0-5) at the 3-month follow-up. Comparable numbers in the laser ablation group were 2 (range, 0-7) actinic keratoses at 4 weeks and 2 (range, 1-7) in the laser ablation group. The reduction in the number of actinic keratoses did not differ significantly between groups at 4 weeks, but there was a significantly greater reduction in the quantity of actinic keratoses at 3 months in the PDT group (p=0.016). The investigators reported that there were more adverse events associated with PDT, but they did not provide details on rates of these adverse events.
 
Several trials have compared PDT with surgery for treating nodular BCC. In 2008, Mosterd et al published an RCT evaluating 5-ALA PDT for patients with nodular BCC (Mosterd, 2008). The study included 149 patients with 173 primary nodular BCC; 85 tumors were assigned to PDT and 88 to surgical excision. Two patients, each with 1 tumor, dropped out before treatment. At 3 months, 78 of 83 (94%) tumors in the 5-ALA-PDT group and 86 of 88 (98%) tumors in the surgery group had resolved completely; this difference was not statistically different. Long-term follow-up data were published in 2013 (Roozeboom, 2013). Investigators reported on 106 tumors with at least 5 years of follow-up. Over 5 years, treatment failure occurred in 2 tumors in the surgery group and 23 tumors in the PDT group. The cumulative probability of tumor recurrence by 60 months was 30.7% (95% CI, 21.5% to 42.6%) in the PDT group and 2.3% (95% CI, 0.6% to 8.8%) in the surgical excision group. Both treatment failures in the surgery group were due to incomplete excision of the tumors. Treatment failure rates were higher for thicker tumors. The rate of recurrence-free survival at 5 years was over 90% for tumors greater than 0.7mm thick and between 60% and 70% of thinner tumors.
 
Squamous Cell Carcinoma
Squamous cell carcinoma in situ (Bowen disease)
A Cochrane review on interventions for cutaneous Bowen disease was published by Bath-Hextall in 2013 (Bath-Hextall, 2013). The investigators identified a total of 7 RCTs evaluating PDT. Four of these compared 2 PDT protocols, one compared PDT to cryotherapy, one compared PDT to topical 5-fluorouracil (5-FU), and one compared PDT to both PDT and 5-FU. The authors did not pool study findings.
 
The study with the largest sample size (n=225) was a 3-arm trial published in 2006 by Morton et al (Morton, 2006). This was a multicenter study conducted in 11 European countries. A total of 225 patients were randomized to receive MAL PDT, cryotherapy or 5-FU for treatment of Bowen disease. Unblinded assessment of lesion clearance found PDT to be noninferior 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 nonsurgical 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.
 
Nonmetastatic invasive squamous cell carcinoma
In 2013, Lansbury et al published a systematic review of observational studies evaluating interventions for nonmetastatic cutaneous squamous cell carcinoma (SCC) (Lansbury, 2013). The investigators identified 14 prospective studies evaluating PDT. Sample sizes ranged from 4 to 71 patients and only 3 included more than 25 patients. These studies evaluated a variety of different PDT protocols. There was only 1  comparative study, and this study compared 2 different PDT regimens. In a pooled analysis, a mean of 72% of lesions had a compete response to treatment (95% CI, 61.5% to 81.4%). Eight studies addressed recurrence rates in patients who were initial responders. When findings were pooled, the probability of recurrence was 26.4% (95% CI, 12.3% to 43.7%).
 
In 2013, Mei et al in China published a parallel group RCT that included 41 patients with moderate to severe facial acne (Mei, 2013). The trial evaluated the additional value of ALA PDT in patients treated with IPL. A total of 21 patients were randomized to 4 weeks of treatment with IPL plus PDT and 20 patients were randomized to IPL plus placebo PDT. The mean reduction in both inflammatory and noninflammatory lesions was significantly greater in the IPL plus PDT group compared with the IPL-only group at the 4-, 8-, and 12-week follow-ups. For example, in the IPL plus PDT group, the mean number of noninflammatory acne lesions decreased from 31.3 (SD=7.1) at baseline to 14.0 (SD=6.2) at the 12-week follow-up. In the IPL-only group, the mean number of noninflammatory lesions decreased from 28.2 (SD=4.1) at baseline to 18.6 (SD=3.1) at 12 weeks (p<0.05). An improvement of 75a% to 100% in all lesions was attained by 13 patients (62%) in the IPL plus PDT group and 3 (15%) in the IPL-only group. Both treatments were well tolerated and no patients withdrew from the study due to adverse effects of treatment. The study did not evaluate the efficacy of PDT in the absence of IPL therapy.
 
