Pending Policies - Therapy


Dermatologic Applications of Photodynamic Therapy (PDT)

Number:THE801.027

Effective Date:12-01-2017

Coverage:

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Photodynamic therapy (PDT) may be considered medically necessary as a treatment of:

Non-hyperkeratotic actinic keratoses (AK) of the face and scalp;

Low-risk (e.g. superficial and nodular) 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.

PDT is considered experimental, investigational and/or unproven for other dermatologic applications, including but not limited to:

Acne vulgaris;

High-risk basal cell carcinomas;

Hidradenitis suppurativa;

Mycoses;

Non-hyperkeratotic AK for all other body parts (excluding the face and scalp).

PDT as a technique of skin rejuvenation, hair removal, or other cosmetic indications is considered not medically necessary.

NOTE: PDT Treatment typically involves 2 treatments spaced a week apart; more than 1 treatment series may be required.

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, administered orally or intravenously, have been used in nondermatologic applications and are being proposed for use with dermatologic conditions such as actinic keratoses (AK) and nonmelanoma skin cancers. Two common photosensitizing agents are 5-aminolevulinic acid (5-ALA) and its methyl ester, methyl aminolevulinate (MAL). When applied topically, these agents pass readily through abnormal keratin overlying the lesion and accumulate preferentially in dysplastic cells. 5-ALA and MAL are metabolized by underlying cells to photosensitizing concentrations of porphyrins. Subsequent exposure to photoactivation (maximum absorption at 404 to 420 nm and 635 nm, respectively) generates reactive oxygen species that are cytotoxic, ultimately destroying the lesion. PDT typically involves 2 office visits: one to apply the topical aminolevulinic acid and a second visit to expose the patient to blue light. PDT can cause erythema, burning, and pain. Healing occurs within 10 to 14 days, with generally acceptable cosmetic results. PDT with topical ALA has been investigated primarily as a treatment of actinic keratoses. It has also been investigated as a treatment of other superficial dermatologic lesions, such as Bowen’s disease, acne vulgaris, mycoses, hidradenitis suppurativa, and superficial and nodular basal cell carcinoma (BCC). Potential cosmetic indications include skin rejuvenation and hair removal.

AK are rough, scaly, or warty premalignant growths on 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 keratosis may progress to squamous cell carcinoma (SCC). Available treatments for AK can be divided into surgical and nonsurgical methods. Surgical treatments used to treat 1 or a small number of dispersed individual lesions include excision, curettage (either alone or combined with electrodessication), and laser surgery. Nonsurgical treatments include cryotherapy, topical chemotherapy (5-fluorouracil [5-FU] or masoprocol creams), chemexfoliation (chemical peels), and dermabrasion. Topical treatments are generally used in patients with multiple lesions and involve extensive areas of skin. Under some circumstances, combinations treatments may be used.

Nonmelanoma skin cancers are the most common malignancies in the white population. BCC is most often found in light-skinned people and is the 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 an 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 nonmelanoma skin lesions and those not in problematic areas, such as the face and digits. Other established treatments include topical 5-FU, imiquimod, and cryotherapy. Poor cosmesis resulting from surgical procedures and skin irritation induced by topical agents can be significant problems. Typically, surgery and radiation are the preferred treatments for low-risk basal cell cancer and Bowen’s disease. If PDT is selected for these indications because of contraindications to surgery or radiation, patients and physicians need to be aware that it may have a lower cure rate compared with surgery or radiation.

Regulatory Status

In 1999, Levulan® Kerastick™, a topical preparation of aminolevulinic acid (ALA), in conjunction with illumination with the BLU-U™ Blue Light Photodynamic Therapy Illuminator, was approval by the United States (U.S.) Food and Drug Administration (FDA) for the following indication: “The Levulan Kerastick for topical solution plus blue light illumination using the BLU-U Blue Light Photodynamic Therapy Illuminator is indicated for the treatment of nonhyperkeratotic actinic keratoses of the face and scalp.” The product is applied in the physician’s office. FDA product code: MVF.

A 5-ALA patch technology is available outside of the U.S. through an agreement between Intendis (part of Bayer HealthCare) and Photonamic. The 5-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 FDA approval in 2004. Metvixia® (Galderma, Switzerland; Photocure, Norway) consists of the topical application of MAL (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 AK 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.

Rationale:

The medical policy was created in March 2006 and has been updated regularly with searches of the MEDLINE database. Key literature is described next and focuses on studies evaluating United States (U.S.) Food and Drug Administration (FDA) approved photosensitizing agents.

Actinic Keratoses

Efficacy of Photodynamic Therapy (PDT) Compared with Placebo

Several randomized controlled trials (RCTs) have been published. For example, in 2003, Pariser et al. conducted a randomized, placebo-controlled trial of 80 patients with actinic keratoses. (1) The authors reported that the complete response (CR) rate for the methyl aminolevulinate (MAL) group was 89% and 38% in the placebo group.

