Medical Policy: 02.01.16
Original Effective Date: January 2002
Reviewed: February 2018
Revised: February 2018
Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.
This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.
Photodynamic therapy (PDT) refers to light activation of a drug that acts as a photosensitizer to destroy the target tissue. Photosensitizing agents have been used in non-dermatologic applications and are being proposed for use with dermatologic conditions such as actinic keratoses, non-melanoma skin cancers (basal cell carcinoma or squamous cell carcinoma in situ [Bowen's disease]), acne vulgaris, mycoses, port wine stains and hidradenitis suppurativa.
Photodynamic therapy (PDT) is a two-step process and typically involves two office visits spaced a week apart. More than one treatment series may be required. In step one the medication is topically applied to the affected tissue and allowed to absorb for a set period of time. The drug accumulates and is retained in dysplastic cells of the skin to a greater degree than normal tissue (i.e. the drug has a greater affinity for dysplastic cells. In step two, the affected skin tissue is exposed to the light source. The photoactivation (maximum absorption of 404 to 420 nm and 635 nm) of the drug creates a cytotoxic reaction within the cells that destroys the lesion(s). The cytotoxic effect is dependent on light and oxygen. Two common photosensitizing agents are 5-aminolevulinac acid (5-ALA) and methyl aminolevulinate (MAL). PDT can cause erythema, burning, and pain. Healing occurs within 10 to 14 days, with generally acceptable cosmetic results.
Actinic keratoses are rough, scaly, warty premalignant growths on the sun-exposed skin that are very common in older people with fair complexions, with a prevalence of greater than 80% in fair skinned people older than 60 years of age. In some cases, actinic keratoses may progress to squamous cell carcinoma (SCC) 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), dermabrasion and photodynamic therapy (PDT). PDT with topical ALA has been investigated primarily as a treatment of actinic keratoses. Topical treatments are generally used in patients with multiple lesions and the involvement of extensive areas of the skin. Under some circumstances, combinations of different treatment methods may be used.
In 2010, Szeimies et. al. reported on a phase 3 clinical trial using a stable 5-aminolaevulinic acid nanoemulsion formulation (BF-200 ALA) developed for PDT for actinic keratosis. The multicenter, double-blind, interindividual 2 armed-trial randomized 122 patients to BF-200 ALA or placebo. The patients had 4 to 8 mild-to-moderate actinic keratosis lesions on the face and/or bald scalp. BF-200 ALA was used in combination with 1 of 2 different light sources. The efficacy of BF-200 ALA after the first PDT treatment was evaluated at 12 weeks. For patients who were not completely cleared of actinic keratoses received a second PDT treatment, with the final evaluation 12 weeks later for all participants. The results showed PDT with BF-200 ALA was superior to PDT with placebo in respect to patient complete clearance rate (per-protocol group, 64% vs 11%; p< 0.001) and lesion complete clearance rate (per-protocol group, 81% vs 22%) after the last PDT treatment. Statistically significant differences in the patient and lesion complete clearance rates and adverse event profiles were observed for the 2 light sources (Aktilite CL128 and PhotoDyn 750) at both time points of the assessment. The patient and lesion complete clearance rates after illumination with the Aktilite CL128 were 96% and 99%, respectively. No adverse events to include discomfort/pain were mentioned by patients related to application of the gel prior to PDT treatment. Burning and itching were reported during or after the red light illumination. Moreover, 100% of patients treated using Aktilite CL128 had burning after the second PDT session. Of the patients treated using PhotoDyn 750, 60% reported pain during or after PDT. A limitation of the study was its lack of follow-up for patients beyond study protocols. The authors concluded BF-200 ALA is very effective, well tolerated new formulation for AK treatment with PDT and is superior to registered MAL medication. Efficacies and adverse events vary greatly with the different light sources used.