2015 Update
A literature search conducted through December 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
 
Efficacy of PDT Compared With an Alternative Intervention
A number of published RCTs compare PDT with other therapies, and a systematic review of these studies has been published. Patel et al, in 2014, reviewed RCTs with at least 10 patients that addressed the efficacy of topical PDT compared with an alternative (ie, non-PDT) treatment of actinic keratosis (Patel, 2014). A total of 13 studies with 641 participants met the review’s inclusion criteria. Studies compared PDT with cryotherapy (n=6), fluorouracil (n=2), imiquimod (n=4), and carbon dioxide laser (n=1). Seven studies used ALA and the other 6 used MAL as the PDT sensitizer. Most studies focused on lesions located on the face or scalp. None of the included studies were double-blind. In 12 of the 13 studies, primary outcome was a measure related to the clearance rate of lesions. Data from 4 RCTS comparing PDT and cryotherapy were suitable for meta-analysis. The pooled lesion response rate 3 months after treatment was significantly higher with PDT than with cryotherapy (pooled relative risk (RR), 1.14, 95% confidence interval [CI], 1.11 to 1.18). Due to heterogeneity among the interventions, other data were not pooled.
 
Efficacy of Different PDT Protocols
Several RCTs have compared different approaches to applying PDT in the treatment of actinic keratoses (Zane, 2014; Giehl. 2014; Neittaanmaki-Perttu, 2014; Rubel, 2014). No clear evidence of superiority of one approach over another emerges from this body of evidence, and some of the alternative approaches, eg, daylight PDT, are not FDA-cleared.
 
Evidence from multiple RCTs has found that PDT improves the net health outcome in patients with nonhyperkeratotic actinic keratoses on the face or scalp compared with placebo or other active interventions. There is insufficient evidence that any PTD protocol is superior to any other protocol.
 
Basal Cell Carcinoma
The Cochrane review did not distinguish among BCC subtypes.
More recently, in 2014, Wang et al published a meta-analysis of RCTs on PDT for treating BCC, both superficial and nodular (Wang, 2012). To be included in the systematic review, studies needed to include adults with 1 or more primary BCCs, randomize participants to PDT versus placebo or another treatment and report the complete clearance rate, recurrence rate, cosmetic outcomes, and/or adverse events. A total of 8 RCTs with 1583 patients, published between 2001 and 2013, met inclusion criteria. Three trials included patients with superficial BCC, 3 included patients with nodular BCC, and 1 included patients with both types of low-risk BCC. Four trials compared PDT and surgery, 2 compared PDT and cryotherapy, 1 compared PDT and pharmacologic treatment, and 1 was placebo controlled.
 
In meta-analysis of 7 studies, the estimated probability of complete clearance after treatment was similar in the PDT and non-PDT groups (RR, 0.97, 95% CI, 0.88 to 1.06). In subgroup analyses by treatment type, PDT was associated with a significantly higher clearance rate only when compared with placebo. In a pooled subgroup analyses by tumor type, results were similar except that the upper CI for nodular BCC just crossed 1 and was thus not statistically significant, and the upper CI for superficial BCC was just below 1 and thus was statistically significant. For nodular BCC, the RR (95% CI) was 0.93 (0.85 to 1.01) and for superficial BCC, the RR (95% CI) was 0.93 (0.88 to 0.98). Only 1 study on superficial BCC contributed data to this subgroup analysis.
 
