Dermatologic Applications of Photodynamic Therapy - CAM 20144

Description:
Photodynamic therapy (PDT) refers to light activation of a photosensitizer to generate highly reactive intermediaries, which ultimately cause tissue injury and necrosis. Photosensitizing agents are being proposed for use with dermatologic conditions such as actinic keratoses (AKs) and nonmelanoma skin cancers.

For individuals who have nonhyperkeratotic AKs on the face or scalp who receive PDT, the evidence includes randomized controlled trials (RCTs). The relevant outcomes are symptoms, change in disease status, quality of life (QOL), and treatment-related morbidity. Evidence from multiple RCTs has found that PDT improves the net health outcome in patients with nonhyperkeratotic AKs 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 who have nonhyperkeratotic AKs on the upper extremities who receive PDT, the evidence includes RCTs. The relevant outcomes are symptoms, change in disease status, QOL, and treatment-related morbidity. In two placebo-controlled RCTs, significantly more patients had a complete clearance of AKs with ALA/PDT with blue light compared to placebo at 12 weeks, and a third found a significantly greater reduction in mean lesion count at four weeks. Two small RCTs compared ALA/PDT using red light to imiquimod or 5-fluorouracil and found similar efficacy between the active treatment groups after six months of follow-up The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have low-risk basal cell carcinoma who receive PDT, the evidence includes RCTs and systematic reviews of RCTs. The relevant outcomes are symptoms, change in disease status, QOL, and treatment-related morbidity. 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 a 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 in situ who receive PDT, the evidence includes RCTs. The relevant outcomes are symptoms, change in disease status, QOL, and treatment-related morbidity. 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 nonmetastatic invasive squamous cell carcinoma who receive PDT, the evidence includes observational studies and a systematic review of observational studies. The relevant outcomes are overall survival, symptoms, change in disease status, QOL, 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. The relevant outcomes are symptoms, change in disease status, QOL, and treatment-related morbidity. 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 vs placebo. Several trials have found that PDT is 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. 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 stain) who receive PDT, the evidence includes case series, systematic reviews of uncontrolled series, and an RCT for port-wine stain. The relevant outcomes are symptoms, change in disease status, QOL, 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.

Background 
Photodynamic Therapy
PDT refers to light activation of a photosensitizer to generate highly reactive intermediaries, which ultimately cause tissue injury and necrosis. Two common photosensitizing agents are 5- aminolevulinic acid (5-ALA) and its methyl ester, methyl aminolevulinate. When applied topically, these agents pass readily through abnormal keratin overlying the lesion and accumulate preferentially in dysplastic cells. The agents 5-ALA and methyl aminolevulinate are metabolized by underlying cells to photosensitizing concentrations of porphyrins. Subsequent exposure to photoactivation (maximum absorption at 404 to 420 nm and 635 nm) generates reactive oxygen species that are cytotoxic, ultimately destroying the lesion. PDT can cause erythema, burning, and pain. Healing occurs within 10 to 14 days, with generally acceptable cosmetic results. PDT with topical ALA has been investigated primarily as a treatment of actinic keratoses.

Regulatory Status 
In 1999, Levulan® Kerastick™, a topical preparation of ALA, in conjunction with illumination with the BLU-U™ Blue Light Photodynamic Therapy Illuminator, was approved by the U.S. Food and Drug Administration (FDA) for the treatment of nonhyperkeratotic AKs of the face and scalp. In 2018, the indication was expanded to include nonhyperkeratotic AKs of the upper extremities. The product is applied in the physician’s office. FDA product code: MVF.

In 2016, the FDA approved Ameluz® (aminolevulinic acid hydrochloride) gel, 10% (BF-200 ALA; Biofrontera AG) in combination with PDT using BF-RhodoLED lamp, to be used for the lesion-directed and field-directed treatment of AKs of mild-to-moderate severity on the face and scalp. The treatment is to be administered by a health care provider.

5-ALA patch technology is available outside of the US through an agreement between Intendis (now 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 the FDA approval in 2004. Metvixia® (Galderma; Photocure) consists of the topical application of methyl aminolevulinate (in contrast to ALA used in the Kerastick™ procedure), followed by exposure with the Aktilite CL128 lamp, a red light source (in contrast to the blue light source in the Kerastick™ procedure). Broadband light sources (containing the appropriate wavelengths), intense pulsed light (FDA product code: ONF), pulsed dye lasers and potassium-titanyl-phosphate lasers have also been used. Metvixia® is indicated for the treatment of nonhyperkeratotic AKs of the face and scalp in immunocompetent patients when used with lesion preparation (débridement using a sharp dermal curette) in the physician's office when other therapies are unacceptable or considered medically less appropriate. FDA product codes: GEX and LNK.

Related Policies
20107 Psoralens with Ultraviolet A (PUVA) in Psoriasis
20147 Light Therapy for Psoriasis
80106 Oncologic Applications of Photodynamic Therapy, Including Barrett’s Esophagus
90308 Photodynamic Therapy for Choroidal Neovascularization

Policy
Photodynamic therapy may be considered MEDICALLY NECESSARY as a treatment of:

  • Actinic keratoses of the face and scalp (see policy guidelines).
  • Actinic keratoses of the upper extremities (see policy guidelines).
  • Low-risk (e.g., superficial and nodular) basal cell skin cancer only when surgery and radiation are contraindicated.
  • Cutaneous squamous cell carcinoma in situ (Bowen disease) only when surgery and radiation are contraindicated.

Photodynamic therapy is considered investigational for other dermatologic applications, including, but not limited to, acne vulgaris, high-risk basal cell carcinomas, hidradenitis and mycoses.

Photodynamic therapy as a technique of skin rejuvenation, hair removal or other cosmetic indications is considered NOT MEDICALLY NECESSARY.

Policy Guidelines
Surgery and radiation are the preferred treatments for low-risk basal cell cancer and Bowen disease (see Rationale section). If photodynamic therapy 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 than surgery or radiation.

Photodynamic therapy typically involves two office visits: one to apply the topical aminolevulinic acid and a second visit to expose the patient to blue light. The second physician office visit, performed solely to administer blue light, should not warrant a separate Evaluation and Management CPT code. Photodynamic protocols typically involve two treatments spaced a week apart; more than one treatment series may be required.

Based on characteristics of patients enrolled in randomized controlled trials, four or more lesions per site (face, scalp or upper extremities) is an appropriate threshold for use of photodynamic therapy for patients with nonhyperkeratotic actinic keratosis.

Coding
See the Codes table for details.

Benefit Application
BlueCard/National Account Issues
Plans that have contract language regarding medical necessity that includes criteria regarding cost effectiveness may wish to consider the relative cost effectiveness of photodynamic therapy compared to other equally effective nonsurgical treatments. Photodynamic therapy has not been shown to be more effective for the treatment of actinic keratosis or superficial basal cell carcinoma than other nonsurgical treatments. Compared with cryotherapy, cosmetic outcomes and patient tolerance may be improved. Photodynamic therapy may result in better clearance and cosmetic outcomes in comparison with cryotherapy or topical 5-fluorouracil for the treatment of Bowen’s disease.

Rationale 
The evidence review was created in November 2001 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through October 22, 2021.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life (QOL), and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, two domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice. The key literature is described next and focuses on studies evaluating the U.S. Food and Drug Administration (FDA) approved photosensitizing agents.

Actinic Keratoses
Clinical Context and Therapy Purpose
The purpose of photodynamic therapy (PDT) is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with nonhyperkeratotic actinic keratoses (AKs) on the face or scalp.

The question addressed in this evidence review is: Does the use of PDT improve the net health outcome for nonhyperkeratotic AKs on the face or scalp.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with nonhyperkeratotic AKs on the face, scalp, or upper extremities. AKs are rough, scaly or 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, AKs may progress to squamous cell carcinoma

Interventions
The therapy being considered is photodynamic therapy.