In 2012, Dirschka et. al. reported on an industry sponsored randomized, multicenter, observer-blinded placebo controlled, interindividual trial comparing BF-200 ALA for the treatment of actinic keratosis with MAL cream and placebo. Six hundred patients, each with four to eight mild to moderate actinic keratoses (AK) lesions on the face and/or the bald scalp were enrolled in 26 study centers. Patients received one PDT, if residual lesions remained at 3 months after treatment, PDT was repeated. PDT with BF-200 ALA was superior to placebo PDT with respect to patient complete clearance rate (78.2% vs 17.1%); P< 0.0001) and lesion complete clearance rate 90.4% vs 37.1%) at 3 months after the last PDT. Moreover, superiority was demonstrated over the MAL cream regarding the primary endpoint patient complete clearance (78.2% vs 64.2%; P< 0.05). Significant differences in the patient and lesion complete clearance rates and severity of treatment-related adverse events were observed for the narrow and broad spectrum light sources. The authors concluded BF-200 ALA is very effective and well tolerated new formulation for AK treatment with PDT and is superior to a registered MAL medication. Efficacies and adverse events vary greatly with the different light sources used.
In 2013 Dirschka et. al. reported on the follow-up phase of patients from 2 phase 3 studies that compared BF-200 ALA (n=329) with placebo (n=117) or MAL (n=247) for the treatment of actinic keratosis. No safety concerns were reported. Recurrence rates were similar for BF-200 ALA and MAL. The percentage of patients who achieve complete clearance with PDT and remained completely clear for at least 12 months after PDT were 47% for BF-200 ALA and 36% for MAL treatment. The authors reported that the follow-up phase data confirmed the efficacy and safety of PDT with BF-200 ALA.
In 2014, 3 RCTs compared different light sources for PDT in the treatment of actinic keratosis. One trial used 5-ALA, the second trial used MAL cream, and the third reported on the use of MAL and 5BF-200 ALA using daylight-mediated PDT. There was no clear evidence of the superiority of the differing light sources over another. Some of the alternative approaches (e.g. daylight PDT) have not been cleared by the FDA.
In 2016, Reinhold et. al. published results from a double-blind RTC comparing BF-200 ALA with placebo for the field-directed treatment of mild-to-moderate actinic keratoses with PDT using the BF-RhodoLED lamp. After a maximum of 2 PDT treatments the results, measured 12 weeks after the last PDT, showed a patient complete clearance rate of 91% using BF-200 ALA vs 22% using placebo (p< 0.001), and a lesion complete clearance rate of 94.3% using BF-200 ALA vs 32.9% using placebo (p< 0.001). There were treatment adverse events in 100% of the BF-200 ALA group and in 69% of the placebo group. The adverse events were application-site events and included site pain, erythema, pruritus, scab, exfoliation, edema, and vesicles. Local skin reactions were of a mild-to-moderate intensity. Application-site pain was the most common individual adverse event in both groups (96.4% for BF-200 ALA vs 50.0% for placebo) and was rated as severe by 49% of the BF-200 ALA group and 3% of the patients treated with placebo. One of 32 patients in the placebo group and no patients in the BF-200 ALA group displayed a new lesion after PDT. The authors concluded that field directed therapy with BF-200 ALA and BF-RhodoLED lamp is highly effective and well tolerated for multiple mild-to-moderate AK lesions, providing greatly improved skin quality.
In 2017, Yazdanyar et. al. published results from a clinical trial on pain during topical PDT, which compared MAL (Metvix) with 5-ALA (Ameluz). Patients with mild-to-moderate actinic keratoses on forehead and scalp were treated with MAL-PDT and ALA-PDT on 2 similar areas of forehead and scalp. Fourteen patients completed the MAL-PDT and ALA-PDT treatments. The pattern of pain intensity was similar for both groups. Both treatments were painful, which gradually intensified during the first minute of treatment, reaching a maximum within the first 5 minutes. The pain eased immediately after the PDT treatment. The authors reported no significant difference in pain intensity between MAL-PDT and ALA- PDT, during the treatment (p=1.0) and 30 minutes after the treatment (p=0.19). Pain was the only outcome reported in this trial. The authors concluded no significant difference between the pain response during PDT using MAL-PDT and ALA-PDT.