When data from 6 studies were pooled, there was not a statistically significant difference in the recurrence rate at 1 year in the PDT and non-PDT groups. Surgery was associated with a significantly lower rate of recurrence compared with PDT, and there was not a significant difference in recurrence rates when PDT was compared with cryotherapy and pharmacologic therapy. In meta-analyses of cosmetic outcomes at 1 year, there was a significantly higher probability of a good to excellent outcome with PDT compared with surgery (RR, 1.87, 95% CI, 1.54 to 2.26) or cryotherapy (RR, 1.51, 95% CI, 1.30 to 1.76).
 
Systematic reviews of RCTs have found that PDT does not appear to be as effective as surgery for superficial and nodular BCC. These systematic reviews have not found statistically significant differences in clinical response rates with PDT compared with cryotherapy for BCC, which suggests, but does not conclusively demonstrate, similar efficacy. Cosmetic outcomes have been better after PDT compared with surgery and cryotherapy. In the small number of trials available, PDT was more effective than placebo.
 
There is evidence from randomized controlled trials (RCTs) that photodynamic therapy (PDT) is an effective treatment for selected patients with actinic keratoses of the face and scalp compared with placebo or cryotherapy. The evidence to date suggests that PDT is less effective than surgery and radiotherapy and of similar efficacy to cryotherapy for treating low-risk basal cell carcinoma (BCC) (eg, superficial and nodular). Moreover, the evidence suggests that cosmetic outcomes are better after PDT compared with surgery and cryotherapy. Evidence from randomized controlled trials RCTs suggests that, in patients with Bowen disease (BD), PDT has similar or higher efficacy compared with cryotherapy and 5-fluorouacil, and better cosmetic outcomes. Thus, PDT may be considered medically necessary for treating non-hypertonic actinic keratoses of the face and scalp, and for treating low-risk BCC and BD when surgery and radiation are contraindicated.
 
There is insufficient evidence that PDT improves the net health outcome for other dermatologic conditions compared with accepted treatments, and therefore they are considered investigational.
 
Practice Guidelines and Position Statements
The v1.2015 clinical practice guideline on basal cell skin cancers from the National Comprehensive Cancer Network (NCCN) states: “Since cure rates may be lower, superficial therapies should be reserved for those patients where surgery or radiation is contraindicated or impractical. Superficial therapies include topical treatment with 5-FU or imiquimod, photodynamic therapy (PDT) and cryotherapy.” Moreover, the guideline describes BCC histologic subtypes that have low-risk of recurrence as nodular, superficial, and other nonaggressive growth patterns, such as keratotic, infundibulocystic, and fibroepithelioma of Pinkus. For patients with low-risk BCCs, the guideline states, “…topical therapies such as 5-FU (5-fluorouracil), imiquimod, PDT (eg, porfimer sodium or topical amino levulinic acid) or vigorous cryotherapy may be considered even though the cure rate may be lower.” (NCCN, 2015)
 
2017 Update
A literature search conducted through January 2017 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Zou and colleagues identified 5 RCTs comparing PDT and surgical excision in patients with nodular BCC that had at least 3 months of follow-up (Zou, 2016). The rate of complete response was significantly lower in the PDT group compared with the surgical excision group at 1 year (RR=0.89; 95% CI, 0.80 to 0.99) and at 3 years (RR=0.73; 95% CI, 0.63 to 0.85) and there were not significant differences in complete response at 2 years, 4 years, or 5 years. The rate of recurrence was significantly higher in the PDT group than the surgical excision group at all-time points.
 
A 2016 non-inferiority RCT by Roozeboom and colleagues compared MAL-PDT to imiquimod cream and to fluorouracil cream in patients with superficial BCC (Roozeboom, 2016).  A total of 601 patients were randomized, 202 to MAL-PDT, 198 to imiquimod, and 201 to fluorouracil. A total of 490 (82%) patients completed the 1-year follow-up and 417 (69%) completed the 3-year follow-up. Median follow-up was 35 months. The estimated tumor-free survival rates at 3 years were 58% (95% CI, 47.8% to 66.9%) in the PDT group, 79.7% (95% CI, 71.6% to 85.7%) in the imiquimod group, and 68.2% (95% CI, 58.1% to 76.3%) in the fluorouracil group. Results of the non-inferiority analysis were that imiquimod was superior to MAL-PDT and imiquimod was non-inferior to MAL-PDT.
 
