Actinic Keratoses Treatments

Number: 0567

Policy

Aetna considers destruction of actinic keratoses lesions using either of the following methods medically necessary:

1. Cryosurgery with liquid nitrogen
2. Topical diclofenac, imiquimod, ingenol mebutate gel, or 5-fluorouracil (5-FU) with or without tretinoin cream. 

Aetna considers either of the following methods of removal of actinic keratoses medically necessary when squamous cell carcinoma is suspected, and submission of a specimen for histological analysis is needed:

1. Curettage 
2. Excision.

Aetna considers the following methods of destruction of actinic keratoses medically necessary for members who have failed to adequately respond to topical imiquimod or 5-FU, or to cryosurgery:

• Chemical peel (chemoexfoliation)
• Dermabrasion
• Laser therapy  
• Photodynamic therapy (e.g., Ameluz [aminolevulinic acid hydrochloride gel 10 % in combination with red light photodynamic therapy (PDT) or Levulan Kerastick [aminolevulinic acid hydrochloride solution 20 % and blue light].

Aetna considers the following internventions experimental and investigational for the treatment of actinic keratoses because their safety and effectiveness for this indication has not been established (not an all-inclusive list):

• Cream containing sunscreen, piroxicam and a retinoic/glycolic gel
• Intense pulsed light
• Lapatinib
• Microneedling
• Microwave therapy
• Non-ablative fractional thulium laser
• Thermal photodynamic therapy
• Topical calcipotriol
• Topical piroxicam
• Topical vitamin D and analogs.

Background

Actinic keratoses (AKs), also known as solar keratoses, are common, sun-induced pre-cancerous skin lesions that are confined to the epidermis.  The lesions typically appear as circumscribed, rough, scaly patches on sun exposed skin, ranging from flesh-colored to reddish-brown.  Although most AKs are asymptomatic, some may exhibit signs and symptoms such as thickening, burning, tenderness, or itching.  Actinic keratoses may also progress to squamous cell carcinoma (SCC), a form of skin cancer.

Actinic keratoses (AKs) most commonly occur in sun-exposed areas such as the face, head, neck, forearms, hands and upper back. Actinic cheilitis is a variant of AKs found on the lip.

Actinic keratoses are most prevalent in fair-skinned individuals with a history of significant sun exposure.  The prevalence of AKs increases with advancing age, and AKs are more common in men than women.  Actinic keratoses are more common in immunosuppressed patients and in patients with some genetic disorders (such as xeroderma pigmentosum).

The overall reported prevalence of AKs has been reported to range from 23 to 61.1 %, and the reported annual incidence of AK ranges from 12.6 to 43.4 %.  Due to these high rates of prevalence and incidence, destruction of AKs is the most commonly performed outpatient dermatologic procedure in the United States.

Several studies have demonstrated an association between the presence of AKs and the development of SCCs, and 2 studies suggest a progression rate of 1 to 2 SCCs per 1,000 AKs.  There is consensus that immunosuppressed individuals, people with a prior history of skin cancer, and people with AKs of the lips, nose, ear or eyelid are at increased risk of developing SCC.  Squamous cell carcinoma can and do metastasize, with reported rates of metastasis ranging from 0.5 to 16 %.

Treatment for AKs involves selectively destroying skin lesions (growths) without harming the surrounding skin tissue. Various options exist for managing AKs, and clinicians may consider several factors to determine the most appropriate management strategy, including size, location or growth pattern of the lesion, patient preference, and patient medical history. Common treatments for AK include cryosurgery with liquid nitrogen, topical treatments, and curettage.  Other less common treatments for AK include dermabrasion, excision, chemical peels, laser therapy, and photo-dynamic therapy (PDT).

McIntyre and colleagues (2007) stated that treatment options for AKs include ablative (destructive) therapies such as cryosurgery, curettage with electrosurgery, and PDT.  Topical therapies are used in patients with multiple lesions.  Fluorouracil has been the traditional topical treatment for AKs, although imiquimod 5 % cream and diclofenac sodium 3 % gel are effective alternative therapies.  This is in agreement with the recommendations of Newman and Weinberg (2007).  Furthermore, Iraji et al (2008) noted that the use of diclofenac is associated with a few side effects, which include pruritus, rashes, dry skin, and scaling.  These side effects are usually minimal and tolerable.  A meta-analysis of 3 randomized trials (n = 364) found that treatment with diclofenac gel resulted in complete resolution of AKs in approximately 40 % of patients as compared with 12 % with placebo.  Thus, this topical medication is suggested as the first line treatment for AKs.

Cryosurgery with Liquid Nitrogen

Cryosurgery with liquid nitrogen, the most common treatment for AKs in the United States, is most appropriate when discrete AKs are present.  With this procedure, liquid nitrogen is applied directly to AK lesions as a method of destruction. The skin surface freezes, causing it and the lesion cells to slough off. New skin then forms. The procedure generally does not require the use of a local anesthetic and involves only mild pain and minor side effects, such as temporary post-procedural erythema.

Topical Drug Therapy

With topical drug therapy, medicated creams, gels or lotions are applied to the surface of the skin to remove multiple lesions, above and below the surface of the skin. The patient applies the medication at home as directed. Topical treatments, such as the chemotherapeutic agent 5-fluorouracil (5-FU), are most commonly used for patients with multiple lesions.  The 5-FU cream is applied to the entire region that is affected, and the recommended course of treatment involves several applications per day over a 2 to 4 week time span.  5-fluorouracil selectively targets the damaged skin, causing an inflammatory response with erythema, necrosis, and erosion.  Numerous side effects are associated with 5-FU, including pain or irritation, tenderness, ulceration, burning, and inflammation.  As a result, patient compliance is a significant concern with this treatment.

Experts suggest topical fluorouracil (5‐FU) may be the most efficacious with comparable tolerability compared to imiquimod. The British Academy of Dermatology (BAD, 2007) has assigned a grade A recommendation with level 1 quality of evidence for 5‐FU. A wide range of open trials, dose ranging studies, and manipulations of the vehicle has been reported over the last 35 years, as well as two randomized controlled trials, confirming efficacy. Witheiler et al. used 5% 5‐FU cream on the face as control in a right/left comparison with a single application of Jessner’ solution (14% lactic acid, 14% salicylic acid, 14% resorcinol in ethanol) followed by a 35% TCA peel. There was a mean reduction in Aks on both sides of the face from 18 to 4 (78% reduction with 5‐FU and 79% reduction with TCA. This benefit was sustained for 12 months. Alternative therapies such as imiquimod, have also been proven to be effective. However, there is limited long term data on relapse after treatment with imiquimod.