A number of published RCTs have compared photodynamic therapy (PDT) with other therapies, and a systematic review of these studies has been published. In 2014, Patel et. al. reviewed RCTs with at least 10 patients that addressed the efficacy of topical PDT compared with an alternative (i.e. non-PDT) treatment of actinic keratosis. Thirteen studies met the reviewers’ inclusion criteria. The meta-analysis consisted of 641 participants, with a total of 2174 AKs treated with cryotherapy and 2170 AKs treated with PDT. Compared with cryotherapy, the pooled relative risk for the meta-analysis for completed response (lesion clearance) was 1.14 (95% Ci, 1.11-1.18) at 3 months after treatment. Visual inspection of a funnel plot revealed no publication bias, which was confirmed by the Begg test (P=.80). The authors concluded photodynamic therapy has a 14% better chance of complete lesion clearance at 3 months after treatment then cryotherapy for thin AKs on the face and scalp.
In 2010, Szeimies et. al. reported 12-month follow-up data from a study comparing PDT using a self-adhesive patch with cryotherapy. A total of 148 patients were randomized to a 5-ALA patch group, 49 to a placebo group, and 149 to a cryotherapy group. The study used a test of non-inferiority of PDT vs cryosurgery. Fourteen patients who dropped out were excluded from the analysis comparing PDT with cryotherapy. The rate of complete clearance of all lesions was 67% (86/129) in the 5-ALA group, 52% (66/126) in the cryosurgery group, and 12% (5/43) in the placebo group. The clearance rate was significantly higher in the 5-ALA patch group than in either comparator group. Results were similar in the analysis of clearance rates on a per lesion basis. The 360 patients with at least 1 lesion cleared at 12 weeks were followed for an additional 9 months; 316 patients completed the final visit 1 year after treatment. Overall clearance rate on a lesion basis was still statistically higher in the 5-ALA patch group than in the placebo (in both studies) and the cryosurgery (in the second study) groups. Moreover, 32% of patients in the 5-ALA group from the first study, and 50% of patients in the 5-ALA group from the second study, were still completely free from lesions by the end of the trial. The corresponding rate in the cryosurgery group was 37%. In the safety analysis, there were high rates of local reaction to patch application and cryotherapy at the time of treatment; however, no serious adverse events due to study intervention were documented. The authors concluded 5-ALA patch PDT proved to be superior to cryosurgery in the non-inferiority study setting.
A 2012, Serra-Guillen et. al. in a randomized pilot study compared PDT using MAL alone, imiquimod alone, and the combination of the 2 treatments. Patients with nonhyperkeratonic actinic keratoses on the face and/or scalp were randomized 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) treatment as with group 1 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 CR in the PDT plus imiquimod group compared with PDT only (p=0.004). A study limitation was that the PDT-only group had shorter follow-up, which could at least partially explain the lower rate of CR.
In 2014, Zane et. al. published results of an RCT on the treatment of multiple actinic keratoses of the face and scalp. The trial compared MAL-PDT with diclofenac 3% plus hyaluronic acid gel (DHA). Two hundred patients were enrolled. At 3 months, the complete remission rate was 85.9% for patients using MAL-PDT and 51.8% for patients using with DHA (p< 0.001). Incomplete responses to MAL-PDT were followed by a second treatment. At 12 months, the complete remission rate was 37% for patients treated with MAL-PDT and 7% for patients treated with DHA. Based on these results, the authors determined MAL-PDT was “superior in comparison with DHA for the treatment of actinic keratosis.” Potential weaknesses in the DHA arm were that patients self-administered the DHA gel and had a longer treatment cycle (90 days) than the MAL-PDT arm.
Evidence from multiple RCTs and systematic reviews has suggested that PDT improves the net health outcome in patients with nonhyperkeratotic actinic keratoses of the face or scalp compared with placebo or other active interventions.