Several RCTs and a Cochrane review have been published. The Cochrane review, published by Barbaric and colleagues in 2016, addressed a variety of light therapies for acne, including PDT (Barbaric, 2016). For studies on MAL-PDT, only data on investigator-assessed change in lesion counts were suitable for pooling. A meta-analysis of 3 studies on MAL-PDT did not find a significant difference from placebo on investigator-assessed change in inflamed lesion counts (mean difference [MD], -2.85; 95% CI, -7.51 to 1.81) or change in non-inflamed lesion counts (MD = -2.01; 95% CI, -7.07 to 3.05). Authors concluded that there is a lack of high-quality evidence on light therapies for treating acne and low certainty in the usefulness of PDT.
Pariser and colleagues published a multicenter double-blind placebo-controlled RCT evaluating MAL-PDT for severe facial acne (Pariser, 2016). A total of 153 patients were randomized and included in the intention-to-treat analysis, 100 to MAL-PDT and 53 to a matching vehicle (ie, placebo) cream. All patients received 4 treatments, 2 weeks apart and were evaluated up to 12 weeks after the first treatment. One hundred twenty nine (84%) patients completed the study. The primary outcome, change from baseline in facial inflammatory lesion count at 12 weeks, was significantly lower in the MAL-PDT group (mean, -15.6) than the placebo group (mean, -7.8; p=0.006). Change in facial non-inflammatory lesion count at 12 weeks did not differ significantly between groups (-11.8 vs -10.7; p=0.85). The most commonly reported adverse events were pain (n=17, 17% in the MAL-PDT group and 0 in the placebo group) and a skin burning cessation (n=15, 15% in the PDT group and 5, 9% in the placebo group). Most adverse events were mild-to-moderate although 12 patients in the MAL-PDT group dropped out due to treatment-related adverse events.
 
ONGOING AND UNPUBLISHED CLINICAL TRIALS
Some currently unpublished trials that might influence this review are listed below:
 
Ongoing
(NCT02647151) Efficacy and Safety of Treatment of Actinic Keratoses With Photodynamic Therapy Between MAL Cream and ALA Gel; planned enrollment 509; projected completion date March 2016 (ongoing).
 
(NCT02644187) Pain Relief During Photodynamic Therapy for Actinic Keratoses With a New Irradiation Protocol; planned enrollment 30; projected completion date December 2016.
 
(NCT02367547) an industry-sponsored or cosponsored trial. Superficial Basal Cell Cancer's Photodynamic Therapy: Comparing Three Photosensitises: HAL and BF-200 ALA Versus MAL; planned enrollment 99; projected completion date December 2022.
 
2018 Update
A literature search was conducted through November 2018.  There was no new information identified that would prompt a change in the coverage statement.
 
2019 Update
A literature search was conducted through September 2019.  There was no new information identified that would prompt a change in the coverage statement.  The key identified literature is summarized below.
 
Wu et al conducted a prospective, multicenter RCT involving 100 patients (age range, 16-50 years) to measure the efficacy of different dose levels of hemoporfin with PDT in treating port wine stain (Wu, 2018). In the trial, 40 patients received hemoporfin 2.5 mg/kg intravenously, 40 received hemoporfin 5 mg/kg intravenously, and 20 received a saline placebo. Ten minutes after infusion, all patients received PDT. After an evaluation at week 8, 75% of the high-dose group reported improvements in skin lesions compared with 40% of the low-dose group and 15% of the placebo group. Adverse events were mild and resolved within a week. Limitations included short follow-up and a small sample size.
  