A 2009 double-blind RCT conducted in Germany by Hauschild et al. evaluated PDT with 5-aminolevulinic acid (5-ALA) using a self-adhesive patch. (2) Eligibility criteria included white patients, age 18 years and older, with skin type I to IV (pale to olive complexion), and actinic keratoses (AK) on the head of mild or moderate grade, as defined by Cockerell (maximum diameter, 1.8 cm; interlesional distance, at least 1 cm). Patients were randomized to 5-ALA patches containing 5-ALA 8 mg or identical placebo patches. Patches were square, measuring 4 cm2, and patients received 3 to 8 of them, depending on the number of study lesions. The primary efficacy outcome was the complete clinical clearance rate 12 weeks after PDT. A total of 99 of 103 randomized patients were included in the primary efficacy analysis. Complete clinical clearance rate on a per patient basis (all lesions cleared) was 62% (41/66) in the 5-ALA patch group and 6% (2/33) in the placebo patch group; there was a statistically significant difference favoring PDT.

Efficacy of PDT Compared With an Alternative Intervention

A number of published RCTs have compared 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. (3) Thirteen studies (total N=641 participants) met the reviewers’ 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 facial or scalp lesions. No study in the review was double-blinded. In 12 of the 13 studies, the 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.

Representative RCTs are described next.

In 2006, Morton et al. published an industry-sponsored, 25-center, randomized, left-right comparison of single PDT and cryotherapy in 119 subjects with AK on the face or scalp. (4) At 12-week follow-up, PDT resulted in a significantly higher rate of cured lesions (86.9%) than cryotherapy (76.2%). Lesions with a non-CR were retreated after 12 weeks; a total of 108 (14.9%) of 725 lesions received a second PDT session; 191 (26.8%) of 714 lesions required a second cryotherapy treatment. At 24 weeks, groups showed equivalent clearance (85.8% vs 82.5%, respectively). Greater skin discomfort was reported 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%, respectively), with more subjects rated as having excellent outcomes at 24 weeks after PDT (77.2% vs 49.7%, respectively). With PDT, 22.5% had cosmetic ratings of fair or good compared with 49.9% for cryotherapy.

In 2010, Szeimies et al. in Germany reported 12-month follow-up data from a study comparing PDT using a self-adhesive patch to cryotherapy. (5) The study had the same eligibility criteria and primary outcome as the Hauschild study (2) (previously described). 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 noninferiority of PDT versus cryosurgery. Fourteen patients who dropped out were excluded from the analysis comparing PDT and 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 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) or the cryosurgery (in the second study) groups. Thirty-two percent 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. 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, but no serious adverse effects due to study intervention were documented.

A 2012 randomized pilot study from Spain compared PDT using MAL alone, imiquimod alone, and the combination of the 2 treatments. (6) Patients with nonhyperkeratonic AK on the face and/or scalp were randomized to 1 of 3 groups: 1 session of PDT with MAL (n=40); self-administered imiquimod 5% cream for 4 weeks (n=33); or 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 AK 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 limitation of the study was that the PDT-only group had shorter follow-up, which could at least partially explain the lower rate of CR.

Efficacy of Different PDT Protocols

Several RCTs have compared different approaches to applying PDT in the treatment of actinic keratoses. (7-10) No clear evidence of the superiority of 1 approach over another emerges from this evidence, and some of the alternative approaches (e.g., daylight PDT) are not FDA-cleared.

Efficacy of PDT for other Body Parts (Excluding the Face and Scalp)

In 2012, Schmieder et al. (11) noted another small study suggesting that ALA-PDT could be a effective treatment for AK of the dorsal hands/forearms. However, the studies designed to provide sufficient statistical power to test this hypothesis were lacking in the published literature. Schmieder and colleagues compared the safety and efficacy of blue light ALA-PDT versus blue light placebo vehicle (VEH) in the treatment of AKs of the upper extremities and evaluated the effect of occlusion after the application was completed. ALA or VEH was applied to both dorsal hands/forearms for the 3-hour incubation period before blue light treatment (10 J/cm2). One extremity of each subject was covered with an occlusive dressing during the incubation period. Treatment was repeated at week 8 if any AK lesions remained. The median AK lesion clearance rate at week 12 was 88.7% for extremities treated with occluded ALA (ALA+OCC), 70.0% for extremities treated with nonoccluded ALA, 16.7% for extremities treated with occluded VEH (VEH+OCC), and 5.6% for extremities treated with nonoccluded VEH (p<.0001). ALA+OCC resulted in a significantly higher clearance rate compared with the nonoccluded extremity at weeks 8 (p=.0006) and 12 (p=.0029). Thirty-four percent (12/35) of extremities treated with ALA+OCC had complete clearance of lesions at week 12 compared with 0% (0/35) of extremities treated with VEH+OCC (p=.0002). The authors concluded that the safety profile in this study is consistent with previously reported side effects ALA-PDT. Blue light ALA-PDT following a 3-hour incubation appears efficacious for AK clearance of the upper extremities. Incubation using an occlusive dressing significantly increases the efficacy of the procedure and increases the incidence and severity of some acute inflammatory side effects of PDT.