Patients with nonhyperkeratotic AKs on the face, scalp or upper extremities are actively managed by dermatologists and oncologists in an outpatient setting.

Comparators
The following therapies are currently being used to treat nonhyperkeratotic AKs on the face, scalp or upper extremities: pharmacologic therapy, cryotherapy, and laser therapy. Available treatments for AKs can be divided into surgical and nonsurgical methods. Surgical treatments used to treat one or a small number of dispersed individual lesions include excision, curettage (either alone or combined with electrodessication) and laser surgery. Nonsurgical treatments include cryotherapy, topical chemotherapy (5-fluorouracil [5-FU] or masoprocol creams), chemexfoliation (chemical peels) and dermabrasion. Topical treatments are generally used in patients with multiple lesions and involve extensive areas of skin. Under some circumstances, combinations of treatments may be used.

Outcomes
The general outcomes of interest are symptoms, change in disease status, QOL, and treatment-related morbidity. Specific outcomes of interest include complete clearance of actinic keratoses, percentage of AKs cleared, severity of adverse events, patient-reported outcomes, and recurrence of lesions.1 Effectiveness measurements should be measured at 2 – 4 months after treatment to ensure that treatment-associated inflammation has resolved. Recurrence should be assessed no sooner than 6 – 12 months after therapy. Most adverse events are transient and occur during or right after treatment. Treatment location-specific incidence of and progression to squamous cell carcinoma should be reported whenever long-term follow-up is possible but may not be practical in some clinical trials.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

  • To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
  • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
  • To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
  • Studies with duplicative or overlapping populations were excluded.

Actinic Keratoses on the Face or Scalp
Review of Evidence
Systematic Reviews
Patel et al. (2014) published a systematic review of RCTs with at least 10 patients that addressed the efficacy of topical PDT compared with an alternative (i.e., non-PDT) treatment of AKs.2 Thirteen studies (N=641 participants) met the reviewers’ inclusion criteria. Studies compared PDT with cryotherapy (n=6), 5-FU (n=2), imiquimod (n=4) and carbon dioxide laser (n=1). Seven studies used 5-aminolevulinic acid (ALA), and the other six used methyl aminolevulinate (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 four RCTs comparing PDT with cryotherapy were suitable for meta-analysis. The pooled lesion response rate three 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.

Ezzedine et al. (2020) performed a systematic review and network meta-analysis of RCTs evaluating the efficacy and acceptability of interventions for AK of the face, ears, and/or scalp.3 For the outcome of complete clearance (number of patients with 100% cleared lesions), 21 RCTs contributed to the network. The most efficacious interventions as measured by surface under the cumulative ranking curve (SUCRA) included 5-FU 5% (85%), 5-FU 4% (78%), ALA-PDT (70%), imiquimod 5% (67%), 5-FU 0.5% (63%), and ingenol mebutate (60%). Results were similar in an analysis of partial clearance (number of patients with ≥75% cleared lesions) using data from 10 RCTs. Using data from 9 RCTs, rates of withdrawal due to adverse events were most favorable, as measured by SUCRA, for 5-FU combined with salicylic acid (81%), imiquimod 2.5% (71%), 5-FU 4% (71%), 5-FU 5% (66%) and imiquimod 3.75% (55%). However, rates of withdrawal due to adverse events were not significantly different for any of these agents in comparisons with placebo.

Steeb et al. (2021) performed a systematic review and network meta-analysis of RCTs evaluating the long-term efficacy (≥12 months) of interventions for AK of the face and/or scalp.4 Seventeen trials reporting initial and follow-up results of 15 unique RCTs (N=4252) were included. For the outcome of participant complete clearance, the most favorable RRs were with ALA-PDT (8.06; 95% CI, 2.07 to 31.37; moderate certainty in the evidence) followed by imiquimod 5% (RR, 5.98; 95% CI, 2.26 to 15.84; very low certainty in the evidence), photodynamic therapy with MAL-PDT (RR, 5.95; 95% CI, 1.21 to 29.41; low certainty in the evidence), and cryosurgery (RR, 4.67; 95% CI, 1.36 to 16.66; very low certainty in the evidence). For the outcome of lesion-specific clearance (number of cleared lesions compared with baseline), ALA-PDT had the most favorable RR (5.08; 95% CI, 2.49 to 10.33; moderate certainty in the evidence). For the outcome of participant partial clearance, network meta-analysis was not possible because of poor reporting.

Randomized Controlled Trials
Pariser et al. (2003) conducted a randomized, placebo-controlled trial of 80 patients with AKs.5 They reported the complete response (CR) rate for the MAL group was 89% and 38% in the placebo group.

Morton et al. (2006) published an industry-sponsored, 25-center, randomized, left-right comparison of single PDT and cryotherapy in 119 subjects with AKs on the face or scalp.6 At a 12-week follow-up, PDT resulted in a higher rate of cured lesions (86.9%) than cryotherapy (76.2%). Lesions with a non-CR 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 rates (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 percentages 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.

A double-blind RCT conducted in Germany by Hauschild et al. (2009) evaluated PDT with -ALA using a self-adhesive patch.7 Eligibility criteria included white patients, age 18 years and older, with skin type I to IV (pale to olive complexion), and AKs on the head of mild or moderate grade, as defined by Cockerell (maximum diameter, 1.8 cm; intralesional distance, at least 1 cm). Patients were randomized to ALA patches at 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 ALA patch group and 6% (2/33) in the placebo patch group; there was a statistically significant difference favoring PDT.

Szeimies et al. (2010) reported on a phase 3 clinical trial using a stable 5-aminolevulinic acid nanoemulsion formulation (BF-200 ALA) developed for PDT for AKs.8 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 AKs 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 AKs 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 a placebo in respect to patient complete clearance rate (per-protocol group, 64% vs 11%; p<.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 (discomfort, pain) were mentioned by patients related to the 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.

Szeimies et al. (2010) in Germany reported 12-month follow-up data from a study comparing PDT using a self-adhesive patch with cryotherapy.9, The study had the same eligibility criteria and primary outcome as the Hauschild et al. (2009) study (previously described). A total of 148 patients were randomized to a 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 with cryotherapy. The rate of complete clearance of all lesions was 67% (86/129) in the 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 ALApatch 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 ALA patch group than in the placebo (in both studies) and the cryosurgery (in the second study) groups. Moreover, 32% of patients in the ALA group from the first study and 50% of patients in the 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.

A randomized pilot study by Serra-Guillen et al. (2012) Spain compared PDT using MAL alone, imiquimod alone, and the combination of the 2 treatments.10, Patients with nonhyperkeratonic AKs 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 AKs 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 higher rate of CR in the PDT plus imiquimod group compared with PDT only (p=.004). A study limitation was that the PDT-only group had a shorter follow-up, which could at least partially explain the lower rate of CR.

Dirschka et al. (2012) reported on an industry-sponsored randomized, multicenter, observer-blind, placebo-controlled, interindividual trial comparing BF-200 ALA for the treatment of AKs with MAL cream and placebo.11, Six hundred patients with 4 to 8 mild-to-moderate AKs lesions on the face and/or bald scalp were enrolled in 26 study centers. Five hundred forty-nine patients completed the study. Early dropouts were reported, including 15 patients for unexplained reasons, 4 patients with adverse events associated with treatment, and 2 patients with protocol violations. The trial results showed PDT with BF-200 ALA was superior to placebo PDT with respect to patient complete clearance rate (78.2% vs 17.1%; p<.001) and lesion complete clearance rate (90.4% vs 37.1%) at 3 months after the last PDT, respectively. Superiority was demonstrated over the MAL cream for the primary endpoint of patient complete clearance (78.2% vs 64.2%; p<.05). Significant differences in the patient and lesion complete clearance rates and severities of treatment-related adverse events were observed for the narrow- and broad-spectrum light sources. Patient clearance rates and lesion clearance rates were higher compared with MAL. Table 1 provides the data on the light source affecting the clearance rates.