Non-melanoma skin cancers are the most common malignancies in the Caucasian population. Most often found in light skinned individuals, basal cell carcinoma (BCC) is most common of the cutaneous malignancies. Although BCC 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-fuorouracil, topical imiquimod, and cryotherapy. Poor cosmesis resulting from surgical procedures can be a significant problem.
In 2015, Wang et. al. published a systematic review of RCTs on photodynamic therapy (PDT) for treating BCC, both superficial and nodular types. To be selected, studies had to include adults with one or more primary BCCs, randomize participants to PDT, placebo, or another treatment, and report the complete clearance rate, recurrence rate, cosmetic outcomes, and/or adverse events rate. Eight RCTs (total N=1583 patients), published between 2001 and 2013, met inclusion criteria. Three trials included patients with superficial BCC; three included patients with nodular BCC, and one included patients with both types of low-risk BCC. Four trials compared PDT with surgery, two compared PDT with cryotherapy, one compared PDT with pharmacologic treatment, and one was placebo-controlled.
In a meta-analysis of 7 studies, the estimated probability of complete clearance after treatment was similar in the PDT and the 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 compared with placebo. Surgery was associated with a significantly lower rate of recurrence compared with PDT, and there was no 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 than with surgery (RR=1.87; 95% CI, 1.54 to 2.26) or cryotherapy (RR=1.51; 95% CI, 1.30 to 1.76). The authors concluded PDT is a useful method for the treatment of BCC, more efficient than placebo and with similar efficiency to cryosurgery and pharmacologic treatment. Even though it is less effective than surgical excision, PDT has cosmetic advantages over surgery and cryosurgery.
A 2016 meta-analysis by Zou et. al. identified 5 RCTs comparing PDT with surgical excision in patients who had nodular BCC and at least 3 months of follow-up. The rate of CR was significantly lower in the PDT group than in 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); there were no significant differences in CR at 2, 4, or 5 years. The rate of recurrence was significantly higher in the PDT group than in the surgical excision group at all time points. More large scale RCTs are required to verify these findings.
In 2007, Rhodes et. al. published 5-year follow-up to an industry-sponsored multicenter randomized trial comparing MAL-PDT with surgery for nodular BCC. A total of 101 adults with previously untreated nodular BCC were randomized to MAL therapy or surgery. At 3 months, CR rates did not differ between groups; however, at 12 months, the CR rate had fallen from 91% to 83% in the MAL-PDT group, and from 98% to 96% in the surgery group. 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 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 in 54% of the surgery patients.
An industry-sponsored multicenter RCT was published in 2008 by Szeimies et. al. This trial compared MAL-PDT with surgery for small (8-20 mm) superficial BCC in 196 patients. At 3 months post-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 lesion recurrence was reported in the surgery group, while the recurrence rate was 9% in the MAL-PDT group. Approximately 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 and 60% after surgery.
A 2016 non-inferiority RCT by Roozeboom et. al. compared MAL-PDT with imiquimod cream and with fluorouracil cream in patients with superficial BCC. 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 noninferiority analysis suggested that imiquimod was superior to MAL-PDT and imiquimod was non-inferior to MAL-PDT.
Systematic reviews of RCTs have found that PDT may not be as effective as surgery for superficial and nodular BCC. In the small number of trials available, PDT was more effective than placebo. The available evidence from RCTs has suggested that PDT has better cosmetic outcomes than surgery.
The largest study (N=225 patients) was a 3-arm trial published in 2006 by Morton et. al. This multicenter trial was conducted in 11 European countries. A total of 225 patients were randomized to 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% vs 86% vs 83%, respectively) at 3 months and superior to cryotherapy and 5-FU (80% vs 67% vs 69%, respectively) at 12 months. Cosmetic outcomes at 3 months were rated higher for PDT than for standard nonsurgical treatments by both investigators and blinded evaluators, with investigators rating cosmetic outcomes 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.