Section Summary: AK

Evidence from multiple RCTs has suggested that PDT improves the net health outcome in patients with nonhyperkeratotic AK of the face or scalp compared with placebo or other active interventions. There is insufficient evidence that any PTD protocol is superior to another. Several RCTs that are related to the use of PDT for AK (excluding the face and scalp) were identified. Although small studies provide promising results, additional long term data with larger sample sizes are needed to determine the safety and efficacy for the use of ALA-PDT for AK other skin areas (excluding the face and scalp).

Basel Cell Carcinoma (BCC)

A 2007 Cochrane review evaluated surgical, destructive (including PDT), and chemical interventions for BCC. (12) Reviewers concluded that surgery and radiotherapy appeared to be the most effective treatments, with the best results obtained with surgery. In addition, they stated that cosmetic outcomes appear to be good with PDT, but additional data with long-term follow-up are needed. Cochrane reviewers did not distinguish among BCC subtypes.

In 2015, Wang et al. published a systematic review of RCTs on PDT for treating BCC, both superficial and nodular. (13) To be selected, studies had to include adults with 1 or more primary BCCs, randomize participants to PDT or placebo or another treatment, and report the complete clearance rate, recurrence rate, cosmetic outcomes, and/or adverse events. Eight RCTs (total N=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 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).

A 2016 meta-analysis by Zou et al. identified 5 RCTs comparing PDT and surgical excision in patients with nodular BCC that had at least 3 months of follow-up. (14) 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.

Representative RCTs are described next.

An industry-sponsored multicenter RCT was published in 2008 by Szeimies et al. (15) This trial compared MAL-PDT to surgery for small (8-20 mm) superficial BCC in 196 patients. 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 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.

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. (16, 17) 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 versus 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.

A 2016 noninferiority RCT by Roozeboom et al. compared MAL-PDT to imiquimod cream and to fluorouracil cream in patients with superficial BCC. (18) 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 noninferior to MAL-PDT.

Section Summary: Basal Cell Carcinoma

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.

Squamous Cell Carcinoma (SCC)

SCC In Situ (Bowen’s Disease)

Bath-Hextall et al. published a Cochrane review of interventions for cutaneous Bowen’s disease in 2013. (19) Reviewers identified 7 RCTs evaluating PDT: 4 compared 2 PDT protocols, 1 compared PDT with cryotherapy, 1 compared PDT with topical 5-fluorouracil (5-FU), and 1 compared PDT with both PDT and 5-FU. Reviewers did not pool study results.

The largest study (N=225 patients) was a 3-arm trial published in 2006 by Morton et al. (20) 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’s 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.

Another representative trial comparing PDT with another intervention in patients with Bowen’s disease was published by Salim et al. in 2003. (21) Forty patients were randomized to topical 5-FU or MAL therapy. Twenty-nine (88%) of 33 lesions in the PDT group cleared completely compared with 22 (67%) of 33 lesions in the 5-FU group. In the 5-FU group, severe eczematous reactions developed around 7 lesions, ulceration of 3, and erosions of 2. No such reactions were noted in the PDT group.

Section Summary: SCC In Situ (Bowen’s Disease)

RCTs have found that PDT has similar or greater efficacy than cryotherapy and 5-FU for patients with Bowen’s disease. Additionally, adverse effects and 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 these other treatments.

Nonmetastatic Invasive SCC

In 2013, Lansbury et al. published a systematic review of observational studies evaluating interventions for nonmetastatic cutaneous SCC. (22) Reviewers identified 14 prospective studies evaluating PDT. Sample sizes ranged from 4 to 71 patients, with only 3 studies included more than 25 patients. These studies evaluated various PDT protocols. There was only 1 comparative study, and it compared 2 different PDT regimens. In meta-analysis, a mean of 72% of lesions had a CR to treatment (95% CI, 61.5% to 81.4%; I2=71%). Eight studies addressed recurrence rates in patients who were initial responders. In meta-analysis, the pooled odds of recurrence was 26.4% (95% CI, 12.3% to 43.7%; I2=72%).