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2020. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Steeb et al published a systematic review of RCTs that evaluated cryosurgery, ingenol mebutate, PDT, colchicine, and 5-FU for the treatment of AK in nonscalp and nonface localizations (Steeb, 2020). Thirteen studies (N=1380 participants) met the reviewers’ inclusion criteria. Studies evaluating PDT included comparisons to placebo (n=4), cryotherapy (n=3), 5-FU (n=2), colchicine (n=1), and imiquimod (n=1). Direct (pairwise) comparison analyses found that PDT was significantly better than placebo in achieving complete clearance (RR, 3.87; 95% CI, 2.14 to 6.97). Ten of the studies were included in a network analysis. Compared to placebo, cryosurgery showed the highest complete clearance rates (RR, 7.73; 95% CI, 3.21 to 18.61), followed by imiquimod (RR, 7.00; 95% CI, 3.06 to 15.98), and PDT (RR, 3.87; 95% CI, 2.14 to 6.97). Cryosurgery was associated with a higher likelihood of complete clearance than PDT (RR, 2.00; 95% CI, 1.04 to 3.84) with a low certainty of evidence. Authors of the review noted caution in directly comparing topical treatments, which may be more suitable as a field-directed treatment of multiple or clustered lesions, with cryosurgery, which is preferable for single or a limited number of AKs.
 
Mpourazanis et al compared PDT to cryotherapy for BCC in a systemic review of 19 RCTs and prospective observational trials (Mpourazanis, 2020). Of these studies, only 5 RCTs were included in the quantitative analysis. For rates of complete clearance, there was no significant difference found between PDT and cryotherapy (2 studies; OR, 0.83; 95% CI, 0.47 to 1.49; I2=0%). Similarly, no difference was found between PDT and cryotherapy for the recurrence rate (3 studies; OR, 4.99; 95% CI, 0.40 to 62.40; I2=87.3%). The review did not distinguish among BCC subtypes.
 
Shen et al published a systematic review of clinical trials and case series evaluating PDT, with a focus on the photosensitizers used, for superficial fungal infections (Shen, 2020). Thirty-four studies were identified for inclusion, including 13 clinical trials and 20 cases (N=440 [n=336 for PDT participants only]). None of the clinical trials were blinded. The follow-up times of the studies varied from no follow-up to 2 years. Quantitative analyses were not performed. The majority of the included studies (n=18) evaluated PDT for onychomycosis. Seven different photosensitizers were evaluated for onychomycosis, ALA (3 studies), MAL (6 studies), porphyrin (1 study), methylene blue (5 studies), rose Bengal (1 study), curcumin (1 study), and aluminum phthalocyanine chloride nanoemulsions (1 study). Treatment with methylene blue had complete cure rates ranging from 70% to 80% (2 trials); whereas mycological cure rates for ALA and MAL ranged from 17% to 57% (2 trials) and 32% (1 trial), respectively. The most common adverse events reported in the included studies were pain/burning/stinging sensation (n=147/323 [45.5%]), erythema (n=66/177 [37.3%]), blistering (n=14/150 [9.3%]), edema (n=48/170 [28.2%]), and hyper-/hypopigmentation (n=10/140 [7.1%]).
 
The American Academy of Dermatology has guidelines addressing use of photodynamic therapy (PDT) in basal cell carcinoma and acne:
 
    • Basal cell carcinoma: Use of topical therapies, including PDT, is most appropriate for low-risk basal cell carcinoma when surgery is impractical or declined by the patient (Kim, 2018). Discussions of the relative effectiveness of topical therapies should be discussed with the patient. The guideline further notes that "Cure rates after surgical excision are 10% to 20% higher than those for topical therapies, including PDT, with excision associated with recurrence rates of less than 5%. Surgical excision may also be less painful and better tolerated."
    • Acne: More studies are needed on the use of PDT or other laser/light devices (Zaenglein, 2016). PDT has the most evidence among laser/light devices for treating acne, but "additional studies are needed to determine the optimal photosensitizer, incubation time, and light source."
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Ezzedine et al performed a systematic review and network meta-analysis of RCTs evaluating the efficacy and acceptability of interventions for AK of the face, ears, and/or scalp (Ezzedine, 2021). For the outcome of complete clearance (number of patients with 100% cleared lesions), 21 RCTs contributed to the network. The most efficacious interventions as measured by surface under the cumulative ranking curve (SUCRA) included 5-FU 5% (85%), 5-FU 4% (78%), ALA-PDT (70%), imiquimod 5% (67%), 5-FU 0.5% (63%), and ingenol mebutate (60%). Results were similar in an analysis of partial clearance (number of patients with ≥75% cleared lesions) using data from 10 RCTs. Using data from 9 RCTs, rates of withdrawal due to adverse events were most favorable, as measured by SUCRA, for 5-FU combined with salicylic acid (81%), imiquimod 2.5% (71%), 5-FU 4% (71%), 5-FU 5% (66%), and imiquimod 3.75% (55%). However, rates of withdrawal due to adverse events were not significantly different for any of these agents in comparisons with placebo.
 