Bath-Hextall et. al. published a Cochrane review to assess the effects of therapeutic interventions for cutaneous Bowen’s disease in 2013. Reviewers identified 7 RCTs evaluating PDT: 4 compared 2 PDT protocols, 1 compared PDT with cryotherapy, 1 compared PDT with topical 5-FU, and 1 compared PDT with both PDT and 5-FU. Reviewers did not pool study results.
The primary outcome measures were complete clearance of lesions after the first treatment cycle and recurrence rate at 12 months. The secondary outcomes included the number of lesions that cleared after each treatment cycle, the number of treatment cycles needed to achieve clearance, the recurrence rates at >12 months, cosmetic outcome, quality of life assessment, and adverse outcomes as reported by both participant and clinician. They included 9 studies, with a total of 363 participants. One study demonstrated statistically significantly greater clearance of lesions of Bowen's disease with MAL-PDT (methyl aminolevulinate with photodynamic therapy) when compared with placebo-PDT (RR (risk ratio) 1.68, 95% CI (confidence interval) 1.12 to 2.52; n = 148) or cryotherapy (RR 1.17, 95% CI 1.01 to 1.37; n = 215), but there was no significant difference when MAL-PDT was compared to 5-FU (5-fluorouracil). One study demonstrated statistically significantly greater clearance of lesions with ALA-PDT (5-aminolevulinic acid with photodynamic therapy) versus 5-FU (RR 1.83, 95% CI 1.10 to 3.06; n = 66), but no statistically significant difference in recurrence rates at 12 months (RR 0.33, 95% CI 0.07 to 1.53).Cryotherapy showed no statistically significant difference in clearance rates (RR 0.99, 95% CI 0.78 to 1.26) or recurrences at 1 year (RR 1.48, 95% CI 0.53 to 4.17) when compared to 5-FU in 1 study of 127 participants. One study compared imiquimod to placebo and demonstrated statistically significantly greater clearance rates in the imiquimod group (9/15 lesions) compared to placebo (0/16) (Fisher's Exact P value < 0.001). The imiquimod group did not report any recurrences at 12 months, but at 18 months, 2/16 participants in the placebo group had developed early invasive squamous cell carcinoma.
The authors concluded, overall, there has been very little good-quality research on treatments for Bowen's disease. There is limited evidence from single studies to suggest MAL-PDT is an effective treatment. Although cosmetic outcomes appear favorable with PDT, five-year follow-up data are needed. Significantly more lesions cleared with MAL-PDT compared to cryotherapy. No significant difference in clearance was seen when MAL-PDT was compared with 5-FU, but one study found a significant difference in clearance in favor of ALA-PDT when compared to 5-FU. There was no significant difference in clearance when cryotherapy was compared to 5-FU. The lack of quality data for surgery and topical cream therapies has limited the scope of this review to one largely about PDT studies. The age group, number, and size of lesions and site(s) affected may all influence therapeutic choice; however, there was not enough evidence available to provide guidance on this. More studies are required in the immunosuppressed populations as different therapeutic options may be preferable. Specific recommendations cannot be made from the data in this review, so we cannot give firm conclusions about the comparative effectiveness of treatments.
There has been very little good-quality research on treatments for Bowen's disease. Based on what studies there are cosmetic outcomes appeared to be better after PDT. There is a lack of RCTs comparing PDT with surgery or radiotherapy in patients with Bowen’s disease, as a result conclusions cannot be drawn about PDT compared with other treatments.
Acne is a common skin condition that occurs when hair follicles become plugged with oil and dead skin cells. It often causes whiteheads, blackheads or pimples, and usually appears on the face, forehead, chest, upper back and shoulders. Acne is most common among teenagers, though it affects people of all ages, and there is a significant demand for effective acne therapies. Photodynamic therapy has been investigated for a treatment of acne. Photodynamic therapy involves the application of photosensitizing agent such as aminolevulinic acid (ALA) or methyl aminolevulinic acid (MAL) prior to exposure to a blue or red light.