Section Summary: Nonmetastatic Invasive SCC

No RCTs evaluating PDT for treatment of nonmetastatic invasive SCC were found. There are a number of small, uncontrolled studies, and they represent insufficient evidence on which to draw conclusions about the efficacy and safety of PDT for patients with this condition.

Acne

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. (23) 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 noninflamed 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 low certainty in the usefulness of PDT.

In 2016, Pariser et al. published a multicenter double-blind placebo-controlled, randomized trial evaluating MAL-PDT for severe facial acne. (24) 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 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 noninflammatory 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.

A randomized, single-blind, split-faced trial was published in 2010 by Orringer et al. (25) The trial included 44 patients with facial acne. A randomly selected side of the face received ALA-PDT and the other side went untreated. 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 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 effects, which tended to be mild. A limitation of the study was the high dropout rate.

In 2013, Mei et al. in China published an RCT of 41 patients with moderate-to-severe facial acne. (26) The trial evaluated the additive value of ALA PDT in patients treated with IPL. Twenty-one patients were randomized to 4 weeks IPL plus PDT and 20 patients were randomized to IPL plus placebo PDT. Mean reductions in both inflammatory and noninflammatory lesions were significantly greater in the IPL plus PDT group than in the IPL-only group at the 4-, 8-, and 12-week follow-ups. For example, in the IPL plus PDT group, the mean (SD) number of noninflammatory acne lesions decreased from 31.3 (7.1) at baseline to 14.0 (6.2) at 12-week follow-up. In the IPL-only group, the mean (SD) number of noninflammatory lesions decreased from 28.2 (4.1) at baseline to 18.6 (3.1) at 12 weeks (p<0.05). An improvement of 75% to 100% in all lesions was attained by 13 (62%) patients in the IPL plus PDT group and by 3 (15%) patients in the IPL-only group. Both treatments were well tolerated, and no one withdrew from the trial due to treatment adverse events. The trial did not evaluate the efficacy of PDT in the absence of IPL therapy.

In some studies, higher rates of adverse events with PDT have been reported. For example, a 2006 study by Wiegell et al. in Denmark evaluated patients 12 weeks after MAL-PDT (n=21) or a control group (n=15). (27) There was a 68% reduction from baseline in inflammatory lesions in the treatment group and no change in the control group (p=0.023). However, all patients experienced moderate-to-severe pain after treatment and 7 (33%) of 21 in the treatment group did not receive the second treatment due to pain.

Section Summary: Acne

Several RCTs and a Cochrane review have evaluated PDT for treatment of acne. The Cochrane 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 cessation of treatment. Trials tended to have relatively small sample sizes and used a variety of comparison interventions.

Other Dermatologic Conditions

No controlled studies using FDA-approved photosensitizing agents for PDT in other dermatologic conditions were identified. Only case series were identified, including series on PDT for hidradenitis suppurativa (28, 29) and PDT for interdigital mycoses. (30) Most series were small (e.g., <25 patients). There are a few systematic reviews. For example, a 2015 systematic review by Mostafa and Tarakji of studies evaluating PDT for oral lichen planus identified 5 case reports (31) and a 2015 systematic review by Yazdani Abyaneh et al. identified 15 case series (total N=223 patients) on PDT for actinic cheilitis. (32) In 2011, Xiao et al. in China published a large retrospective case series. (33) 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 patients (5.1%) 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.

Section Summary: Other Dermatologic Conditions

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).

Practice Guidelines and Position Statements

Canadian Dermatology Association

In 2015, the Canadian Dermatology Association published the following recommendations on dermatologic use of PDT:

Basal cell carcinoma (BCC): PDT may be used for superficial BCC when nonsurgical treatment is desired, there are multiple carcinomas, and when cosmetic outcome is important. PDT is not appropriate for nodular BCC. (34)

Actinic keratosis: PDT is among the recommended treatment options for actinic keratosis, although the guidance includes the statement that cryosurgery or a surgical procedure are preferred for isolated actinic keratosis and hypertonic lesions. (35)

National Comprehensive Cancer Network (NCCN)

NCCN guidelines on basal cell skin cancers (v.1.2018) state:

“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 [5- fluorouracil] or imiquimod, photodynamic therapy (PDT) and cryotherapy.” In addition, NCCN concluded that, although the cure rate may be lower, for patients with low-risk superficial BCC where surgery or radiation is contraindicated or impractical, first-line treatment with alternative therapies such as PDT, cryotherapy, 5-FU, or imiquimod may be considered. (36)

The NCCN guidelines on squamous cell skin cancer (v1.2018) stated that PDT is currently being utilized at some NCCN 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. (37)

British Association of Dermatologists

In 2008, the British Association of Dermatologists published guidelines stating the following on PDT:

“Multicentre randomized controlled studies now demonstrate high efficacy of topical photodynamic therapy (PDT) for actinic keratoses, Bowen's disease (BD) and superficial basal cell carcinoma (BCC), and efficacy in thin nodular BCC, while confirming the superiority of cosmetic outcome over standard therapies. Long-term follow-up studies are also now available, indicating that PDT has recurrence rates equivalent to other standard therapies in BD and superficial BCC, but with lower sustained efficacy than surgery in nodular BCC. In contrast, current evidence does not support the use of topical PDT for squamous cell carcinoma.... There is an accumulating evidence base for the use of PDT in acne, while detailed study of an optimized protocol is still required.” (38)

International Society for PDT in Dermatology (ISPTD)

The ISPTD published consensus-based guidelines on the use of PDT for nonmelanoma skin cancer in 2005. Based on both efficacy and cosmetic outcome, ISPTD recommended PDT as a first-line therapy for actinic keratosis. ISPTD considered aminolevulinic acid not to have sufficient tissue penetration for nodular BCC. Based on 2 randomized controlled and 3 open-label studies, it was concluded that MAL-PDT could be effective for nodular BCC lesions less than 2 millimeters (mm) in depth, if debulked. The guidelines recommended PDT for superficial BCC as “a viable alternative when surgery would be inappropriate or the patient or physician wishes to maintain normal skin appearance.” The guidelines also concluded that PDT is at least as effective as cryotherapy or 5-fluorouracil for Bowen’s disease but that there is insufficient evidence to support the routine use of topical PDT for SCC. (39)

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 1.

Table 1. Summary of Key Trials

NCT Number

Trial Name

Planned Enrollment

Completion Date

Ongoing

NCT02647151

Efficacy and Safety of Treatment of Actinic Keratoses With Photodynamic Therapy Between MAL Cream and ALA Gel

50

Mar 2016 (ongoing, no study results posted)

NCT02644187

Pain Relief During Photodynamic Therapy for Actinic Keratoses With a New Irradiation Protocol

30

Mar 2016 (completed, no study results posted)

NCT02367547a

Superficial Basal Cell Cancer's Photodynamic Therapy: Comparing Three Photosensitises: HAL and BF-200 ALA Versus MAL

99

Dec 2022 (recruiting)

Table Key: NCT: national clinical trial; a Denotes industry-sponsored or cosponsored trial.

Summary of Evidence

For individuals who have nonhyperkeratotic actinic keratoses (AK) who receive photodynamic therapy (PDT), the evidence includes randomized controlled trials (RCTs). Relevant outcomes are symptoms, change in disease status, quality of life, and treatment-related morbidity. Evidence from multiple RCTs has found that PDT improves the net health outcome in patients with nonhyperkeratotic AK 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 outcome for individuals with AK on the face or scalp.

For individuals who have nonhyperkeratotic AK on other skin areas (excluding the face and scalp) the evidence includes several RCTs. Although some small studies provide promising results, additional long term data with larger sample sizes are needed to determine the safety and efficacy for the use of aminolevulinic acid- photodynamic therapy (ALA-PDT) for AK other skin areas (excluding the face and scalp).

For individuals who have low-risk basal cell carcinoma (BCC) who receive PDT, the evidence includes RCTs and systematic reviews of RCTs. Relevant outcomes are symptoms, change in disease status, quality of life, and treatment-related morbidity. 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 evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have squamous cell carcinoma (SCC) in situ who receive PDT, the evidence includes RCTs. Relevant outcomes are symptoms, change in disease status, quality of life, and treatment-related morbidity. RCTs have found that PDT has similar or greater efficacy compared with cryotherapy and 5- fluorouracil. Additionally, adverse events/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 nonmetastatic invasive SCC who receive PDT, the evidence includes observational studies and a systematic review of observational studies. Relevant outcomes are overall survival, symptoms, change in disease status, quality of life, and treatment-related morbidity. Conclusions cannot be drawn from small, uncontrolled studies. RCTs are needed to determine the safety and efficacy of PDT for this condition. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have acne who receive PDT, the evidence includes RCTs and a systematic review. Relevant outcomes are symptoms, change in disease status, quality of life, and treatment-related morbidity. The available RCTs have not consistently found significantly better outcomes with PDT compared with comparison interventions and a meta-analysis did not find significantly better results with PDT versus placebo. Several trials have found that PTD is associated with high rates of adverse events leading to cessation of treatment. Trials 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 skin conditions (e.g., hidradenitis suppurativa, mycoses, or port wine stain) who receive PDT, the evidence case series and systematic reviews of uncontrolled series. Relevant outcomes are symptoms, change in disease status, quality of life, and treatment-related morbidity. 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.

Contract:

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coding:

CODING:

Disclaimer for coding information on Medical Policies

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

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

96567, 96573, 96574

HCPCS Codes

J7308, J7309, J7345

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does have a national Medicare coverage position. Coverage may be subject to local carrier discretion.