After 4 weeks of treatment with 5% fluorouracil (5‐FU) and a 2‐month follow‐up, 94% of treated actinic keratoses had resolved. Following 16 weeks of 5% imiquimod application and a 2 month follow‐up, 66% of actinic keratoses had cleared (p<0.01). Complete clearance occurred in 63% of patients with 5% 5‐FU and 24% of patients with 5% imiquimod at 2 months post‐therapy completion (p<0.05). After one year of posttherapy follow‐up, 87% of Aks were still cleared with 5% 5-FU, whereas 72% of actinic keratoses were cleared with 5% imiquimod, indicating a low recurrence rate with both therapies. The adverse event profile did not differ significantly between the two therapies. In this study, 5% 5‐FU cream achieved faster and more complete clearance of actinic keratoses as compared to 5% imiquimod cream. The two modalities had comparable adverse event profiles (Tanghetti, et al., 2007).

Diclofenac is a nonsteroidal anti‐inflammatory drug (NSAID) of the acetic acid chemical class. The mechanism of action of topical diclofenac sodium in the treatment of actinic keratoses (AK) is unknown.

Imiquimod cream (Aldara, Zyclara) is indicated for the treatment of AK. Imiquimod is a Toll‐7 like receptor agonist that activates immune cells. Its specific mechanism of action for treating actinic keratosis (AK), however, is unknown. A consensus panel on the treatment of AK (Berman et al, 2006) stated that imiquimod and 5-FU are the most effective field-directed therapies for AK (for multiple lesions or an entire area at risk).

Imiquimod was effective in the treatment of AK, preventing potential development of SCC. In a meta-analysis, Hadley and colleagues (2006) evaluated benefit and harm associated with treating AK with imiquimod 5 % cream, an immune response modifier.  Five randomized, double-blind trials lasted 12 to 16 weeks with 1,293 patients were studied.  Complete clearance occurred in 50 % of patients treated with imiquimod, compared to 5 % treated with vehicle, and the number needed to treat (NNT) for 1 patient to have his/her keratosis completely cleared after 12 to 16 weeks was 2.2 (95 % confidence interval [CI]: 2.0 to 2.5).  For partial (greater than or equal to 75 %) clearance the NNT was 1.8 (1.7 to 2.0).  The proportion of patients with any adverse event, any local adverse event, or any treatment-related adverse event was substantially higher with imiquimod than with vehicle, and numbers needed to harm for 1 additional adverse event with imiquimod over 12 to 16 weeks ranged from 3.2 to 5.9.  Particular local adverse events with imiquimod included erythema (27 %), scabbing or crusting (21 %), flaking (9 %), erosion (6 %), edema (4 %), and weeping (3 %).

On January 25, 2012, the FDA ingenol mebutate gel (Picato; 0.015 %, 0.05 %) for the topical treatment of AKs. The gel is applied once-daily on the face and scalp for 3 consecutive days, and the 0.05 % gel is used once-daily on the trunk and extremities for 2 consecutive days (Spencer, 2012). Ingenol mebutate (Picato) is a dermatologic agent indicated for the topical treatment of actinic keratosis. The mechanism of action by which Picato (ingenol mebutate) induces cell death in treating actinic keratosis lesions is unknown. Siller et al (2009) noted that the sap of the plant Euphorbia peplus is a traditional remedy for skin conditions, including AKs. The active constituent of the sap is ingenol mebutate (ingenol-3-angelate), formerly known as PEP005.  In a phase II clinical trial, these researchers investigated the safety (and secondarily the efficacy) of 2 applications of ingenol mebutate gel in 58 patients with biopsy-confirmed AKs.  Five pre-selected lesions were treated with ingenol mebutate gel, 0.0025 %, 0.01 % or 0.05 %, or vehicle gel, on days 1 and 2 (Arm A) or days 1 and 8 (Arm B).  There were no significant differences in tolerability or efficacy between Arms A and B.  Treatment was well-tolerated.  The most common local skin responses were dose-related erythema, flaking/scaling/dryness and scabbing/crusting.  Efficacy was greatest with ingenol mebutate gel, 0.05 %, which resulted in complete clinical clearance of 71 % of treated lesions (p < 0.0001 vs vehicle gel).  In addition, 67 % of patients treated with ingenol mebutate gel, 0.05 % had clinical clearance of at least 4 of 5 treated lesions (p = 0.0185 versus vehicle gel).  Ingenol mebutate gel is being developed as a short-course topical therapy for AKs and non-melanoma skin cancer.

In a randomized, double-blinded study, Anderson et al (2009) evaluated the safety and effectiveness of ingenol mebutate gel at 3 dosing regimens for the treatment of AKs. Patients with non-facial AKs applied vehicle gel for 3 days, ingenol mebutate gel, 0.025 % for 3 days, or ingenol mebutate gel, 0.05 % for 2 or 3 days, with an 8-week follow-up period.  All 3 active treatments were significantly more effective than vehicle at clearing AKs lesions, with a dose-response observed.  The partial clearance rate (primary efficacy end point) for patients treated with ingenol mebutate gel ranged from 56.0 % to 75.4 % compared with 21.7 % for vehicle gel (p = 0.0002 to p < 0.0001 versus vehicle).  The complete clearance rate was also significantly higher (p < or = 0.0006) for patients in the ingenol mebutate gel treatment groups (range of 40.0 % to 54.4 %) compared with vehicle (11.7 %), as was the baseline clearance rate (range of 42.0 % to 57.9 % for ingenol mebutate gel compared with 13.3 % for vehicle, p < 0.0001 to 0.0007 versus vehicle).  The median percentage reduction in baseline AKs lesions for patients treated with ingenol mebutate gel ranged from 75 % to 100 % compared with 0 % for vehicle gel (p < 0.0001 versus vehicle).  Active treatment was well-tolerated at all dosages.  The mechanism of action of this agent is the localized induction of necrosis followed by a transient inflammatory response, and this was manifested in most patients as transient local skin responses consisting primarily of erythema, flaking/scaling, and crusting. There was no evidence of treatment-related scarring. The authors concluded that short-course, field-directed therapy with ingenol mebutate gel for AKs on non-facial sites seems to be effective with a favorable safety profile and potential benefits over topical agents that require a more prolonged course of treatment.