Table 1. Summary of Key RCT Results for Light Source Effects on Clearance Rates

One BF-200 ALA treatment w/ PDT
Study Patients/Lesions Patient Total Clearance Rate Lesion Total Clearance Rate
    Narrow-Light Spectrum, % Broad-Light Spectrum, % Narrow-Light Spectrum, % Broad-Light Spectrum, %
Dirschka et al. (2012)11,          
248/1504 54.0 46.5 77.1 69.7
One MAL treatment w/ PDT 247/1557 37.0 35.0 73.0 59.1
Two BF-200 ALA treatments w/ PDT 123/NR 84.8 71.5 93.6 86.3
Two MAL treatments 150/NR 67.5 61.3 89.3 76.3

ALA: 5-aminolevulinic acid; BF-200 ALA: nanoemulsion-based 5-ALA formulation; MAL: methyl aminolaevulinate; NR: not reported; PDT: photodynamic therapy; RCT: randomized controlled trials.

Dirschka et al. (2013) 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 AKs.12, No safety concerns were reported. Recurrence rates were similar for BF-200 ALA and MAL. The percentage of patients who achieved 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. No p-values or CIs were reported.

Zane et al. (2014) published the results of an RCT on the treatment of multiple AKs of the face and scalp.13, 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 DHA (p<.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.

Reinhold et al. (2016) published results from a double-blind RTC comparing BF-200 ALA with placebo for the field-directed treatment of mild-to-moderate AKs with PDT using the BF-RhodoLED lamp.14, 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 versus 22% using a placebo (p<.001), and a lesion complete clearance rate of 94.3% using BF-200 ALA versus 32.9% using a placebo (p<.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 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. Trialists indicated that this result may be the preventive effect of field-directed AKs treatment.

Karrer et al. (2021) reported findings from an RCT comparing MAL-PDT with cryosurgery in 58 patients with AK of the face.15, Patients received either 5 full-face treatments with MAL-PDT or a single freeze-thaw cryosurgery cycle, followed by additional intervention in the case of non-cleared or newly developed AK. At 24 months of follow-up, the primary outcome, the cumulative number of new AKs after visit 1, was not significantly different between MAL-PDT and cryosurgery (mean difference, -2.5; 95% CI, -6.2 to 1.2). Overall, complete clearance of AKs was significantly greater with MAL-PDT (mean difference, 43.5%; 95% CI, -12.5 to 39.3); however, no differences were detected in grade I or II lesions.

Cortelazzi et al. (2021) reported results of an RCT evaluating the effect of imiquimod 3.75% versus MAL-PDT in patients with AK of the scalp.16, Nine bald male patients were randomized to receive a single session of treatment on either the right or left side of the scalp, and were assessed at up to 12 months of follow-up. By degree of AK, rates of clearance for imiquimod versus MAL-PDT were 68.8% and 48.0% for degree I, 64.5% and 69.8% for degree II, and 75% and 66.7% for degree III, respectively.

Section Summary: Actinic Keratoses on the Face or Scalp
Evidence from meta-analyses and multiple RCTs has suggested that PDT improves the net health outcome as measured by complete clinical clearance of lesions in patients with nonhyperkeratotic AKs of the face or scalp compared with placebo or other active interventions. Study limitations for the trials comparing MAL with BF-200 ALA included results using different light sources and the use of non-FDA-approved light sources, self-reported pain assessments, and self-administered topical treatment.

Actinic Keratoses on the Upper Extremities
Systematic Reviews
Steeb et al. (2020) published a systematic review of RCTs that evaluated cryosurgery, ingenol mebutate, PDT, colchicine, and 5-FU for the treatment of AK in nonscalp and nonface localizations.4 Thirteen studies (N=1380 participants) met the reviewers’ inclusion criteria. Studies evaluating PDT included comparisons to placebo (n=4), cryotherapy (n=3), 5-FU (n=2), colchicine (n=1), and imiquimod (n=1). Direct (pairwise) comparison analyses found that PDT was significantly better than placebo in achieving complete clearance (RR, 3.87; 95% CI, 2.14 to 6.97). Ten of the studies were included in a network analysis. Compared to placebo, cryosurgery showed the highest complete clearance rates (RR, 7.73; 95% CI, 3.21 to 18.61), followed by imiquimod (RR, 7.00; 95% CI, 3.06 to 15.98), and PDT (RR, 3.87; 95% CI, 2.14 to 6.97). Cryosurgery was associated with a higher likelihood of complete clearance than PDT (RR, 2.00; 95% CI, 1.04 to 3.84) with a low certainty of evidence. Authors of the review noted caution in directly comparing topical treatments, which may be more suitable as a field-directed treatment of multiple or clustered lesions, with cryosurgery, which is preferable for single or a limited number of AKs.

Randomized Controlled Trials
Three placebo-controlled RCTs used ALA and PDT with blue light (Tables 2 and 3).17,18,19 The largest and most recent of these, Jiang et al. (2019), was the basis for the FDA approval of Levulan Kerastick for the treatment of AKs on the upper extremities.17 Two of these had a similar design: individual patients were randomized to active treatment or placebo, patients were re-treated at 8 weeks if any AKs remained, and outcomes were reported at 8 and 12 weeks. In both, significantly more patients had a complete clearance of all lesions after 12 weeks. The most common adverse events were stinging/burning during light treatment and erythema after light treatment. No subjects withdrew from treatment due to adverse events in Jiang et al. (2019), and 2 requested an early withdrawal in Schmieder et al. (2012). Schmieder et al. (2012) additionally randomized patients to occlusion or no occlusion on alternate extremities and found better results with occlusion. Taub et al. (2011) was a small (n=15), 4-week, intra-individual study in which patients were randomized to receive active treatment or placebo on alternate arms.19 At 4 weeks, no patients experienced complete clearance, but the mean lesion count was significantly lower in the treatment group compared to the placebo.

Two other small RCTs compared ALA/PDT using red light to imiquimod20 or 5-FU21 and found similar efficacy between the active treatment groups after 6 months of follow-up (Tables 2 and 3).

Study limitations are summarized in Tables 3 and 4.

Table 2. Characteristics of RCTs of PDT for AKs on the Upper Extremities

Study; Trial Countries Sites Dates Design Participants Interventions
            Active Comparator
Jiang et al. (2019)17
NCT02137785
U.S. 13 2014-2015 Parallel groups 269 adults 18 or older with 4 to 15 Grade 1 or 2 AKs on 1 upper extremity 20% ALA-blue light PDT
N=135
VEH-PDT
N=134
Schmieder et al. (2012)18
NCT01458587
U.S. 3 2012 Parallel groups 70 adults 18 or older with at least 4 Grade 1 or 2 AKs on the dorsal hand/forearm 20% ALA-blue light PDT
N=35
VEH-PDT
patients
N=35
Taub et al. (2011)19 U.S. NR NR Intra-individual, randomized to alternate upper extremities 15 adults (ages 42 to 79 years) with 4 or more AK lesions on the dorsal sides of both hands and forearms 20% ALA-blue light PDT VEH-PDT
Sotiriou et al. (2009)20 Greece 1 NR Intra-individual, randomized to alternate upper extremities 30 adults with Grade 1 or 2 AKs on the dorsal hand/forearm; at least 6 comparable lesions of similar severity on both sides 20% ALA-red light PDT Imiquimod 5% cream
Kurwa et al. (1999)21 England NR NR Intra-individual, randomized to alternate upper extremities 17 adults (ages 53 to 79 years) with a long history of AKs affecting the forearms
and hands
20% ALA-red light PDT 5-FU cream

AKs: actinic keratoses; ALA: aminolevulinic acid; NR: not reported; PDT: photodynamic therapy; RCT: randomized controlled trial; VEH: vehicle (placebo); 5-FU:5-fluorouracil.