A national coverage position for Medicare may have been changed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

References:

1. Pariser DM, Lowe NJ, Stewart DM, et al. Photodynamic therapy with topical methyl aminolevulinate for actinic keratosis: results of a prospective randomized multicenter trial. J Am Acad Dermatol. Feb 2003; 48(2):227-232. PMID 12582393

2. Hauschild A, Stockfleth E, Popp G, et al. Optimization of photodynamic therapy with a novel self-adhesive 5- aminolaevulinic acid patch: results of two randomized controlled phase III studies. Br J Dermatol. May 2009; 160(5):1066-1074. PMID 19222455

3. Patel G, Armstrong AW, Eisen DB. Efficacy of photodynamic therapy vs other interventions in randomized clinical trials for the treatment of actinic keratoses: a systematic review and meta-analysis. JAMA Dermatol. Dec 2014; 150(12):1281-1288. PMID 25162181

4. Morton C, Campbell S, Gupta G, et al. Intraindividual, right-left comparison of topical methyl aminolaevulinate- photodynamic therapy and cryotherapy in subjects with actinic keratoses: a multicentre, randomized controlled study. Br J Dermatol. Nov 2006; 155(5):1029-1036. PMID 17034536

5. Szeimies RM, Stockfleth E, Popp G, et al. Long-term follow-up of photodynamic therapy with a self-adhesive 5- aminolaevulinic acid patch: 12 months data. Br J Dermatol. Feb 1 2010; 162(2):410-414. PMID 19804593

6. Serra-Guillen C, Nagore E, Hueso L, et al. A randomized pilot comparative study of topical methyl aminolevulinate photodynamic therapy versus imiquimod 5% versus sequential application of both therapies in immunocompetent patients with actinic keratosis: clinical and histologic outcomes. J Am Acad Dermatol. Apr 2012; 66(4):e131-137. PMID 22226430

7. Zane C, Facchinetti E, Rossi MT, et al. A randomized clinical trial of photodynamic therapy with methyl aminolaevulinate vs. diclofenac 3% plus hyaluronic acid gel for the treatment of multiple actinic keratoses of the face and scalp. Br J Dermatol. May 2014; 170(5):1143-1150. PMID 24506666

8. Giehl KA, Kriz M, Grahovac M, et al. A controlled trial of photodynamic therapy of actinic keratosis comparing different red light sources. Eur J Dermatol. May-Jun 2014; 24(3):335-341. PMID 24876164

9. Neittaanmaki-Perttu N, Karppinen TT, Gronroos M, et al. Daylight photodynamic therapy for actinic keratoses: a randomized double-blinded nonsponsored prospective study comparing 5-aminolaevulinic acid nanoemulsion (BF-200) with methyl-5-aminolaevulinate. Br J Dermatol. Nov 2014; 171(5):1172-1180. PMID 25109244

10. Rubel DM, Spelman L, Murrell DF, et al. Daylight photodynamic therapy with methyl aminolevulinate cream as a convenient, similarly effective, nearly painless alternative to conventional photodynamic therapy in actinic keratosis treatment: a randomized controlled trial. Br J Dermatol. Nov 2014; 171(5):1164-1171. PMID 24861492

11. Schmieder GJ, Huang EY, Jarratt M., et al. A multicenter, randomized, vehicle-controlled phase 2 study of blue light photodynamic therapy with aminolevulinic acid HCl 20% topical solution for the treatment of actinic keratoses on the upper extremities: the effect of occlusion during the drug incubation period. J Drugs Dermatol. 2012 Dec; 11(12):1483-9. PMID 23377520

12. Bath-Hextall FJ, Perkins W, Bong J, et al. Interventions for basal cell carcinoma of the skin. Cochrane Database Syst Rev. 2007; (1):CD003412. PMID 17253489

13. Wang H, Xu Y, Shi J, et al. Photodynamic therapy in the treatment of basal cell carcinoma: a systematic review and meta-analysis. Photodermatol Photoimmunol Photomed. Jan 2015; 31(1):44-53. PMID 25377432

14. Zou Y, Zhao Y, Yu J, et al. Photodynamic therapy versus surgical excision to basal cell carcinoma: meta- analysis. J Cosmet Dermatol. Jun 30 2016. PMID 27363535

15. Szeimies RM, Ibbotson S, Murrell DF, et al. A clinical study comparing methyl aminolevulinate photodynamic therapy and surgery in small superficial basal cell carcinoma (8-20 mm), with a 12-month follow-up. J Eur Acad Dermatol Venereol. Nov 2008; 22(11):1302-1311. PMID 18624836