Lebwohl et al (2012) examined the safety and effectiveness of a new topical field therapy for AKs, ingenol mebutate gel (0.015 % for face and scalp and 0.05 % for trunk and extremities). In 4 multi-center, randomized, double-blind studies, these investigators randomly assigned patients with AKs on the face or scalp or on the trunk or extremities to receive ingenol mebutate (n = 503) or placebo (n = 502), self-applied to a 25-cm(2) contiguous field once-daily for 3 consecutive days for lesions on the face or scalp or for 2 consecutive days for the trunk or extremities.  Complete clearance (primary outcome) was assessed at 57 days, and local reactions were quantitatively measured.  In a pooled analysis of the 2 trials involving the face and scalp, the rate of complete clearance was higher with ingenol mebutate than with placebo (42.2 % versus 3.7 %, p < 0.001).  Local reactions peaked at day 4, with a mean maximum composite score of 9.1 on the local-skin-response scale (which ranges from 0 to 4 for 6 types of reaction, yielding a composite score of 0 to 24, with higher numbers indicating more severe reactions), rapidly decreased by day 8, and continued to decrease, approaching baseline scores by day 29.  In a pooled analysis of the 2 trials involving the trunk and extremities, the rate of complete clearance was also higher with ingenol mebutate than with placebo (34.1 % versus 4.7 %, p < 0.001).  Local skin reactions peaked between days 3 and 8 and declined rapidly, approaching baseline by day 29, with a mean maximum score of 6.8.  Adverse events were generally mild-to-moderate in intensity and resolved without sequelae.  The authors concluded that ingenol mebutate gel applied topically for 2 to 3 days is effective for field treatment of AKs.

Rosen et al (2012) noted that current topical agents for field therapy of AKs have single mechanisms of action and must be applied for weeks.  Ingenol mebutate gel appears to have a dual mechanism of action:

1. rapid lesion necrosis and
2. specific neutrophil-mediated, antibody-dependent cellular cytotoxicity.

Because of the rapid destruction of AKs lesions after application of ingenol mebutate gel, treatment is necessary for only 2 or 3 days.  The subsequent immune-mediated response targets any residual dysplastic epidermal cells.  This dual mechanism of action should provide efficacy equivalent to that of current topical agents with a substantially shorter treatment period.

Surgical Therapies

Curettage, which involves the use of a curette to scrape away the lesion, is another common method of treatment for AKs. Curettage is a destructive technique which usually treats to a deeper level within the dermis than cryosurgery and is indicated for larger lesions, especially in immunocompromised patients with AKs likely to be more aggressive. In some instances, curettage may be used in combination with electrosurgery to stop bleeding or apply more damage to the affected area. The primary advantage of curettage is the ability to submit the specimen for histological analysis, particularly in cases where invasive SCC is suspected. Disadvantages of curettage include the need for local anesthesia and the potential for scarring.

Excision involves surgical removal or resection of tissue from the body. Like curettage, excision treats to a deeper level within the dermis than cryosurgery and is indicated for larger lesions, especially in immunocompromised patients with AKs likely to be more aggressive. Full-thickness elliptical excision for AK is rarely performed by dermatologists, but is regularly performed by plastic surgeons, general surgeons, and general practitioners.

Shave removal involves excision of a lesion using a razor. It is indicated for lesions suggestive of squamous cell carcinoma requiring histopathological examination. When performed on the lip, this procedure is called a vermilionectomy.

Dermabrasion, Chemical Peel, Laser Therapy

According to the American Academy of Dermatology, dermabrasion, chemical peels (utilizing alpha-hydroxy acids or trichloroacetic acid), and laser resurfacing by carbon dioxide laser have also been effective in the treatment of extensive AK.  

Dermabrasion involves removal of skin blemishes by abrasion (as in sandpaper) which removes the surface of the epidermis of the skin.

With chemical peels (chemoexfoliation), a topical agent, such as an acid, is applied to the skin causing it to blister and peel. The top layers slough off and are usually replaced within seven days by new epidermis (the skin’s outermost layer). This technique requires local anesthesia and can cause temporary discoloration and irritation.

Laser therapy is a finely controlled treatment that uses a laser to burn away AKs and is an option for lesions in small or narrow areas. Laser surgery is useful for people taking blood thinners and as a secondary therapy when other techniques are unsuccessful. Local anesthesia is usually necessary and scarring and pigment loss may occur.

Photodynamic Therapy

An interventional procedure assessment by the National Institute for Clinical Excellence (NICE, 2006) concluded that there is adequate evidence to support the use of PDT for AK, as well as for basal cell carcinoma and Bowen's disease. The assessment found insufficient evidence for PDT for invasive SCC of the skin.

Photodynamic Therapy (PDT) is a two-step treatment that uses drugs, called photosensitizing agents, along with light to kill cells. The drugs only work after they have been activated by certain kinds of light. In the first step, a topical solution, such as aminolevulinic acid (Levlulan Kerastick or Ameluz), is applied to each lesion using an applicator. Once applied, exposure to a specific wavelength of light (blue or red) causes cellular destruction.

Photodynamic therapy with the topical agent 5-aminolevulinic acid (5-ALA) is used to selectively photosensitize the atypical cells of the AK lesion.  Approximately 14 to 18 hours following application of the 5-ALA, the skin is exposed to a light source and the cells of the AK lesion are destroyed.  Common side effects of PDT include erythema, stinging/burning, edema, and scaling or crusting of the lesion.  The primary disadvantage of PDT is the need for treatment over a 2-day period. 

One PDT system currently has approval for the treatment of AKs.  In 1999, DUSA Pharmaceuticals, Inc. received Food and Drug Administration (FDA) approval for Levulan Kerastick.  Levulan Kerastick involves the use of both a drug (20 % ALA topical solution) and a device (the Levulan Kerastick) for application of ALA and the BLU-U^™ Illuminator as the light source).  An interventional procedure assessment by the National Institute for Clinical Excellence (NICE, 2006) concluded that there is adequate evidence to support the use of PDT for AK, as well as for basal cell carcinoma and Bowen's disease.  The assessment found insufficient evidence for PDT for invasive SCC of the skin. In November 2015, Galderma Laboratories Inc. withdrew its drug Metvixia (methyl aminolevulinate HCl Cream, 16.8%) from the United States market. It continues to be marketed in other countries. In May 2016, the FDA notified Biofrontera Inc that their product, Ameluz gel (aminolevulinic acid hydrochloride gel, 10%), was approved in combination with photodynamic therapy (PDT) using BF-RhodoLED lamp, a narrowband, red light illumination source, for lesion-directed and field-directed treatment of mild-to-moderate AKs on the face and scalp.