Table 3. Results of RCTs of PDT for AKs on the Upper Extremities

Study Complete Clearance Lesion Reduction
Jiang et al. (2019)17    
ALA-PDT 8 weeks: 35/135 (25.9%)
12 weeks:42/135 (31.1%)
 
VEH-PDT 8 weeks: 12/134 (9.0%)
12 weeks: 17/134 (12.7%)
 
P-value 0.0001 at 8 and 12 weeks  
Schmieder et al. (2012)18    
ALA-PDT 8 weeks: 8/35 (22.9%)
12 weeks: 12/35 (34.3%)
 
VEH-PDT 8 weeks: 0/35 (0%)
12 weeks: 1/35 (2.9%)
 
P-value 0.002 at 12 weeks; 8 weeks NR  
Taub et al. (2011)19   Mean (SD) lesion count reduction at 4 weeks
ALA-PDT   58.4% (22.2)
VEH-PDT   24.8% (20.6)
P-value   0.004
Sotiriou et al. (2009)20    
ALA-PDT 4 weeks: 87/124 (70.16%)
6 months: 81/124 (65.32%); 95% CI, 56.9 to 73.7%
 
Imiquimod 4 weeks: 21/115 (18.26%)
6 months: 64/115 (55.65%) ; 95% CI, 46.6 to 64.7%
 
p-value <.05 at 4 weeks
> 0.05 at 6 months
 
Kurwa et al. (1999)21   Mean reduction in lesion area at 6 months:
ALA-PDT   73% (95% CI 61%-84%).
5-FU   70% (95% CI 61% to 80%)
Difference   2% (95% CI, –10% to 14%; P =.721)

AKs: actinic keratoses; ALA: aminolevulinic acid; CI: confidence interval;NR: not reported;PDT: photodynamic therapy; RCT: randomized controlled trial; SD: standard deviation; VEH: vehicle (placebo); 5-FU:5-fluorouracil.

Table 4. Study Relevance Limitations

Study Populationa Interventionb Comparatorc Outcomesd Follow-Upe
Jiang et al. (2019)17
NCT02137785
         
Schmieder et al. (2012)18
NCT01458587
         
Taub et al. (2011)19       1. complete clearance not reported 1. 4 weeks
Sotiriou et al. (2009)20     Patient applied    
Kurwa et al. (1999)21     Patient applied    

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.
c  Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
d  Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
e  Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 5. Study Design and Conduct Limitations

Study Allocationa Blindingb Selective Reportingc Data Completenessd Powere Statisticalf
Jiang et al. (2019)17
NCT02137785
3. allocation concealment method not reported 1. Outcome assessors, but not patients, were blinded        
Schmieder et al. (2012)18
NCT01458587
3. allocation concealment method not reported 1. Outcome assessors, but not patients, were blinded        
Taub et al. (2011)19 3. allocation concealment method not reported 1. Outcome assessors, but not patients, were blinded     1. small sample size (N=15), no power calculation  
Sotiriou et al. (2009)20 3. allocation concealment method not reported 1. Not blinded     1. small sample size (N=30), no power calculation  
Kurwa et al. (1999)21 3. allocation concealment method not reported 1. Not blinded     1. small sample size (N=17), no power calculation  

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
f  Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Section Summary: Actinic Keratoses on the Upper Extremities
A systematic review of interventions for nonface and nonscalp AKs found PDT to be superior to placebo for complete clearance, but found a significant increase in complete clearance with cryotherapy versus PDT. In 2 placebo-controlled RCTs, significantly more patients had a complete clearance of AKs with ALA/PDT with blue light compared to placebo at 12 weeks, and a third found a significantly greater reduction in mean lesion count at 4 weeks. Two small RCTs compared ALA/PDT using red light to imiquimod or 5-FU and found similar efficacy between the active treatment groups after 6 months of follow-up.

Low-Risk Basal Cell Carcinoma
Clinical Context and Therapy Purpose
The purpose of PDT is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with low-risk basal cell carcinoma (BCC).

The question addressed in this evidence review is: Does the use of PDT improve the net health outcome for low-risk BCC?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with low-risk BCC. Nonmelanoma skin cancers are the most common malignancies in the white population. Most often found in light-skinned individuals, BCC 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. Patients with low-risk BCC are actively managed by dermatologists and oncologists in an outpatient setting.

Interventions
The therapy being considered is PDT.

Comparators
The following therapies are currently being used to treat BCC: pharmacologic therapy, cryotherapy, surgery and radiotherapy. 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.

Outcomes
The general outcomes of interest are symptoms, change in disease status, QOL and treatment-related morbidity. Specific outcomes of interest include complete clearance rate, recurrence rate, cosmetic outcomes and adverse events.22 Clearance rates are assessed after the first treatment cycle. Recurrence rates should be evaluated at least 12 months from treatment. Cosmetic outcomes should be evaluated after 12 months. Most adverse events are transient and occur during or right after treatment.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

  • To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
  • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
  • To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
  • Studies with duplicative or overlapping populations were excluded.

Systematic Reviews
Mpourazanis et al. (2020) compared PDT to cryotherapy for BCC in a systematic review of 19 RCTs and prospective observational trials.23 Of these studies, only five RCTs were included in the quantitative analysis. For rates of complete clearance, there was no significant difference found between PDT and cryotherapy (two studies; odds ratio [OR], 0.83; 95% CI, 0.47 to 1.49; I2=0%). Similarly, no difference was found between PDT and cryotherapy for the recurrence rate (three studies; OR, 4.99; 95% CI, 0.40 to 62.40; I2=87.3%). The review did not distinguish among BCC subtypes.

Wang et al. (2017) published a systematic review of RCTs on PDT for treating BCC, both superficial and nodular types.22 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 (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 trial 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 seven 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 the 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 one 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 meta-analysis by Zou et al. (2016) identified five RCTs comparing PDT with surgical excision in patients who had nodular BCC and at least three months of follow-up.24 The rate of CR was significantly lower in the PDT group than in the surgical excision group at one year (RR, 0.89; 95% CI, 0.80 to 0.99) and at three years (RR, 0.73; 95% CI, 0.63 to 0.85); there were no significant differences in CR at two, four or five years. The rate of recurrence was significantly higher in the PDT group than in the surgical excision group at all time points.

A Cochrane review by Bath-Hextall et al. (2007) evaluated surgical, destructive (including PDT), and chemical interventions for BCC.25 Reviewers concluded that surgery and radiotherapy appeared to be the most effective treatments, with the best results obtained using 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.

Randomized Controlled Trials
A noninferiority RCT by Roozeboom et al. (2016) compared MAL-PDT with imiquimod cream and with fluorouracil cream in patients with superficial BCC.26 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 one-year follow-up and 417 (69%) completed the three-year follow-up. Median follow-up was 35 months. The estimated tumor-free survival rates at three 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.

An industry-sponsored multicenter RCT was published by Szeimies et al. (2008).27 This trial compared MAL-PDT with surgery for small (8 – 20 mm) superficial BCC in 196 patients. At three months posttreatment, 92% of lesions treated with MAL-PDT showed a clinical response, compared with 99% of lesions treated with surgery (per-protocol analysis). At a 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.

Rhodes et al. (2007) published a year-year follow-up to an industry-sponsored multicenter randomized trial comparing MAL-PDT with surgery for nodular BCC.28,29 A total of 101 adults with previously untreated nodular BCC were randomized to MAL therapy or surgery. At three 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 a five-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.

Section Summary: Basal Cell Carcinoma
Systematic reviews of RCTs have found that PDT may not be as effective as surgery for low-risk superficial and nodular BCC. In the small number of trials available, PDT was more effective than a placebo. The available evidence from RCTs has suggested that PDT has better cosmetic outcomes than surgery for low-risk BCC.

Squamous Cell Carcinoma
Clinical Context and Therapy Purpose
The purpose of PDT is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with squamous cell carcinoma in situ (Bowen disease).