Karrer et al reported findings from an RCT comparing MAL-PDT with cryosurgery in 58 patients with AK of the face (Karrer, 2021). Patients received either 5 full-face treatments with MAL-PDT or a single freeze-thaw cryosurgery cycle, followed by additional intervention in the case of non-cleared or newly developed AK. At 24 months of follow-up, the primary outcome, the cumulative number of new AKs after visit 1, was not significantly different between MAL-PDT and cryosurgery (mean difference, -2.5; 95% CI, -6.2 to 1.2). Overall, complete clearance of AKs was significantly greater with MAL-PDT (mean difference, 43.5%; 95% CI, -12.5 to 39.3); however, no differences were detected in grade I or II lesions.
 
Cortelazzi et al reported results of an RCT evaluating the effect of imiquimod 3.75% versus MAL-PDT in patients with AK of the scalp (Cortelazzi, 2021). Nine bald male patients were randomized to receive a single session of treatment on either the right or left side of the scalp, and were assessed at up to 12 months of follow-up. By degree of AK, rates of clearance for imiquimod versus MAL-PDT were 68.8% and 48.0% for degree I, 64.5% and 69.8% for degree II, and 75% and 66.7% for degree III, respectively.
 
Zhong et al performed meta-analyses using data from 12 RCTs (n=446) comparing PDT with other treatments in patients with Bowen disease (Zhong, 2020). For the outcome of lesion reduction reported between 1 and 12 months, PDT was associated with a significantly higher lesion reduction rate compared with control groups (OR, 2.86; 95% CI, 1.89 to 4.33). In comparisons with specific control groups, PDT was associated with significant improvements in lesion reduction compared with 5-FU (OR, 3.70; 95% CI, 2.07 to 6.62) and compared with cryotherapy (OR, 2.24; 95% CI, 1.24 to 4.04). No significant differences were observed in recurrence rates between PDT and control groups. Most domains of study quality were assessed as low or unclear risk of bias. The authors reported the potential for publication bias and concluded PDT to be a safe and effective therapy for Bowen disease.
 
A systematic review by Wu et al performed a meta-analysis using data from 13 RCTs (N=422) that compared red light PDT with placebo, pharmacotherapy, or other sources of light in the treatment of acne (Wu, 2021). For the outcome of inflammatory lesions, red light did not differ significantly at any point in time up to 12 weeks compared with other conventional treatment methods (weighted mean difference, 0.701; 95% CI, −0.809 to 2.212). Similar results were reported for the outcome of non-inflammatory lesions (weighted mean difference, -0.527; 95% CI, -3.055 to 2.001). Most domains of study quality were assessed as low or unclear risk of bias. The authors concluded that further study is needed comparing red light PDT with traditional therapies.
 
Wojewoda et al performed a double-blind RCT comparing MAL-PDT with placebo in patients with facial acne (Wojewoda, 2021). The trial randomized 36 patients to MAL-PDT or placebo, each given in either 2 or 4 treatments. After 20 weeks, the number of inflammatory lesions decreased by 74% and 85% with 2 and 4 treatments of MAL-PDT, respectively. However, there were no significant differences in relative change of inflammatory or non-inflammatory lesions in comparisons with the placebo group. No severe adverse effects were reported in either group. Trial limitations included a high rate of attrition and small sample size.
 