Reinhold et al (2016) stated multiple actinic keratosis (AK) lesions may arise from the cancerization of large, sun-damaged skin areas. Although photodynamic therapy (PDT) is considered the most effective therapeutic option, the efficacy and safety of field treatment of multiple AK lesions with PDT has never before been tested in a pivotal trial. The objectives of this study were to evaluate the efficacy, safety and cosmetic outcome of BF-200 ALA (a nanoemulsion formulation containing 10% aminolevulinic acid hydrochloride) combined with the BF-RhodoLED(®) lamp for the field-directed treatment of mild-to-moderate AK with PDT. The study was performed as a randomized, multicentre, double-blind, placebo-controlled, parallel-group, phase III trial with BF-200 ALA and placebo in seven centres in Germany. A total of 94 patients were enrolled in this study; 87 were randomized (55 patients received BF-200 ALA, 32 received placebo). Patients received one PDT. If residual lesions remained at 3 months after treatment, PDT was repeated. Illumination was performed with the PDT lamp BF-RhodoLED (635 nm ± 9 nm) until a total light dose of 37 J cm(-2) was achieved. BF-200 ALA was superior to placebo with respect to patient complete clearance rate (91% vs. 22%, P < 0·0001) and lesion complete clearance rate (94·3% vs. 32·9%, P < 0·0001) after a maximum of two PDTs. The confirmatory analysis of all key secondary variables supported this superiority" should not be skipped since this is an important result. Treatment-emergent adverse events (TEAEs) were experienced by 100% of the BF-200 ALA group and 69% of the placebo group. The most commonly reported TEAEs were TEAEs of the application site. The cosmetic outcome was improved in the BF-200 ALA group compared with placebo. The authors concluded that field-directed therapy with BF-200 ALA and BF-RhodoLED lamp is highly effective and well tolerated for multiple mild-to-moderate AK lesions, providing greatly improved skin quality.

Dirschka et al (2013) reported that two phase III trials of photodynamic therapy (PDT) with BF-200 ALA, a recently approved nanoemulsion formulation of 5-aminolaevulinic acid (ALA) demonstrated high clearance rates in mild-to-moderate actinic keratosis (AK). The comparison to a registered methyl aminolaevulinate (MAL) cream demonstrated significantly superior total patient clearance rates. The objectives of this study were to evaluate long-term efficacy and safety of PDT for AK 6 and 12 months after the last PDT with BF-200 ALA, MAL or placebo. The follow-up phase (FUP) was performed with patients of two phase III studies. Both studies compared BF-200 ALA with placebo, one of the studies additionally with MAL. Overall recurrence rates and various subgroups (light source, lesion severity, lesion location, complete responders after first PDT) were assessed 6 and 12 months after the last PDT. Recurrence rates were similar for BF-200 ALA and MAL, with a tendency to lower recurrence rates for BF-200 ALA. The proportion of patients who were fully cleared during PDT and remained completely clear for at least 12 months after PDT were 47% for BF-200 ALA (both studies) and 36% for MAL treatment. The subgroup that was illuminated with narrow wavelength LED lamps reached 69% and 53% for BF-200 ALA (both studies, respectively) and 41% for MAL. No safety concerns were reported. The authors concluded that the FUP data confirmed the high efficacy and safety of PDT with BF-200 ALA. The slightly lower recurrence rates after BF-200 ALA treatment compared with MAL treatment enhanced the better treatment outcome due to the significantly superior efficacy.

Dirschka et al (2012) stated that photodynamic therapy (PDT) with 5-aminolaevulinic acid (ALA) or its methylester [methyl-5-aminolaevulinate (MAL) or 5-amino-4-oxopentanoate] was recently ranked as first-line therapy for the treatment of actinic keratosis (AK) and is an accepted therapeutic option for the treatment of neoplastic skin diseases. BF-200 ALA (Biofrontera Bioscience GmbH, Leverkusen, Germany) is a gel formulation of ALA with nanoemulsion for the treatment of AK which overcomes previous problems of ALA instability and improves skin penetration. The objectives of this study were to evaluate the efficacy and safety of PDT of AKs with BF-200 ALA in comparison with a registered MAL cream and with placebo. The study was performed as a randomized, multicentre, observer-blind, placebo-controlled, interindividual trial with BF-200 ALA, a registered MAL cream and placebo in a ratio of 3:3:1. Six hundred patients, each with four to eight mild to moderate AK lesions on the face and/or the bald scalp, were enrolled in 26 study centres in Germany, Austria and Switzerland. Patients received one PDT. If residual lesions remained at 3months after treatment, PDT was repeated. PDT with BF-200 ALA was superior to placebo PDT with respect to patient complete clearance rate (78·2% vs. 17·1%; P<0·0001) and lesion complete clearance rate (90·4% vs. 37·1%) at 3months after the last PDT. Moreover, superiority was demonstrated over the MAL cream regarding the primary endpoint patient complete clearance (78·2% vs. 64·2%; P<0·05). Significant differences in the patient and lesion complete clearance rates and severity of treatment-related adverse events were observed for the narrow- and broad-spectrum light sources. The authors concluded that BF-200 ALA is a very effective, well-tolerated new formulation for AK treatment with PDT and is superior to a registered MAL medication. Efficacies and adverse events vary greatly with the different light sources used.

Szeimies et al (2010) stated that photodynamic therapy (PDT) with 5-aminolaevulinic acid (ALA) provides a therapeutic option for the treatment of actinic keratosis (AK). Different strategies are applied to overcome the chemical instability of ALA in solution and to improve skin penetration. A new stable nanoemulsion-based ALA formulation, BF-200 ALA, is currently in clinical development for PDT of AK. The objectives of this study were to evaluate the efficacy and safety of PDT of AK with BF-200 ALA. The study was performed as a randomized, multicentre, double-blind, placebo-controlled, interindividual, two-armed trial with BF-200 ALA and placebo. A total of 122 patients with four to eight mild to moderate AK lesions on the face and/or the bald scalp were included in eight German study centres. The efficacy of BF-200 ALA after one and two PDT treatments was evaluated. BF-200 ALA was used in combination with two different light sources under illumination conditions defined by European competent authorities. PDT with BF-200 ALA was superior to placebo PDT with respect to patient complete clearance rate (per-protocol group: 64% vs. 11%; P < 0.0001) 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 effect profiles were observed for the two light sources, Aktilite CL128 and PhotoDyn 750, at both time points of assessment. The patient and lesion complete clearance rates after illumination with the Aktilite CL128 were 96% and 99%, respectively. The authors concluded that BF-200 ALA is a very effective new formulation for the treatment of AK with PDT. Marked differences between the efficacies and adverse effects were observed for the different light sources used. Thus, PDT efficacy is dependent both on the drug and on the characteristics of the light source and the illumination conditions used.