The question addressed in this evidence review is: Does the use of PDT improve the net health outcome for squamous cell carcinoma in situ (Bowen disease)?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with squamous cell carcinoma in situ. Bowen disease is a squamous cell carcinoma in situ with the potential for significant lateral spread. Metastases are rare, with less than 5% of cases advancing to invasive squamous cell carcinoma. Lesions may appear on the sun-exposed or covered skin.

Patients with squamous cell carcinoma in situ are actively managed by dermatologists and oncologists in an outpatient setting.

Interventions
The therapy being considered is PDT.

Comparators
The following therapies are currently being used to treat n squamous cell carcinoma in situ: pharmacologic therapy, cryotherapy, surgery and radiotherapy.

Outcomes
The general outcomes of interest are symptoms, change in disease status, QOL, and treatment-related morbidity. Specific outcomes of interest include clearance of lesions, recurrence, cosmetic outcomes, and adverse events.30 Clearance rates are assessed after the first treatment cycle. Recurrence rates should be evaluated at least 12 months from treatment. Most adverse events are transient and occur during or right after treatment.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

  • To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
  • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
  • To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
  • Studies with duplicative or overlapping populations were excluded.

Systematic Reviews
Zhong et al. (2020) performed meta-analyses using data from 12 RCTs (n=446) comparing PDT with other treatments in patients with Bowen disease.31 For the outcome of lesion reduction reported between one and 12 months, PDT was associated with a significantly higher lesion reduction rate compared with control groups (OR, 2.86; 95% CI, 1.89 to 4.33). In comparisons with specific control groups, PDT was associated with significant improvements in lesion reduction compared with 5-FU (OR, 3.70; 95% CI, 2.07 to 6.62) and compared with cryotherapy (OR, 2.24; 95% CI, 1.24 to 4.04). No significant differences were observed in recurrence rates between PDT and control groups. Most domains of study quality were assessed as low or unclear risk of bias. The authors reported the potential for publication bias, and concluded PDT to be a safe and effective therapy for Bowen disease.

Bath-Hextall et al. (2013) published a Cochrane review of interventions for cutaneous Bowen disease.30 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. 

Randomized Controlled Trials
The largest study (N=225 patients) was a three-arm trial published by Morton et al. (2006).32 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 three months and superior to cryotherapy and 5-FU (80% vs. 67% vs. 69%, respectively) at 12 months. Cosmetic outcomes at three 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 disease was published by Salim et al. (2003).33 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 seven lesions, ulceration of three, and erosions of two. No such reactions were noted in the PDT group.

Section Summary: Squamous Cell Carcinoma In Situ (Bowen Disease)
A meta-analysis and RCTs have found that PDT has similar or greater efficacy than cryotherapy and 5-FU for patients with Bowen 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 disease; as a result, conclusions cannot be drawn about PDT compared with these other treatments.

Nonmetastatic Invasive Squamous Cell Carcinoma
Clinical Context and Therapy Purpose
The purpose of PDT is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with nonmetastatic invasive squamous cell carcinoma.

The question addressed in this evidence review is: Does the use of PDT improve the net health outcome for nonmetastatic invasive squamous cell carcinoma?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with nonmetastatic invasive squamous cell carcinoma.

Patients with nonmetastatic invasive squamous cell carcinoma are actively managed by dermatologists and oncologists in an outpatient setting.

Interventions
The therapy being considered is PDT.

Comparators
The following therapies are currently being used to treat nonmetastatic invasive squamous cell carcinoma: cryotherapy, surgery and radiotherapy.

Outcomes
The general outcomes of interest are overall survival, symptoms, change in disease status, QOL, surgery, and radiotherapy. Specific outcomes of interest include recurrence, initial response to treatment, cosmetic appearance and death due to disease.34 Recurrence can be assessed during follow-up from one month to 10 years after treatment.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

  • To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
  • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
  • To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
  • Studies with duplicative or overlapping populations were excluded.

Systematic Reviews
Lansbury et al. (2013) published a systematic review of prospective and retrospective studies evaluating interventions for nonmetastatic cutaneous squamous cell carcinoma.34 Reviewers identified 14 prospective studies evaluating PDT. Sample sizes ranged from four to 71 patients, with only three studies including more than 25 patients. The 14 studies evaluated various PDT protocols. Only one was comparative, and it assessed two PDT regimens. In a 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 a meta-analysis, the pooled odds of recurrence were 26.4% (95% CI, 12.3% to 43.7%; I2=72%).

Section Summary: Nonmetastatic Invasive Squamous Cell Carcinoma
No RCTs evaluating PDT for the treatment of nonmetastatic invasive squamous cell carcinoma 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
Clinical Context and Therapy Purpose
The purpose of PDT is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with acne.

The question addressed in this evidence review is: Does the use of PDT improve the net health outcome for acne?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with acne.

Patients with acne are actively managed by dermatologists and primary care providers in an outpatient setting.

Interventions
The therapy being considered is PDT.

Comparators
The following therapies are currently being used to treat PDT: pharmacologic therapy (e.g., benzoyl peroxide,salicyclic acid, topical or systemic retinoids, topical or systemic antibiotics, hormonal agents) and other physical modalities (e.g., laser or light therapy, chemical peels).

Outcomes
The general outcomes of interest are symptoms, change in disease status, QOL, and treatment-related morbidity. Specific outcomes of interest most commonly evaluated in clinical trials include patients' global assessment of improvement, investigators' assessment in change of lesion count, and adverse effects.35 Evaluation of efficacy should ideally take place after at least eight weeks of treatment, though shorter-term data (4 – 8 weeks) may indicate early improvement.

The duration of follow-up would be based on the extent of lesions and four, eight and 12 weeks would be appropriate.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

  • To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
  • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
  • To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
  • Studies with duplicative or overlapping populations were excluded. 

Systematic Reviews
A systematic review by Wu et al. (2021) performed a meta-analysis using data from 13 RCTs (N=422) that compared red light PDT with placebo, pharmacotherapy, or other sources of light in the treatment of acne.36 For the outcome of inflammatory lesions, red light did not differ significantly at any point in time up to 12 weeks compared with other conventional treatment methods (weighted mean difference, 0.701; 95% CI, −0.809 to 2.212). Similar results were reported for the outcome of non-inflammatory lesions (weighted mean difference, -0.527; 95% CI, -3.055 to 2.001). Most domains of study quality were assessed as low or unclear risk of bias. The authors concluded that further study is needed comparing red light PDT with traditional therapies.

A Cochrane review by Barbaric et al. (2016), addressed a variety of light therapies for acne, including PDT.35 For studies on MAL-PDT, only data on the investigator-assessed change in lesion counts were suitable for pooling. A meta-analysis of three studies on MAL-PDT did not find a significant difference from placebo on investigator-assessed change in inflamed lesion counts (mean difference, -2.85; 95% CI, -7.51 to 1.81) or change in noninflamed lesion counts (mean difference -2.01; 95% CI, -7.07 to 3.05). Reviewers concluded there is a lack of high-quality evidence on light therapies for treating acne and a low certainty in the usefulness of PDT.

Randomized Controlled Trials
Tables 6 and 7 summarize the characteristics and results of relevant RCTs.

Table 6. Summary of Key RCT Characteristics 

Study Countries Sites Participants Interventions
        Active Comparator
Wojewoda et al. (2021)37 Sweden 1 36 patients with mild to severe acne, split-faced MAL-PDT (either 2 or 4 treatments) Placebo (either 2 or 4 treatments)
Nicklas et al. (2018)38 Chile 1 46 patients with moderate inflammatory facial acne ALA-PDT Doxycycline plus adapalene gel
Xu et al. (2017)39 China 1 95 patients with moderate-to-severe facial acne Minocycline hydrochloride capsule plus PDT Minocycline hydrochloride capsule without PDT
Pariser et al. (2016)40 U.S. 5 153 patients with severe facial acne MAL-PDT Placebo cream
Orringer et al. (2010)41 U.S. 1 44 patients with facial acne, split-faced ALA-PDT No treatment

ALA: aminolevulinic acid; MAL-PDT: methyl aminolevulinate; PDT: photodynamic therapy; RCT: randomized controlled trial.