16. Rhodes LE, de Rie M, Enstrom Y, et al. Photodynamic therapy using topical methyl aminolevulinate vs surgery for nodular basal cell carcinoma: results of a multicenter randomized prospective trial. Arch Dermatol. Jan 2004; 140(1):17-23. PMID 14732655

17. Rhodes LE, de Rie MA, Leifsdottir R, et al. Five-year follow-up of a randomized, prospective trial of topical methyl aminolevulinate photodynamic therapy vs surgery for nodular basal cell carcinoma. Arch Dermatol. Sep 2007; 143(9):1131-1136. PMID 17875873

18. Roozeboom MH, Arits AH, Mosterd K, et al. Three-year follow-up results of photodynamic therapy vs. imiquimod vs. fluorouracil for treatment of superficial basal cell carcinoma: a single-blind, noninferiority, randomized controlled trial. J Invest Dermatol. Aug 2016; 136(8):1568-1574. PMID 27113429

19. Bath-Hextall FJ, Matin RN, Wilkinson D, et al. Interventions for cutaneous Bowen's disease. Cochrane Database Syst Rev. 2013; 6:CD007281. PMID 23794286

20. Morton C, Horn M, Leman J, et al. Comparison of topical methyl aminolevulinate photodynamic therapy with cryotherapy or Fluorouracil for treatment of squamous cell carcinoma in situ: Results of a multicenter randomized trial. Arch Dermatol. Jun 2006; 142(6):729-735. PMID 16785375

21. Salim A, Leman JA, McColl JH, et al. Randomized comparison of photodynamic therapy with topical 5- fluorouracil in Bowen's disease. Br J Dermatol. Mar 2003; 148(3):539-543. PMID 12653747

22. Lansbury L, Bath-Hextall F, Perkins W, et al. Interventions for non-metastatic squamous cell carcinoma of the skin: systematic review and pooled analysis of observational studies. BMJ. 2013; 347:f6153. PMID 24191270

23. Barbaric J, Abbott R, Posadzki P, et al. Light therapies for acne. Cochrane Database Syst Rev. Sep 27 2016; 9:CD007917. PMID 27670126

24. Pariser DM, Eichenfield LF, Bukhalo M, et al. Photodynamic therapy with methyl aminolaevulinate 80 mg g(-1) for severe facial acne vulgaris: a randomized vehicle-controlled study. Br J Dermatol. Apr 2016; 174(4):770-777. PMID 26663215

25. Orringer JS, Sachs DL, Bailey E, et al. Photodynamic therapy for acne vulgaris: a randomized, controlled, split- face clinical trial of topical aminolevulinic acid and pulsed dye laser therapy. J Cosmet Dermatol. Mar 2010; 9(1):28-34. PMID 20367670

26. Mei X, Shi W, Piao Y. Effectiveness of photodynamic therapy with topical 5-aminolevulinic acid and intense pulsed light in Chinese acne vulgaris patients. Photodermatol Photoimmunol Photomed. Apr 2013; 29(2):90-96. PMID 23458393

27. Wiegell SR, Wulf HC. Photodynamic therapy of acne vulgaris using methyl aminolaevulinate: a blinded, randomized, controlled trial. Br J Dermatol. May 2006; 154(5):969-976. PMID 16634903

28. Gold M, Bridges TM, Bradshaw VL, et al. ALA-PDT and blue light therapy for hidradenitis suppurativa. J Drugs Dermatol. Jan-Feb 2004; 3(1 Suppl):S32-35. PMID 14964759

29. Schweiger ES, Riddle CC, Aires DJ. Treatment of hidradenitis suppurativa by photodynamic therapy with aminolevulinic acid: preliminary results. J Drugs Dermatol. Apr 2011; 10(4):381-386. PMID 21455548

30. Calzavara-Pinton PG, Venturini M, Capezzera R, et al. Photodynamic therapy of interdigital mycoses of the feet with topical application of 5-aminolevulinic acid. Photodermatol Photoimmunol Photomed. Jun 2004; 20(3):144- 147. PMID 15144392

31. Mostafa D, Tarakji B. Photodynamic therapy in treatment of oral lichen planus. J Clin Med Res. Jun 2015; 7(6):393-399. PMID 25883701

32. Yazdani Abyaneh MA, Falto-Aizpurua L, Griffith RD, et al. Photodynamic therapy for actinic cheilitis: a systematic review. Dermatol Surg. Feb 2015; 41(2):189-198. PMID 25627629

33. Xiao Q, Li Q, Yuan KH, et al. Photodynamic therapy of port-wine stains: long-term efficacy and complication in Chinese patients. J Dermatol. Dec 2011; 38(12):1146-1152. PMID 22032688

34. Zloty D, Guenther LC, Sapijaszko M, et al. Non-melanoma skin cancer in Canada. Chapter 4: Management of basal cell carcinoma. J Cutan Med Surg. May-Jun 2015; 19(3):239-248. PMID 25986316

35. Poulin Y, Lynde CW, Barber K, et al. Non-melanoma skin cancer in Canada. Chapter 3: Management of actinic keratoses. J Cutan Med Surg. May-Jun 2015; 19(3):227-238. PMID 25926621

36. National Comprehensive Cancer Network (NCCN). NCCN Practice Guidelines in Oncology: Basal cell skin cancer. Version 1.2018. Available at <http://www.nccn.org> (accessed September 26, 2017).