A systematic evidence review of PDT for actinic keratoses (ICES, 2009) found it to have similar response rates to other commonly used methods of treating AKs.  Eight clinical trials met criteria for inclusion in the review; 4 of which compared PDT with cryotherapy, 2 of which compared PDT with 5-FU, 1 of which compared PDT with aminolevulinic acid with PDT with methylaminolevulinate and 1 comparing PDT with placebo.  The authors reported that the trials that compared PDT with surgery included a total number of 642 patients with 4,430 lesions with AK.  In all the trials, each patient received both treatments, randomly assigning one treatment to each side.  The authors stated that studies of PDT for AKs are limited by short durations of follow-up and a lack of evidence on the effectiveness in prevention of SCC.  One trial assessed the result in the lesions with no specific location.  No differences were observed in cure rate (69 % with PDT with methylaminolevulinate compared to 75 % with cryotherapy).  Two trials compared the results in face and scalp lesions.  In both studies, a higher response rate was observed at 3 months with PDT with methylaminolevulinate, with a range for PDT between 89 and 91 % and between 68 and 76 % for cryosurgery (p < 0.001).  In addition, one of the 2 studies had a 6-month-follow-up, but no significant differences were observed.  Finally, 1 study conducted by Kaufman et al (2008) compared the use of PDT with methyaminolevulinate with cryotherapy in patients with AK located in different areas of the face and scalp, observing a 78 % decrease in the number of lesions with PDT with methylaminolevulinate and 88 % with cryotherapy (p < 0.001 ) at 6 months.  In all the studies, the cosmetic result assessed both by the physicians and patients was significantly higher for PDT with methylaminolevulinate against cryotherapy.  Both studies comparing PDT with 5-FU included a total of 30 patients showing a similar result, with response rates ranging between 70 % and 90 %.  The authors also reported that PDT is associated with a higher cost than other commonly used methods of treating AK.

The British Association of Dermatologists proposes in its clinical practice guidelines the use of only PDT with aminolevulinic acid (PTAA) or methyl aminolevulinate (PTMA) in patients with multiple AK lesions that do not respond to standard cryotherapy or 5-FU treatment (de Berker et al, 2007).  The guidelines note that PDT may be particularly good for superficial and confluent AKs, but is likely to be more expensive than most other therapies.  "Due to expense and inconvenience PDT is probably best reserved for patients with extensive AKs that cannot be controlled with other therapies."   The guidelines reviewed the evidence for PDT for actinic keratoses.  Two studies compared PDT with cryotherapy; 1 showed a higher clearance rate with cryotherapy, whereas another showed a lower clearance rate with cryotherapy.  Cryotherapy appeared to be superior to PDT for lesions of the face and scalp, and for thicker lesions.  The investigators noted that local adverse reactions were reported by 44 % of those receiving PDT and 26 % of those given cryotherapy, although the assessment of cosmetic outcome in studies was higher (98 %) for PDT than cryotherapy (91 %).  A right/left comparison of AK treatment on the back of the hands by PDT and 5-FU showed a similar response to both therapies, clearing 73 % and 70 %, respectively.  The guidelines noted that responses remained similar at 6 months.  The guidelines also noted that the cost-effectiveness of PDT is not established but its use is likely to be limited by the cost of the photo-sensitizing cream.

Guidelines on AK from the European Dermatology Forum (Stockfleth et al, 2006) also noted that the clinical experience in AK patients receiving PDT with methylaminolevulinate shows complete response rate of 70 to 78 % after a single treatment session and 90 % after 2 treatment sessions 1-week apart.  The guidelines noted that negative effects of PDT are local pain, risk of photosensitivity (mainly for aminolevulinic acid) and time delay between application of cream and treatment.  The guidelines note level 2b (individual cohort study) evidence of better cosmetic results with PDT than cryotherapy.  The guidelines state that advantages of PDT include the selective absorption and treatment of subclinical lesions and the flourescence of the photosensitiser can be visualised using Wood’s light before the initiation of therapy.  The guidelines note, on the other hand, the costs of PDT are considerably higher compared to cryotherapy.

Methyl aminolevulinate cream (Metvixia), a porphyrin precursor, in combination with the Aktilite CL128 lamp, a narrowband, red light illumination source, has been approved by the FDA for treatment of thin and moderately thick, non-hyperkeratotic, non-pigmented AK of the face and scalp in immunocompetent patients when used in conjunction with lesion preparation in the physician’s office when other therapies are considered medically less appropriate (Galderma, 2008).

Ortiz-Policarpio and Lui (2009) noted that methyl aminolevulinate (MAL)-hydrochloride cream in combination with PDT provides an effective treatment option for AK, superficial basal cell carcinoma (sBCC), and Bowen's disease (BD).  Good clinical outcomes have been reported in the literature.  Complete responses (CRs) in AK range from 69 % to 93 % at 3 months.  In sBCC, reported CR rates were from 85 % to 93 % at 3 months and almost on par with cryosurgery at 60 months (75 % versus 74 %).  In BD, CR rates were 93 % at 3 months and 68 % at 2 years.  Current evidence has shown that this non-invasive treatment is superior in terms of cosmetic outcome to other management strategies such as surgery.  It also offers the advantages of relative simplicity, low risk of side-effects and decreased complications due to scar formation.

Fai and associates (2009) reported the findings of a retrospective chart review showing the cumulative 4-year experience with MAL-PDT in a hospital outpatient setting.  The medical records selected concerned all patients who completed the MAL-PDT regimen (1 single session for AK and 2 sessions 1 week apart for non-melanoma skin cancers [NMSCs]) and who underwent post-treatment assessments over a follow-up period of at least 12 months.  Present case series included a total of 462 patients: 210 patients with AK, 228 subjects with 348 BCCs, 213 of nodular type BCC (nBCC) and 135 of sBCC, 17 patients with BD and 7 with SCC.  On the whole, following a single session, complete clearance of AK was achieved in 79 % of patients at 3 months and in 68.1 % at 12 months.  As concerns BCCs, regardless of the clinical type, a CR was observed in 71 % of lesions at 3 months, with a rate of recurrence at 12 months of 15 %.  The risk of both initial treatment failure and recurrence was higher for nBCCs than sBCCs.  These findings, even if obtained in very few cases, indicate that BD is very responsive to MAL-PDT, unlike micro-invasive or invasive SCC.  Treatment was generally well-tolerated.  The authors concluded that these findings confirmed that MAL-PDT is a valid approach to patients with AK, BCC and BD, with an acceptable tolerability profile and a very low risk of complications.