Table 7. Summary of Key RCT Results

Study Mean Reduction in Facial Inflammatory Lesion Count Adverse Events (%)
Wojewoda et al. (2021)37    
MAL-PDT Week 20:
2 treatments: -74%
4 treatments: -85%
  • Erythema (20)
  • Hyperpigmentation (7)
  • Ulceration (2)
  • Scarring (2)
Placebo Week 20:
2 treatments: -57%
4 treatments: -83%
  • Erythema (9)
  • Hyperpigmentation (8)
  • Ulceration (1)
  • Scarring (1)
p Week 20:
2 treatments: 0.08
4 treatments: 0.44
 
Nicklas et al. (2018)38    
ALA-PDT -12.0 (median)  
Doxycycline plus adapalene gel    
p .038  
Xu et al. (2017)39    
Minocycline hydrochloride capsule plus PDT -74.4%
  • Pain (16.7)
  • Burning sensation (14.6)
  • Dizziness (6.3)
  • Headache (4.2)
  • Erythema (8.3)
  • Hyperpigmentation (2.1)
Minocycline hydrochloride capsule without PDT -53.3%
  • Dizziness (8.5)
  • Headache (6.4)
p .001  
Pariser et al. (2016)40    
MAL-PDT -15.6
  • Pain (17)
Placebo -7.8  
p .006  
Orringer et al. (2010)41    
MAL-PDT -5.9
  • Mild peeling (4.5)
  • Hyperpigmentation (4.5)
  • A small blister (2.3)
No treatment -2.5  
p .04  

ALA: aminolevulinic acid; MAL-PDT: methyl aminolevulinate; PDT: photodynamic therapy; RCT: randomized controlled trial.

The purpose of limitations tables (see Tables 8 and 9) is to display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence following each table and provides the conclusions on the sufficiency of the evidence supporting the position statement.

Table 8. Study Relevance Limitations

Study Populationa Interventionb Comparatorc Outcomesd Follow-Upe
Wojewoda et al. (2021)37          
Nicklas et al. (2018)38         1. Short follow-up
Xu et al. (2017)39       4. No consensus on quantitative evaluation of acne severity 1. Short follow-up
Pariser et al. (2016)40          
Orringer et al. (2010)41          

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.
c  Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
d  Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
e  Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 9. Study Design and Conduct Limitations

Study Allocationa Blindingb Selective Reportingc Data Completenessd Powere Statisticalf
Wojewoda et al. (2021)37       1. 48% of randomized participants did not complete trial 2. Power not calculated for primary outcome; prespecified sample size not met  
Nicklas et al. (2018)38            
Xu et al. (2017)39         1. Sample size calculations not performed  
Pariser et al. (2016)40       1. 16% of participants did not complete trial    
Orringer et al. (2010)41       1. 34% of participants did not complete trial 1. Sample size calculations not performed  

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
c  Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
d  Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
e  Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
f  Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4.Comparative treatment effects not calculated.

Wojewoda et al. (2021) performed a double-blind RCT comparing MAL-PDT with placebo in patients with facial acne.37 The trial randomized 36 patients to MAL-PDT or placebo, each given in either two or four treatments. After 20 weeks, the number of inflammatory lesions decreased by 74% and 85% with two and four treatments of MAL-PDT, respectively. However, there were no significant differences in relative change of inflammatory or non-inflammatory lesions in comparisons with the placebo group. No severe adverse effects were reported in either group. Trial limitations included a high rate of attrition and small sample size.

Nicklas et al. (2018) conducted an RCT involving 46 patients (age range, 18-30 years; 26 male, 20 female) with moderate inflammatory facial acne.38 In the trial, 23 patients received two sessions of PDT plus topical ALA, while the other 23 patients received treatments of doxycycline plus adapalene gel. Two blinded dermatologists evaluated all patients at baseline and at six and 12 weeks after the start of treatment to count the inflammatory and noninflammatory facial lesions. The PDT group had a significantly higher median percent reduction in noninflammatory lesion count (p=.013) and total lesions (p=.038) at six weeks. Similar results were found at 12 weeks (p=.020 for noninflammatory lesions; p=.026 for total lesions). No severe side effects were observed for either therapy. Trial limitations included a small sample size and a short follow-up.

Xu et al. (2017) conducted an RCT involving 95 patients (age range, 15-35 years; 41 male, 54 female) to compare the efficacy of minocycline plus PDT with minocycline alone in treating moderate-to-severe acne.39, In the trial, all patients took a daily minocycline hydrochloride capsule for 4 weeks, and 48 patients also received PDT once a week for 4 weeks. Both groups were evaluated before the study and at 2, 4, 6, and 8 weeks after the first treatment. The PDT group reported a greater mean percentage reduction in lesion counts from baseline than the minocycline alone group (-74.4% vs -53.3%; p<.001) as well as a greater reduction in noninflammatory lesions (-61.7% vs -42.4%; p<.05). Adverse events were mild and manageable. Limitations included a short follow-up and the lack of broad consensus on quantitative evaluation of acne severity.

Pariser et al. (2016) published a multicenter double-blind placebo-controlled, randomized trial evaluating MAL-PDT for severe facial acne.40 A total of 153 patients were randomized and included in the intention-to-treat analysis. All patients received four treatments, two weeks apart, and were evaluated up to 12 weeks after the first treatment. In total, 84% of patients completed the trial. Mean change from baseline in facial inflammatory lesion count at 12 weeks was significantly lower in the MAL-PDT group than the placebo group (-15.6 and -7.8; p=.006, respectively). Change in facial noninflammatory lesion count at 12 weeks did not differ significantly between groups (-11.8 vs -10.7; p=.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.

In a randomized, single-blind, split-faced trial, Orringer et al. (2010) evaluated the efficacy of ALA-PDT in 44 patients with facial acne.41 For most outcomes, there were no statistically significant differences between the treated and untreated sides of the face. This included a 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=.04). There were few adverse events, which tended to be mild. A trial limitation was the high dropout rate of 34%.

Other studies have reported higher rates of adverse events with PDT. For example, a study by Wiegell et al. (2006) evaluated patients 12 weeks after MAL-PDT (n=21) or a control group (n=15).42 There was a 68% reduction from baseline in inflammatory lesions in the treatment group and no change in the control group (p=.023). However, all patients experienced moderate-to-severe pain after the treatment, and seven (33%) of 21 in the treatment group did not receive the second treatment due to pain.

Section Summary: Acne
Several RCTs and systematic reviews have evaluated PDT for the treatment of acne. Neither review found significant improvements in lesion count with PDT compared with other therapies, and both reviews concluded there is a lack of high-quality evidence on light therapies for treating acne. The available RCTs have not consistently found significantly better outcomes with PDT than with comparator interventions. Several trials found that PDT 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.

Other Noncancerous Dermatologic Conditions
Clinical Context and Therapy Purpose
The purpose of PDT is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with noncancerous dermatologic skin conditions (e.g., hidradenitis suppurativa, mycoses, port-wine stain).

The question addressed in this evidence review is: Does the use of PDT improve the net health outcome for dermatologic conditions, including noncancerous dermatologic skin conditions (e.g., hidradenitis suppurativa, mycoses, port-wine stain)?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with noncancerous dermatologic skin conditions, including hidradenitis suppurativa, mycoses, and port-wine stain.

Patients with noncancerous dermatologic skin conditions (e.g., hidradenitis suppurativa, mycoses, port-wine stain) are actively managed by dermatologists and primary care providers in an outpatient setting.

Interventions
The therapy being considered is PDT.

Comparators
The following therapies are currently being used to treat noncancerous dermatologic skin conditions: pharmacologic therapy, cryotherapy and laser therapy.

Outcomes
The general outcomes of interest are symptoms, change in disease status, QOL, and treatment-related morbidity.