Chun-Hua et al reported a retrospective review of 439 children with port-wine stains treated with PDT (Chun-Hua, 2021). An effective response (>20% fading) occurred in 95.2% of patients, and 74.3% experienced almost complete resolution and great improvement (≥60% fading). Zhang et al (2021) also evaluated a series of 107 children who received PDT for port-wine stains that were resistant to pulsed dye laser (Zhang, 2021). Good-to-excellent improvement was achieved in 32.7% of 107 patients who received a single session of treatment and in 50.8% of patients who received 2 sessions of treatment. These uncontrolled studies are insufficient to draw conclusions about the effect of PDT on health outcomes in patients with port-wine stains.
 
The American Academy of Dermatology has guidelines addressing use of photodynamic therapy (PDT) in basal cell carcinoma and acne:
    • Actinic keratosis (2021): PDT is included in the following recommendations for patients with AK (Eisen, 2021):
        • ALA-red light PDT is conditionally recommended (low quality of evidence)
        • ALA-daylight PDT is conditionally recommended as less painful than but equally effective as ALA-red light PDT (moderate quality of evidence)
        • ALA-blue light PDT is conditionally recommended (moderate quality of evidence)
        • ALA-red light PDT is conditionally recommended over cryosurgery alone (low quality of evidence)
    • Basal cell carcinoma (2018): Use of topical therapies, including PDT, is most appropriate for low-risk basal cell carcinoma when surgery is impractical or declined by the patient (Kim, 2018). Discussions of the relative effectiveness of topical therapies should be discussed with the patient. The guideline further notes that "Cure rates after surgical excision are 10% to 20% higher than those for topical therapies, including PDT, with excision associated with recurrence rates of less than 5%. Surgical excision may also be less painful and better tolerated."
    • Acne (2016): More studies are needed on the use of PDT or other laser/light devices (Zaenglein, 2016). PDT has the most evidence among laser/light devices for treating acne, but "additional studies are needed to determine the optimal photosensitizer, incubation time, and light source."
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Xue et al performed a meta-analysis of 8 RCTs that compared PDT for Bowen disease (Xue, 2022). Compared to other topical treatments (5-FU and cryotherapy), PDT resulted in a higher complete response rate (1.36; 95% CI, 1.01 to 1.84; p=.04; I2=86%), a lower rate of recurrence (0.53; 95% CI, 0.30 to 0.95; p=.03; I2=0%), and better cosmetic outcome (1.34; 95% CI, 1.15 to 1.56; p=.0002; I2=0%). Another systematic review and meta-analysis of 43 studies of PDT included 1943 Bowen disease lesions and 282 cutaneous squamous cell carcinoma lesions (Yongpisarn, 2022). The pooled clearance rate at 1 year was 76% for Bowen disease lesions (95% CI, 71% to 80%; I2=78.9%). The authors concluded that the evidence supported use of PDT for Bowen disease with patient education about the possibility of recurrence, and that further studies are needed.
 
Reshetylo et al published a systematic review of PDT for treatment of hidradenitis suppurativa (Reshetylo, 2022). All of the 18 included studies had a high risk of bias and there was heterogeneity among studies that limited the overall analysis. The authors concluded that there might be clinical benefit with ALA/PDT with blue light, MAL/PDT with red light, and ALA with intralesional diode, but further high-quality studies are needed.
 
Yang et al conducted a systematic review of 19 publications (N=292) with PDT for actinic cheilitis (Yang, 2022). Clinical trials, observational studies, and case series were considered but all of the included studies were uncontrolled cohorts and case series. Rates of complete clinical response were 80% with ALA/PDT, 76.74% with daylight PDT, and 65.14% with traditional PDT. The highest rates of painlessness were reported in patients who received daylight PDT. Local phototoxicity (moderate to severe) occurred most frequently in the traditional PDT group (47.78%) and least frequently in the daylight PDT group (0%). Limitations of the study included lack of control populations, small sample sizes (range, 2 to 43), inclusion of only red light for traditional PDT, differences in follow-up times, and outcome assessment by unblinded investigators. The authors stated that the evidence was of low quality and insufficient to base a recommendation for any particular treatment.
 
A joint guideline from the United States and Canadian Hidradenitis Suppurativa Foundations (2019) provides guidance on diagnosis and complementary and procedural management of hidradenitis suppurativa (Alikhan, 2019). The guideline recommends PDT at a level C (based on consensus, opinion, case studies, or disease-oriented evidence). The authors state that PDT has a limited role in managing hidradenitis suppurativa, mainly due to a lack of large, well-controlled studies.
 