A randomized, single-blind, split-faced trial was published in 2010 by Orringer et. al. The trial included 44 patients with facial acne. A randomly selected side of the face received ALA-PDT and the other side went untreated and severed as a control. Patients received up to 3 treatments at intervals of approximately 2 weeks. Twenty-nine (66%) patients completed the 16-week study. For most outcomes, there were no statistically significant differences between 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 (mean reduction, 5.9) than the untreated side of the face (mean reduction, 2.5; p=0.04). In addition, improvement in mean Leed’s Acne Severity Grading score was significantly greater on the treated side (-1.07) than on the untreated side of the face (-0.52; p=0.001). There were few adverse events, which tended to be mild. A trial limitation was the high dropout rate. The authors concluded the results suggest that, with a specific treatment protocol employed in this study, results with respect to acne improvement can be expected to be rather modest and inconsistent. However, the fact that some patients did improve with the current regimen allows for the possibility that future work examining dose response curves, optimization of light source, definition of ideal photosensitizer application times and conditions, and number of other variables might one day make PDT for acne an important therapeutic tool.
In 2016, Pariser et. al. published a multicenter double-blind placebo-controlled, randomized trial evaluating MAL-PDT for severe facial acne. 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 (i.e., 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 trial. 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 vs 0 in the placebo group) and a skin burning cessation (n=15 [15%] in the PDT group vs 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. The authors concluded, this large controlled randomized clinical study shows potential of PDT using 80 mg/g MAL cream and red light for treatment of severe acne in patients aged 12 years and older, with all skin types. They noted that more follow-up data is needed on the duration of treatment response and longer term effect on scarring.
Several RCTs and a Cochrane review have been published. The Cochrane review, by Barbaric et. al. (2016), addressed a variety of light therapies for acne, including PDT. 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). Reviewers concluded that there is a lack of high-quality evidence on light therapies for treating acne and a low certainty in the usefulness of PDT.
Several RCTs and a Cochrane review have evaluated PDT for treatment of acne. The review did not conduct meta-analyses on most outcomes. For the pooled analysis of studies comparing MAL-PDT and placebo, reviewers did not find a significant difference in investigator assessment of lesion change. The available RCTs have not consistently found significantly better outcomes with PDT than with comparator interventions. Several trials found that PTD was associated with high rates of adverse events leading to the cessation of treatment. Trials tended to have relatively small sample sizes and used a variety of comparison interventions.
No controlled studies using FDA-approved photosensitizing agents for PDT in other dermatologic conditions (e.g. hidradenitis suppurativa, mycoses, port wine stains) were identified. Only case series were identified, including series on PDT for hidradenitis suppurativa and PDT for interdigital mycoses. Most case series were small (e.g., <25 patients). There are a few systematic reviews. For example, a 2015 systematic review by Mostafa and Tarakji evaluated PDT for oral lichen planus (OLP) identified 5 case reports and the authors concluded due to the confined number of relevant published data on PDT, limited sample size and short follow up periods, they could not give definite evidence for the advantage of PDT in treatment of OLP. More clinical studies and verifications with randomized clinical trials, larger numbers of patients and longer follow-up periods are needed to evaluate the effectiveness of PDT in treatment of oral lichen planus (OLP). In 2011, Xiao et. al. published a large retrospective case series. A total of 642 patients with port wine stains were treated with PDT; 507 were included in analyses, and the rest were excluded because they had had previous lesion treatments or were lost to follow-up. After treatment, 26 (5.1%) patients were considered to have complete clearing, 48 (9.5%) had significant (<75% to <100%) clearing, and 77 (15.2%) had moderate (<50% to <75%) clearing. This single uncontrolled study is insufficient to draw conclusions about the effect of PDT on health outcomes in patients with port wine stains.
There is insufficient evidence that PDT improves the net health outcome in patients with these other dermatologic conditions e.g, hidradenitis suppurativa, mycoses, port wine stains.