Comparative Effectiveness across Treatments

There are few studies directly comparing the various treatments for AK to determine which are most effective.  Although the evidence is limited, PDT and 5-FU appear to be equally effective in treatment of AKs.  In 1999, Kurwa et al conducted a study to compare 5-FU (5 %) to PDT (5-ALA followed by irradiation with a halogen lamp emitting red light).  A total of 17 patients with a long history of AKs on the forearms and hands were initially recruited for this study, and patients were randomized to apply 5-FU (twice- daily for 3 weeks) to one hand and receive PDT to the other hand.  Clinical margins of the AKs on both hands were traced prior to treatment and at 1 week, 4 weeks and 6 months following the start of treatment; 14 of the original 17 patients completed the study and the mean lesional areas were compared pre- and post-treatment.  The study reported a mean lesional reduction of 70 % for lesions treated with 5-FU and a 73 % reduction in lesions treated with PDT after 6 months of follow-up.  The difference in response to the 2 treatments was not statistically significant.  No patients exhibited a complete destruction of AKs with either treatment.  Limitations included small sample size, lack of information on selection criteria, lack of information on assessment of patient compliance with 5-FU, and non-blinding study design.  Further, results at 1 and 4 weeks of follow-up were not reported.

Medium-depth chemical peel has been shown to be about as effective as topical 5-FU.  Lawrence et al (1995) initially reported on a study comparing a medium-depth chemical peel (Jessner's solution and 35 % trichloroacetic acid) to 5 % 5-FU in 15 patients.  Following a daily self-administration of 0.025 % tretinoin cream to both sides of the face for 2 weeks, each patient was subjected to the chemical peel on the left side of the face and 5-FU to the right side of the face.  Actinic keratoses were counted prior to treatment and at 1, 6 and 12 months following treatment; 12 of the 15 patients completed the 12-month study, and reported results indicate that "both fluorouracil [5-FU] and the chemical peel induced almost identical percent reductions (75 %) in the number of AK".  The study reports that this reduction in AKs was noted at the 1-month follow-up and persisted throughout the 12-month study period.  As with earlier studies, methodological flaws included non-blinding study design, small sample size, lack on information on selection criteria and characteristics of the study setting, and a lack of information on whether patient compliance with 5-FU was assessed.  Further, the results at 6 and 12 months of follow-up are confounded by intervening treatment of persistent AKs (35 % trichloroacetic acid and cryosurgery at 6 months, shaving at 12 months).  Witheiler et al (1997) later reported a 32-month follow-up on the patients from the Lawrence study.  Results indicated an increase in the mean number of AKs between 12 and 32 months.  However, this study contained flaws in addition to those of the Lawrence study, including the availability of only 8 patients for follow-up and intervening treatment of some AKs during the study period (between 12 and 32 months).

Nashan et al (2012) defined the state of art for destructive and topical treatment options for AKs based on randomized trials that meet criteria like greater than 30 patients in an intention-to-treat analysis, an easily reproducible study design with responses rated towards treatment as the major objective, measured as complete remission.  Epidemiological data included grades and location of treated AKs, operational procedures, cryotherapy (CRYO), laser therapy, 3 % diclofenac in 2.5 % hyaluronic acid ([DCF/HA]), 2.5 %, 3.75 % and 5 % imiquimod (IMI), 0.5 % and 5 % 5-FU, PDT including ALA-patches.

In a Cochrane review, Gupta et al (2012) evaluated the effects of topical, oral, mechanical, and chemical interventions for AK.  These investigators searched the following databases up to March 2011: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library, MEDLINE (from 2005), EMBASE (from 2010), and LILACS (from 1982).  They also searched trials registers, conference proceedings, and grey literature sources.  Randomized controlled trials (RCTs) comparing the treatment of AKs with placebo, vehicle, or another active therapy.  At least 2 authors independently abstracted data, which included adverse events, and assessed the quality of evidence.  They performed meta-analysis to calculate a weighted treatment effect across trials, and we expressed the results as risk ratios (RR) and 95 % CI for dichotomous outcomes (e.g., participant complete clearance rates), and mean difference (MD) and 95 % CI for continuous outcomes (e.g., mean reduction in lesion counts).  These researchers included 83 RCTs in this review, with a total of 10,036 participants.  The RCTs covered 18 topical treatments, 1 oral treatment, 2 mechanical interventions, and 3 chemical interventions, including PDT.  Most of the studies lacked descriptions of some methodological details, such as the generation of the randomization sequence or allocation concealment, and half of the studies had a high-risk of reporting bias.  Study comparison was difficult because of the multiple parameters used to report efficacy and safety outcomes, as well as statistical limitations.  They found no data on the possible reduction of SCC.  The primary outcome 'participant complete clearance' significantly favored four field-directed treatments compared to vehicle or placebo: DCF/HA (RR 2.46, 95 % CI: 1.66 to 3.66; 3 studies with 420 participants), 0.5 % 5-FU (RR 8.86, 95 % CI: 3.67 to 21.44; 3 studies with 522 participants), 5 % IMI (RR 7.70, 95 % CI: 4.63 to 12.79; 9 studies with 1,871 participants), and 0.025 % to 0.05 % ingenol mebutate (IMB) (RR 4.50, 95 % CI: 2.61 to 7.74; 2 studies with 456 participants).  It also significantly favored the treatment of individual lesions with PDT compared to placebo-PDT with the following photo-sensitisers: ALA (blue light: RR 6.22, 95 % CI: 2.88 to 13.43; 1 study with 243 participants, ALA (red light: RR 5.94, 95 % CI: 3.35 to 10.54; 3 studies with 422 participants), and MAL (red light: RR 4.46, 95 % CI: 3.17 to 6.28; 5 studies with 482 participants).  ALA-PDT was also significantly favored compared to cryotherapy (RR 1.31, 95 % CI: 1.05 to 1.64).  The corresponding comparative risks in terms of number of participants completely cleared per 1,000 were as follows: 313 with 3 % diclofenac compared to 127 with 2.5 % hyaluronic acid; 136 with 0.5 % 5-FU compared to 15 with placebo; 371 with 5 % IMI compared to 48 with placebo; 331 with IMB compared to 73 with vehicle; 527 to 656 with ALA/MAL-PDT treatment compared to 89 to 147 for placebo-PDT; and 580 with ALA-PDT compared to 443 with CRYO.  5 % 5-FU efficacy was not compared to placebo, but it was comparable to 5 % IMI (RR 1.85, 95 % Cl: 0.41 to 8.33).  A significant number of participants withdrew because of adverse events with 144 participants affected out of 1,000 taking DCF/HA, compared to 40 participants affected out of 1,000 taking 2.5 % hyaluronic acid alone, and 56 participants affected out of 1,000 taking 5 % IMI compared to 21 participants affected out of 1,000 taking placebo.  Based on investigator and participant evaluation, IMI treatment and PDT resulted in better cosmetic outcomes than CRYO and 5-FU.  The authors concluded that for individual lesions, PDT appears more effective and has a better cosmetic outcome than CRYO.  For field-directed treatments, diclofenac, 5-FU, IMI, and IMB had similar efficacy, but their associated adverse events and cosmetic outcomes are different.  More direct comparisons between these treatments are needed to determine the best therapeutic approach.