37. National Comprehensive Cancer Network (NCCN). NCCN Practice Guidelines in Oncology: Squamous cell skin cancer. Version 1.2018. Available at <http://www.nccn.org> (accessed September 26, 2017).

38. Morton CA, McKenna KE, Rhodes LE, et al. Guidelines for topical photodynamic therapy: update. Br J Dermatol. Dec 2008; 159(6):1245-1266. PMID 18945319

39. Braathen LR, Szeimies RM, Basset-Seguin N, et al. Guidelines on the use of photodynamic therapy for nonmelanoma skin cancer: an international consensus. International Society for Photodynamic Therapy in Dermatology, 2005. J Am Acad Dermatol. Jan 2007; 56(1):125-143. PMID 17190630

40. Centers for Medicare and Medicaid Services. National Coverage Determination (NCD) for Treatment of Actinic Keratosis (250.4). 2011; Available at <https://www.cms.gov> (accessed September 26, 2017).

41. Dermatologic Applications of Photodynamic Therapy. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2016 December) Medicine 2.01.44.

Policy History:

Date Reason
12/1/2017 Document updated with literature review. The following was added to the experimental, investigational and /or unproven coverage statement: Non-hyperkeratotic actinic keratoses (AK) for all other body parts (excluding the face and scalp). Added to Coverage: NOTE: Photodynamic typically involves 2 treatments spaced a week apart; more than 1 treatment series may be required. Title changed from: Photodynamic Therapy (PDT) for the Treatment of Actinic Keratoses (AK) and Other Skin Lesions.
4/15/2017 Reviewed. No changes.
6/15/2016 Document updated with literature review. The following was added to coverage: 1) “low risk” to identify risk level for basal cell carcinoma and 2) “nodular” included as an example of basal skin cancer.
7/1/2014 Reviewed. No changes.
2/1/2013 Document updated with literature review. Coverage unchanged.
10/15/2010 Document updated with literature review. Changed coverage statements: deleted requirement of ten or more lesions to be to be medically necessary for non-hyperkeratotic actinic keratoses, deleted type of light and method of treatment, only PDT is reviewed.
9/1/2008 Revised/updated entire document
9/15/2006 Coverage Revised.
3/1/2006 New medical document

Archived Document(s):

Title:Effective Date:End Date:
Dermatologic Applications of Photodynamic Therapy (PDT)07-01-202104-14-2022
Dermatologic Applications of Photodynamic Therapy (PDT)09-01-202006-30-2021
Dermatologic Applications of Photodynamic Therapy (PDT)06-15-201908-31-2020
Dermatologic Applications of Photodynamic Therapy (PDT)04-15-201806-14-2019
Dermatologic Applications of Photodynamic Therapy (PDT)12-01-201704-14-2018
Photodynamic Therapy (PDT) for the Treatment of Actinic Keratoses (AK) and Other Skin Lesions04-15-201711-30-2017
Photodynamic Therapy (PDT) for the Treatment of Actinic Keratoses (AK) and Other Skin Lesions06-15-201604-14-2017
Photodynamic Therapy (PDT) for the Treatment of Actinic Keratoses (AK) and Other Skin Lesions07-15-201506-14-2016
Photodynamic Therapy (PDT) for the Treatment of Actinic Keratoses (AK) and Other Skin Lesions07-01-201407-14-2015
Photodynamic Therapy (PDT) for the Treatment of Actinic Keratoses (AK) and Other Skin Lesions02-01-201306-30-2014
Photodynamic Therapy (PDT) for the Treatment of Actinic Keratoses (AK) and Other Skin Lesions10-15-201001-31-2013
Photodynamic Therapy (PDT) for the Treatment of Actinic Keratoses (AK) and Other Skin Lesions08-15-201010-14-2010
Photodynamic Therapy (PDT) for the Treatment of Actinic Keratoses (AK) and Other Skin Lesions09-01-200808-14-2010
Photodynamic Therapy (PDT) for the Treatment of Actinic Keratoses (AK) and Other Skin Lesions09-15-200608-31-2008
Photodynamic Therapy (PDT) for the Treatment of Actinic Keratoses (AK) and Other Skin Lesions03-01-200609-14-2006
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