For individuals who have nonhyperkeratotic actinic keratoses on the face or scalp who receive photodynamic therapy (PDT), the evidence includes RCTs and systematic reviews of RCTs. The evidence 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. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcomes.
For individuals who have low-risk basal cell carcinoma who receive photodynamic therapy (PDT), the evidence includes RCTs and systematic reviews of RCTs. Systematic reviews of RCTs have found that PDT may not be as effective as surgery for superficial and nodular basal cell carcinoma. In the small number of trials available, PDT was more effective than placebo. The available evidence from RCTs has suggested that PDT has better cosmetic outcomes than surgery. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcomes.
For individuals who have squamous cell carcinoma in situ who receive photodynamic therapy (PDT), the evidence includes RCTs and systematic review. RCTs have found that PDT has similar or greater efficacy compared with cryotherapy and 5-fluorouracil. Additionally, adverse events and cosmetic outcomes appear to be better after PDT. Few RCTs have compared PDT with surgery or radiotherapy; as a result, conclusions cannot be drawn about PDT compared with these other standard treatments. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
For individuals who have acne who receive photodynamic therapy (PDT), the evidence includes RCTs and a systematic review. The available RCTs have not consistently found significantly better outcomes with PDT compared with other interventions, and a meta-analysis did not find significantly better results with PDT versus placebo. Several trials have found that PDT is associated with high rates of adverse events leading to the cessation of treatment. Trials have tended to have relatively small sample sizes and used a variety of comparison interventions. The evidence is insufficient to determine the effects of the technology on health outcomes.
For individuals who have noncancerous dermatologic skin conditions (e.g. hidradenitis suppurativa, mycoses, port wine stains) who receive photodynamic therapy (PDT), the evidence includes case series and systematic reviews of uncontrolled series. Further randomized controlled trials (RCTs) are needed to determine the safety and efficacy of PDT for these conditions. The evidence is insufficient to determine the effects of the technology on health outcomes.
PDT involves the application of a photosensitizing agent on the skin followed by irradiation with a light source. Photosensitizing agents often used include methyl aminolevulinate (MAL) and 5-aminolevulinic acid (ALA). These two agents have similar efficacy outcomes and pain scores when used to treat patients with nodular BCC. Multiple randomized trials and a meta-analysis including 4 of these trials have shown that rates of excellent or good cosmetic outcomes were higher with PDT versus surgery, even though surgery was superior to PDT in terms of efficacy (complete clearance, 1 year and 5 year recurrence rates).
Reviews of clinical trials reported cure rates from 70% to 90% by PDT for patients with BCC. Most of the studies of PDT for BCC have focused on the superficial and nodular histologic subtypes, and several have found higher cure rates for superficial versus nodular subtypes. Ulceration and thickness are associated with lower response to therapy, and within the nodular subtype, cure rates are better with thinner lesions. Clinical studies have demonstrated PDT activity against “difficult-to-treat” lesion within 24 month complete response rate of 78%. Currently PDT is being utilized at some NCCN Member Institutions for premalignant or superficial low risk lesions on any location on the body although response rates may be higher on the face and scalp.
Although MAL is an approved photosensitizer for PDT, it is no longer produced in the United States.
Given the limited penetration beyond epidermis and lower cure rates than with surgical techniques, superficial therapies should be reserved for those patients with SCC in situ. Recommended superficial therapies include topical fluorouracil (5-FU), topical imiquimod, photodynamic therapy (PDT), and cryotherapy.
PDT involves the application of a photosensitizing agent on the skin followed by irradiation with a light source. Photosensitizing agents often used include methyl aminolevulinate (MAL) and 5-aminolevulinic acid (ALA). For SCC in situ rates of initial complete clearance following PDT with ALA or MAL range between 52% and 98% according to prospective studies (n=23-96 lesions). Most of these studies reported recurrences, such that durable complete response rates range from 48% to 89%. Small randomized trials have shown that differences in PDT techniques can cause significant differences in clearance rate for SCC in situ, which likely contributes to the broad range of rates reported in the literature. One small randomized trial showed that fewer treatments were required for complete clearance with PDT versus cryotherapy, and two randomized trials shows that durable complete response rates were high with PDT. Another small randomized trial in patients with SCC in situ showed that PDT was associated with higher rates of initial complete clearance compared with 5-FU, and two randomized trials showed that durable complete response were hight with PDT.