Duration of follow-up would be based on the type and extent of lesions and would typically occur in weeks to months after treatment.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

  • To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
  • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
  • To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
  • Studies with duplicative or overlapping populations were excluded.

Systematic Reviews
Shen et al. (2020) published a systematic review of clinical trials and case series evaluating PDT, with a focus on the photosensitizers used, for superficial fungal infections.43 Thirty-four studies were identified for inclusion, including 13 clinical trials and 20 cases (N=440 [n=336 for PDT participants only]). None of the clinical trials were blinded. The follow-up times of the studies varied from no follow-up to two years. Quantitative analyses were not performed. The majority of the included studies (n=18) evaluated PDT for onychomycosis. Seven different photosensitizers were evaluated for onychomycosis, ALA (three studies), MAL (six studies), porphyrin (one study), methylene blue (five studies), rose Bengal (one study), curcumin (one study), and aluminum phthalocyanine chloride nanoemulsions (one study). Treatment with methylene blue had complete cure rates ranging from 70% to 80% (two trials); whereas mycological cure rates for ALA and MAL ranged from 17% to 57% (two trials) and 32% (one trial), respectively. The most common adverse events reported in the included studies were pain/burning/stinging sensation (n=147/323 [45.5%]), erythema (n=66/177 [37.3%]), blistering (n=14/150 [9.3%]), edema (n=48/170 [28.2%]) and hyper-/hypopigmentation (n=10/140 [7.1%]).

Randomized Controlled Trials
Wu et al. (2018) conducted a prospective, multicenter RCT involving 100 patients (age range, 16 – 50 years) to measure the efficacy of different dose levels of hemoporfin with PDT in treating a port-wine stain.44 In the trial, 40 patients received hemoporfin 2.5 mg/kg intravenously, 40 received hemoporfin 5 mg/kg intravenously, and 20 received a saline placebo. Ten minutes after infusion, all patients received PDT. After an evaluation at week 8, 75% of the high-dose group reported improvements in skin lesions compared with 40% of the low-dose group and 15% of the placebo group. Adverse events were mild and resolved within a week. Limitations included a short follow-up and a small sample size.

Case Series
No controlled studies using FDA-approved photosensitizing agents for PDT in other dermatologic conditions were identified for conditions other than a port-wine stain and onychomycosis. Only case series were identified, including series on PDT for hidradenitis suppurativa45,46 and PDT for interdigital mycoses.47 Most series were small (e.g., < 25 patients). There are a few systematic reviews. For example, a systematic review by Mostafa and Tarakji (2015) evaluated PDT for oral lichen planus identified five case reports,48 and a systematic review by Yazdani Abyaneh et al. (2015) identified 15 case series (N=223 patients) on PDT for actinic cheilitis.49 Xiao et al. (2011) in China published a large retrospective case series.50 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 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. Similarly, Chun-Hua et al. (2021) reported a retrospective review of 439 children with port-wine stains treated with PDT.51 An effective response (> 20% fading) occurred in 95.2% of patients, and 74.3% experienced almost complete resolution and great improvement (≥60% fading). Zhang et al. (2021) also evaluated a series of 107 children who received PDT for port-wine stains that were resistant to pulsed dye laser.52 Good-to-excellent improvement was achieved in 32.7% of 107 patients who received a single session of treatment and in 50.8% of patients who received two sessions of treatment. These uncontrolled studies are insufficient to draw conclusions about the effect of PDT on health outcomes in patients with port-wine stains.

Section Summary: Other Noncancerous 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).

Summary of Evidence
For individuals who have nonhyperkeratotic AKs on the face or scalp who receive PDT, the evidence includes meta-analyses and RCTs. Relevant outcomes are symptoms, change in disease status, QOL and treatment-related morbidity. Evidence from multiple RCTs has found that PDT improves the net health outcome as measured by complete clinical clearance of lesions in patients with nonhyperkeratotic AKs on the face or scalp compared with placebo or other active interventions. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have nonhyperkeratotic AKs on the upper extremities who receive PDT, the evidence includes a systematic review and RCTs. Relevant outcomes are symptoms, change in disease status, QOL, and treatment-related morbidity. A systematic review of interventions for nonface and nonscalp AKs found PDT to be superior to placebo for complete clearance, but found a significant increase in complete clearance with cryotherapy versus PDT. In two placebo-controlled RCTs, significantly more patients had a complete clearance of AKs with ALA/PDT with blue light compared to placebo at 12 weeks, and a third found a significantly greater reduction in mean lesion count at four weeks. Two small RCTs compared ALA/PDT using red light to imiquimod or 5-fluorouracil and found similar efficacy between the active treatment groups after six months of follow-up The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have low-risk BCC who receive PDT, the evidence includes RCTs and systematic reviews of RCTs. Relevant outcomes are symptoms, change in disease status, QOL, and treatment-related morbidity. Systematic reviews of RCTs have found that PDT may not be as effective as surgery for low-risk superficial and nodular basal cell carcinoma. In the small number of trials available, PDT was more effective than a placebo. The available evidence from RCTs has suggested that PDT has better cosmetic outcomes than surgery for low-risk BCC. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have squamous cell carcinoma in situ who receive PDT, the evidence includes a meta-analysis and RCTs. The relevant outcomes are symptoms, change in disease status, QOL and treatment-related morbidity. 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. Current guidance from the National Comprehensive Cancer Network notes that topical modalities, including PDT, may have lower cure rates than with surgical treatment. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have nonmetastatic invasive squamous cell carcinoma who receive PDT, the evidence includes observational studies and a systematic review of observational studies. The relevant outcomes are overall survival, symptoms, change in disease status, QOL, 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 that the technology results in an improvement in the net health outcome.

For individuals who have acne who receive PDT, the evidence includes RCTs and systematic reviews. Relevant outcomes are symptoms, change in disease status, QOL, and treatment-related morbidity. The available RCTs have not consistently found significantly better outcomes with PDT compared with other interventions, and meta-analyse s 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 tended to have relatively small sample sizes and used a variety of comparison interventions. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have noncancerous dermatologic skin conditions (e.g., hidradenitis suppurativa, mycoses, port-wine stain) who receive PDT, the evidence includes case series, systematic reviews of uncontrolled series, and an RCT for port-wine stain. Relevant outcomes are symptoms, change in disease status, QOL, and treatment-related morbidity. RCTs are needed to determine the safety and efficacy of PDT for these conditions. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. 

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in ‘Supplemental Information’ if they were issued by, or jointly by, a U.S. professional society, an international society with U.S. representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American Academy of Dermatology
The American Academy of Dermatology has guidelines addressing use of photodynamic therapy (PDT) in basal cell carcinoma and acne:

  • Actinic keratosis (2021): PDT is included in the following recommendations for patients with AK:53
    • ALA-red light PDT is conditionally recommended (low quality of evidence)
    • ALA-daylight PDT is conditionally recommended as less painful than but equally effective as ALA-red light PDT (moderate quality of evidence)
    • ALA-blue light PDT is conditionally recommended (moderate quality of evidence)
    • ALA-red light PDT is conditionally recommended over cryosurgery alone (low quality of evidence)
  • Basal cell carcinoma (2018): Use of topical therapies, including PDT, is most appropriate for low-risk basal cell carcinoma when surgery is impractical or declined by the patient.54 Discussions of the relative effectiveness of topical therapies should be discussed with the patient. The guideline further notes that "Cure rates after surgical excision are 10% to 20% higher than those for topical therapies, including PDT, with excision associated with recurrence rates of less than 5%. Surgical excision may also be less painful and better tolerated."
  • Acne (2016): More studies are needed on the use of PDT or other laser/light devices.55 PDT has the most evidence among laser/light devices for treating acne, but "additional studies are needed to determine the optimal photosensitizer, incubation time, and light source."