Gupta and Paquet (2013) performed a network meta-analysis for 8 treatments [ALA- PDT, CRYO, DCF/HA, 0.5 % or 5.0 % 5-FU, 5 % IMI, 0.015 to 0.05 % IMB, MAL-PDT, and placebo/vehicle (including placebo-PDT)] to determine their relative efficacies.  As part of a prior Cochrane systematic review, different databases and grey literature were searched for RCTs up to April 2012.  The inclusion criteria were parallel-group studies with non-immunosuppressed participants:

1. reporting "participant complete clearance" and
2. comparing at least 2 of the interventions.

A total of 32 publications met the criteria and they included the following number of individual or pooled studies (n) and total number of participants (N) for the different interventions: 0.5 % 5-FU (n = 4, N = 169), 5.0 % 5-FU (n = 2, N = 44), ALA-PDT (n = 6, N = 739), CRYO (n = 2, N = 174), DCF/HA (n = 5, N = 299), IMI (n = 14, N = 1,411), IMB (n = 3, N = 560), MAL-PDT (n = 7, N = 557), and placebo (n = 32, N = 2520).  Network analyses using a random effects Bayesian model were carried out with the software ADDIS v1.16.1.  The interventions were ranked as followed based on calculated probabilities and odd ratios: 5-FU > ALA-PDT ~ IMI ~ IMB ~ MAL-PDT > CRYO > DCF> placebo.  This efficacy ranking was obtained based on the current available data on "participant complete clearance" from RCTs and the analysis model used.  However, several other factors should also be considered when prescribing a treatment for AK.

Topical Vitamin D and Analogs

In an investigator-blinded, half-side comparison study, Seckin et al (2009) examined if AK may benefit from the anti-proliferative and pro-differentiative effects of topical vitamin D.  Patients applied calcipotriol cream to 1 side and Ultrabase cream as placebo to the other side of the scalp and/or face for 12 weeks.  The total number of AK and diameters and total scores of the target lesions were determined at each visit.  A total of 9 patients were included, 8 of whom completed the treatment.  There was a statistically significant difference between the total number of AK at baseline and at week 12 on calcipotriol applied side whereas no difference was detected on placebo applied side (p = 0.028 versus p = 1.00).  The mean total score of the target lesions reduced significantly at week 12 on calcipotriol side; however, no significant reduction was found on placebo side (p = 0.017 versus p = 0.056).  Although side effects were more common on calcipotriol side, the difference was not statistically significant.  The authors concluded that topical calcipotriol may show promise in the treatment of AK.  Moreover, they stated that more studies are needed to confirm its efficacy.

Wat and Dytoc (2014) provided evidence-based clinical guidelines for the off-label use of topical vitamin D in the treatment of dermatologic disease.  A systematic literature review was conducted via the MEDLINE, Embase, and CENTRAL databases for off-label uses of topical vitamin D analogs in the treatment of dermatologic disease other than psoriasis.  The data were synthesized, and evidence-based recommendations were rendered according to the highest level of evidence available.  A total of 165 articles met the inclusion criteria.  A moderate to strong recommendation was given for the use of topical vitamin D in combination with corticosteroids and phototherapy in vitiligo and as monotherapy for various ichthyoses, morphea, pityriasis alba, prurigo nodularis, and polymorphous light eruption.  There is evidence showing that topical vitamin D is ineffective in the treatment of AK, seborrheic keratosis, lichen planus, seborrheic dermatitis, alopecia areata, chemotherapy-induced alopecia, and hypertrophic scars.  The authors concluded that topical vitamin D analogs have an important role in the off-label treatment of dermatologic disease, but higher quality studies are still needed.

In a systematic review, Wat and colleagues (2014) provided evidence-based recommendations to guide physicians in the application of intense pulsed light (IPL) for the treatment of dermatologic disease.  A literature search of the CENTRAL (1991 to May 6, 2013), EMBASE (1974 to May 6, 2013), and MEDLINE in-process and non-indexed citations and MEDLINE (1964 to present) databases was conducted.  Studies that examined the role of IPL in primary dermatologic disease were identified, and multiple independent investigators extracted and synthesized data.  Recommendations were based on the highest level of evidence available.  Level 1 evidence was found for the use of IPL for the treatment of melasma, acne vulgaris, and telangiectasia.  Level 2 evidence was found for the treatment of lentiginous disease, rosacea, capillary malformations, AKs, and sebaceous gland hyperplasia.  Level 3 or lower evidence was found for the treatment of poikiloderma of Civatte, venous malformations, infantile hemangioma, hypertrophic scars, superficial basal cell carcinoma, and Bowen's disease.  The authors concluded that IPL is an effective treatment modality for a growing range of dermatologic disease and in some cases may represent a treatment of choice.  It is typically well-tolerated.  Moreover, they stated that further high-quality studies are needed.

Furthermore, an UpToDate review on “Treatment of actinic keratosis” (Jorizzo, 2014) does not mention the use of intense pulsed light and vitamin D as therapeutic options.