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2023. No new literature was identified that would prompt a change in the coverage statement.
CPT/HCPCS:
96573Photodynamic therapy by external application of light to destroy premalignant lesions of the skin and adjacent mucosa with application and illumination/activation of photosensitizing drug(s) provided by a physician or other qualified health care professional, per day
96574Debridement of premalignant hyperkeratotic lesion(s) (ie, targeted curettage, abrasion) followed with photodynamic therapy by external application of light to destroy premalignant lesions of the skin and adjacent mucosa with application and illumination/activation of photosensitizing drug(s) provided by a physician or other qualified health care professional, per day
J0134Injection, acetaminophen (fresenius kabi) not therapeutically equivalent to j0131, 10 mg
J0136Injection, acetaminophen (b braun) not therapeutically equivalent to j0131, 10 mg
J0173Injection, epinephrine (belcher) not therapeutically equivalent to j0171, 0.1 mg
J0283Injection, amiodarone hydrochloride (nexterone), 30 mg
J0611Injection, calcium gluconate (wg critical care), per 10 ml
J0689Injection, cefazolin sodium (baxter), not therapeutically equivalent to j0690, 500 mg
J0701Injection, cefepime hydrochloride (baxter), not therapeutically equivalent to maxipime, 500 mg
J0703Injection, cefepime hydrochloride (b braun), not therapeutically equivalent to maxipime, 500 mg
J0877Injection, daptomycin (hospira), not therapeutically equivalent to j0878, 1 mg
J0891Injection, argatroban (accord), not therapeutically equivalent to j0883, 1 mg (for non-esrd use)
J0892Injection, argatroban (accord), not therapeutically equivalent to j0884, 1 mg (for esrd on dialysis)
J0893Injection, decitabine (sun pharma) not therapeutically equivalent to j0894, 1 mg
J0898Injection, argatroban (auromedics), not therapeutically equivalent to j0883, 1 mg (for non-esrd use)
J0899Injection, argatroban (auromedics), not therapeutically equivalent to j0884, 1 mg (for esrd on dialysis)
J1456Injection, fosaprepitant (teva), not therapeutically equivalent to j1453, 1 mg
J1574Injection, ganciclovir sodium (exela) not therapeutically equivalent to j1570, 500 mg
J1611Injection, glucagon hydrochloride (fresenius kabi), not therapeutically equivalent to j1610, per 1 mg
J1643Injection, heparin sodium (pfizer), not therapeutically equivalent to j1644, per 1000 units
J2021Injection, linezolid (hospira) not therapeutically equivalent to j2020, 200 mg
J2184Injection, meropenem (b. braun) not therapeutically equivalent to j2185, 100 mg
J2247Injection, micafungin sodium (par pharm) not thereapeutically equivalent to j2248, 1 mg
J2251Injection, midazolam hydrochloride (wg critical care) not therapeutically equivalent to j2250, per 1 mg
J2272Injection, morphine sulfate (fresenius kabi) not therapeutically equivalent to j2270, up to 10 mg
J2281Injection, moxifloxacin (fresenius kabi) not therapeutically equivalent to j2280, 100 mg
J2311Injection, naloxone hydrochloride (zimhi), 1 mg
J2401Injection, chloroprocaine hydrochloride, per 1 mg
J2402Injection, chloroprocaine hydrochloride (clorotekal), per 1 mg
J3244Injection, tigecycline (accord) not therapeutically equivalent to j3243, 1 mg
J3371Injection, vancomycin hcl (mylan) not therapeutically equivalent to j3370, 500 mg
J3372Injection, vancomycin hcl (xellia) not therapeutically equivalent to j3370, 500 mg
J7308Aminolevulinic acid hcl for topical administration, 20%, single unit dosage form (354 mg)
J7309Methyl aminolevulinate (mal) for topical administration, 16.8%, 1 gram
J7345Aminolevulinic acid hcl for topical administration, 10% gel, 10 mg
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