National Comprehensive Cancer Network
For treatment of precancers (diffuse actinic keratoses, field cancerization), the NCCN (squamous cell skin cancer, v.2.2021 ) made the following recommendations: "Accepted treatment modalities include cryotherapy, topical 5-fluorouracil (5-FU) with or without calcipotriol (calcipotriene), topical imiquimod, topical ingenol mebutate, photodynamic therapy (e.g., aminolevulinic acid, porfimer sodium), and curettage and electrodesiccation. For hyperkeratotic actinic keratoses, pretreatment with topical tazarotene, curettage or topical keratolytics (topical urea, lactic acid and salicylic acid) prior to above therapies may be considered."56

For basal cell skin cancer, the NCCN (v.2.2021 ) made the following recommendations: “In patients with superficial basal cell skin cancer, therapies such as topical imiquimod, topical 5-fluorouracil, photodynamic therapy (e.g., aminolevulinic acid (ALA), porfimer sodium) or cryotherapy may be considered, even though the cure rates may be lower than with surgical treatment modalities.”57

For squamous cell skin cancers, the NCCN (v.2.2021 ) made the following recommendations: “In patients with SCC [squamous cell carcinoma] in situ (Bowen’s disease) alternative, therapies such as topical 5-fluorouracil, topical imiquimod, photodynamic therapy (e.g., ALA, porfimer sodium) or vigorous cryotherapy may be considered, even though the cure rates may be lower than with surgical treatment modalities.”56

U.S. Preventive Services Task Force Recommendations
Not applicable.

Ongoing and Unpublished Clinical Trials
Some currently ongoing and unpublished trials that might influence this review are listed in Table 10.

Table 10. Summary of Key Trials 

NCT No. Trial Name Planned Enrollment Completion Date
Ongoing      
NCT03573401 A Randomized, Double Blind, Vehicle-controlled Multicenter Phase III Study to Evaluate the Safety and Efficacy of BF-200 ALA (Ameluz®) and BF-RhodoLED® in the Treatment of Superficial Basal Cell Carcinoma (sBCC) With Photodynamic Therapy (PDT). 186 Feb 2026
NCT03909646 Surgical Excision Versus Photodynamic Therapy and Topical 5-fluorouracil in Treatment of Bowen's Disease: a Multicenter Randomized Controlled Trial 250 Dec 2025
NCT03642535 Aminolevulinic Acid-photodynamic Therapy for Facial Actinic Keratosis Treatment and Prevention: A Long-term (3 Years) Follow-up of Prospective, Randomized, Multicenter-clinical Trial 300 Jun 2025
NCT04167982 Efficacy and Safety of Painless 5-aminolevulinic Acid Photodynamic Therapy for the Treatment of Moderate and Severe Acne Vulgaris-- A Multi-center, Randomized Controlled Clinical Trial 234 Nov 2022
NCT02367547a Superficial Basal Cell Cancer's Photodynamic Therapy: Comparing Three Photosensitises: Hexylaminolevulinate and Aminolevulinic Acid Nano Emulsion Versus Methylaminolevulinate 117 Dec 2025
NCT03573401a A Randomized, Double-Blind, Vehicle-controlled Multicenter Phase III Study to Evaluate the Safety and Efficacy of BF-200 ALA (Ameluz®) and BF-RhodoLED® in the Treatment of Superficial Basal Cell Carcinoma (sBCC) With Photodynamic Therapy (PDT) 186 Feb 2026
Unpublished      
NCT03025724a Photodynamic Therapy for Treatment of Cutaneous Squamous Cell Carcinoma in Situ 40 Jan 2020 (last update Jan 2017)
NCT03511326a Subject Reported Outcomes on Satisfaction, Safety and Efficacy With Luxerm® in the Field-directed Treatment of Thin or Non-hyperkeratotic and Non-pigmented Actinic Keratosis of the Face or the Scalp 50 Nov 2017 (completed)
NCT01482104 A Randomized Controlled Blinded Multi-centre Study of Photodynamic Therapy With Methyl-aminolevulinate Comparing a Simplified Regime With the Approved Regime in Patients With Clinical Low-risk Superficial and Nodular Basal Cell Carcinoma. 277 Oct 2017 (completed)
NCT02685592 Photodynamic Therapy for Lentigo Maligna Using 5-aminolevulinic Acid Nanoemulsion as a Light Sensitizing Cream (LM PDT) 10 Mar 2018 (completed)

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

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Coding Section

Codes

Number

Description

CPT  96567  Photodynamic therapy by external application of light to destroy premalignant and/or malignant lesions of the skin and adjacent mucosa (e.g., lip) by activation of photosensitive drug(s), each phototherapy exposure session
 

96567 (effective 1/1/2018) 

Photodynamic therapy by external application of light to destroy premalignant lesions of the skin and adjacent mucosawith application and illumination/activation of photosensitive drug(s), per day
  96573 (effective 1/1/2018) Photodynamic therapy by external application of light to destroy premalignant lesions of the skin and adjacent mucosa with application and illumination/activation of photosensitizing drug(s) provided by a physician or other qualified health care professional, per day 
  96574 (effective 1/1/2018)  Debridement of premalignant hyperkeratotic lesion(s) (ie, targeted curettage, abrasion) followed with photodynamic therapy by external application of light to destroy premalignant lesions of the skin and adjacent mucosa with application and illumination/activation of photosensitizing drug(s) provided by a physician or other qualified health care professional, per day 
ICD-9 Procedure     
ICD-9 Diagnosis  702.0  Actinic keratosis (code does not indicate location) 
  173.0-173.9  Other malignant neoplasm of skin code range 
  232.0-232.9  Carcinoma in situ of skin code range (includes Bowen disease) 
 HCPCS J7308 

Aminolevulinic hydrochloric acid for topical administration, 20%, single unit dosage form (354 mg) 

  J7309

Methyl aminolevulinate (MAL) for topical administration, 16.8%, 1 gram 

  J7345 (effective 1/1/2018)

Aminolevulinic acid hcl for topical administration, 10% gel, 10 mg 

ICD-10-CM (effective 10/01/14)  L57.0  Actinic keratosis 
  C44.0-C44.9  Other malignant neoplasm of skin code range 
  D04.0-D04.9  Carcinoma in situ of skin code range 
ICD-10-PCS (effective 10/01/14)    ICD-10-PCS codes are only used for inpatient services. There is no specific ICD-10-PCS code for the initiation of this therapy. 
  6A600ZZ; 6A601ZZ  Extracorporeal therapies, physiological systems, phototherapy skin, codes for single and multiple 
Type of Service  Medicine 
Place of Service  Physician’s office 

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.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

"Current Procedural Terminology© American Medical Association. All Rights Reserved" 

History From 2014 Forward     

01/05/2022 

Annual review, no change to policy intent. Updating rationale and references. 

01/08/2021 

Annual review, no change to policy intent. 

11/19/2020 

Interim review, removing the word nonhyperkeratotic from policy bullets 1 and 2. No other changes made. 

01/07/2020 

Annual review, adding medical necessity criteria for treatment of nonhyperkeratotic actinic keratoses of the upper extremities. Also updating description, regulatory status, guidelines, rationale and references. 

01/15/2019 

Annual review, no change to policy intent. Updating background, rationale and references. 

02/12/2018 

Annual review, no change to policy intent. Updating regulatory status, rationale and references.

11/27/2017 

Updating with 2018 coding. No other changes. 

01/10/2017 

Annual review, no change to policy intent. Updating background, description, rationale and references. 

01/28/2016 

Annual review, no change to policy intent. Updating background, description, guidelines, rationale and references. 

02/05/2015 

Interim review, updating policy verbiage to indicate treatment of low risk basal cell skin cancer may be medically necessary and high risk basal cell skin cancer treatment would be investigational. Also updated description, background, regulatory status, rationale, rererences and guidelines. Added coding.

09/17/2014

Annual review. Updated description/background, rationale, references, regulatory status. Added additional related policy and ICD-9 & 10 coding. No change to policy intent.

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