Results from randomized trials in patients with SCC in situ suggest that 5-FU may be associated with lower risk of adverse events compared with PDT or cryotherapy, but due to inconsistent results across trials it is unclear whether risk of toxicity differs between cryotherapy and PDT. All three treatment modalities are associated with risk of including erythema, burning, crusting, stinging, itching, edema/blistering, and ulceration/erosions. All three also occasionally lead to pigmentary changes or scarring.
Currently PDT is being utilized at some NCCN Member Institutions for SCC in situ lesions. Although MAL is an approved photosensitizer for PDT, it is no longer produced in the United States.
The International Society for Photodynamic Therapy in Dermatology (ISPDT) published consensus based guidelines on the use of photodynamic therapy (PDT) for non-melanoma skin cancer in 2005.
In 2012, the International Society of Photodynamic Therapy in Dermatology (ISPDT) published consensus based guideline for photodynamic therapy (PDT) for skin field cancerization. Field cancerization is a term that describes the presence of genetic abnormalities in a tissue chronically exposed to a carcinogen. With respect to the skin, this term is used to define the presence of multiple non-melanoma skin cancer, its precursors, actinic keratoses and dysplastic keratinocytes in sun exposed areas. The multiplicity of the lesions and the extent of the area influence the treatment decision. ISPDT recommendations includes the following: “PDT is a suitable therapeutic option for patients with multiple AKs and a diagnosis of field cancerization. It may be one of the best options due to the combination of high and sustained response rate, limited downtime for patients and an excellent aesthetic outcome.”
In 2017, American Academy of Dermatology issued a guideline on nonmelanoma skin cancer which included the following recommendation: “nonsurgical approaches (topicals, radiation, photodynamic therapy) have lower cure rates and should only be considered for low risk BCC or cSCC if surgery is impractical or contraindicated.”
In 1999 Levulan® Kerastick™ is a topical preparation of ALA used in conjunction with illumination with the BLU-U™ Blue Light Photodynamic Therapy Illuminator, a blue light source. It is approved by the U.S. Food and Drug Administration (FDA) for the treatment of non-hyperkeratotic actinic keratoses of the face and scalp. The product is applied in the physician's office.
Another variant of PDT for skin lesions is Metvixia® and the Aktilite CL 128 lamp, each of which received FDA approval in 2004. Metvixia consists of the topical application of methyl aminolevulinate (MAL) followed by exposure with the Aktilite CL 128 lamp, a red light source. Metvixia is indicated for the treatment of non-hyperkeratotic actinic keratoses of the face and scalp in immunoincompetent 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.
A 5-aminoleveulinic 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.
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 actinic keratoses of mild-to-moderate severity on the face and scalp. The treatment is to be administered by a health care provider.
Photodynamic therapy may be considered medically necessary as a treatment of:
Photodynamic therapy is considered investigational for all other dermatologic applications, including, but not limited to the following:
Based on review of the peer reviewed medical literature, the literature includes RCTs, case series, and systematic reviews. The available evidence have not consistently found significantly better outcomes with PDT compared with other interventions, and systematic review meta-analysis did not find significantly better results with PDT versus placebo. Several trials have found that PDT is associated with high rates of adverse events leading to the cessation of treatment. Trials have tended to have relatively small sample sizes. Further randomized controlled trials (RCTs) are needed to determine safety and efficacy of PDT for these conditions. The evidence is insufficient to show that photodynamic therapy improves net health outcomes for all other conditions except as indicated above and therefore would be considered investigational.
To report provider services, use appropriate CPT* codes, Modifiers, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or diagnosis codes.
Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc. They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.
*CPT® is a registered trademark of the American Medical Association.