Topical Piroxicam

In a proof of concept study, Babino et al (2016) conducted an 18-month exploratory open-label study on AK to evaluate the tolerability and effectiveness of a new topical formulation of piroxicam and sunscreen. Enrolled subjects applied a galenic formulation of piroxicam 0.8 %, vehiculated in a topical product containing sun filters with high (50+) and broad spectrum (UVA) actions, twice-daily for 6 months.  Subjects were then followed-up for additional 12 months.  A total of 38 subjects with a total of 69 AK lesions participated in the trial.  The primary outcome was the evolution of the Actinic Keratosis Erythema Scale Atrophy (A.K.E.S.A) score assessing erythema, scale, and atrophy of a target AK lesion.  Secondary outcomes were the percentage of treated lesions with complete (100 %) or partial (greater than or equal to 75 %) clearance and the evaluation skin tolerability.  A.K.E.S.A. mean (S.D.) score at baseline was 7.5 (1.2).  After 6 months of treatment, A.K.E.S.A. score decreased to 0.9 (1.1), a -88 % reduction versus baseline.  At the end of follow-up, A.K.E.S.A. score was 0.8 (1.2).  A complete response was achieved in 38 of the 69 lesions (55 %, 95 % CI: 43 % to 66 %) and clearance was maintained 1 year post-treatment.  A partial clearance was observed in 57 of 69 treated lesions (83 %, 95 % CI: 73 % to 91 %); adverse events were limited to mild local irritation.  The authors concluded that their experience suggested that 6-month topical piroxicam 0.8 % was effective and well-tolerated in AK; clinical effectiveness was maintained 1 year post-treatment.  The main drawback of this study was that it was an open-label. non-controlled trial.  They stated that future controlled trials are needed to compare the tolerability and effectiveness of this topical piroxicam preparation with standard treatments in the management of AK.

Furthermore, an UpToDate review on “Treatment of actinic keratosis” (Jorizzo, 2016) does not mention piroxicam as a therapeutic option.

Topical Corticosteroid for Ingenol Mebutate-Induced Local Skin Responses

Erlendsson et al (2016) noted that ingenol mebutate (IngMeb) is approved for treatment of AK and may cause unpredictable local skin responses (LSR). These investigators examined if IngMeb-induced LSR, pain, and pruritus could be alleviated with a topical glucocorticoid and, further, evaluated effectiveness, cosmetic outcome, and patient satisfaction in patients with severe photo-damage.  In this blinded, RCT, patients with multiple AK and field cancerization of the face or scalp were treated in 2 areas with IngMeb (0.015 %) daily for 3 days.  After finalized IngMeb treatment, 1 area was randomized to receive topical clobetasol propionate (0.05 %) twice-daily for 4 days.  Assessments included LSR (0 to 24; days 1, 4, 8, 15, 57), pain (0 to 10) and pruritus (0 to 3; days 1 to 15), AK clearance (days 15, 57), and cosmetic outcome (0 to 3; day 57).  Clobetasol propionate application had no influence on LSR (p = 0.939), pain (p = 0.500), pruritus (p = 0.312), or AK cure rate (p = 0.991).  Overall, IngMeb cleared 86 % of all AK lesions, exerting a therapeutic effect on all AK severity grades; cure rates were 88 %, 70 %, and 60 % for grade I, II, and III AK, respectively.  Skin texture improved significantly in remedied areas (2.0 versus 1.0; p < 0.001); no hypo-pigmentation, hyper-pigmentation, or scarring were observed.  The authors concluded that application of clobetasol propionate did not alleviate IngMeb-induced LSR after 3 days of IngMeb treatment.

Lapatinib

In a phase II clinical trial, Jenni and colleagues (2016) examined the effects of lapatinib on cutaneous SCC (cSCC) scheduled for resection and in co-existing precursor lesions (AK and BD).  These researchers initiated a prospective single-center, open-label, non-controlled clinical study with translational intentions to investigate changes in size and histopathological features in cSCC after a 14-day period of neoadjuvant lapatinib therapy at a dose of 1,500 mg/day prior to surgery, to quantify the impact on AK and BD in the same patient after 56 days and to evaluate the tolerability in patients with cSCC and precursor lesions.  A total of 10 immunocompetent male patients were included with a mean age of 73 years (range of 59 to 87); 8 patients were treated with the study medication lapatinib 1,500 mg/day for a total duration of 56 days according to the protocol and were available for full analysis, whereas 2 patients had to discontinue treatment during the first 2 weeks because of adverse events (AEs -- diarrhea, pancreatitis).  Tolerability was acceptable with only 1 related grade III AE.  A reduction in tumor size of cSCC was documented in 2 of 8 evaluable patients after 14 days of treatment.  The mean regression of captured precursor lesions was 30 % after 56 days of treatment and 36 % 28 days after therapy cessation.  The authors concluded that short-term lapatinib resulted in a cSCC tumor reduction in 2 of 8 patients.  In addition, there was a clinically documented reduction of AK in 7 of 8 patients encouraging larger clinical trials, especially in high-risk patients with cSCC such as organ transplant recipients.

Cream Containing Sunscreen, Piroxicam and a Retinoic/Glycolic Gel

Puviani and colleagues (2018) noted that lesion and field-targeted treatments of AKs are commonly indicated for grade I and II type lesions.  Grade III lesions are in general more difficult to treat.  A film-forming medical device containing piroxicam 0.8 % and sunscreen (SPF 50+) (PS) has been shown to be effective in the treatment of grade I and II AK lesions.  Topical and oral retinoids have been utilized in AKs and non-melanoma skin cancers.  Topical glycolic acid promotes keratolysis and stimulates collagen synthesis for repair and skin rejuvenation and could be useful in AK treatment strategies.  A gel containing retinoid acid (0.02 %) and glycolic acid (4 %) (RC) is commercially available.  In a pilot study, these researchers examined the efficacy and local tolerability of a combined treatment approach with PS and RC in subjects with multiple grade II and III AK lesions.  A total of 22 subjects (16 men and 6 women; mean age of 68 years) with more than 5 AK lesions were enrolled after obtaining their informed consent in a 3-month trial; PS cream was applied twice-daily every day and RC gel was applied twice-daily for 2 consecutive days every week.  The primary end-point was the evolution of the AK mean number from baseline to the end of the trial.  Secondary end-points were the thickness of the target lesion (expressed in mm3) and the erythema score (hemoglobin content), evaluated using a standardized computer-based image acquisition analysis system (Anthera 3D).  At baseline, the mean (SD) lesion number was 7.7 (3) for grade II and 1.4 (1) for grade III AK.  At the end of the study, a significant (p = 0.001) reduction was observed for both grade II (- 81 %; from 7.7 to 1.5) and grade III (-22 %) lesions; 6 grade III lesions out of 31 (20 %), presented at baseline, completely disappeared at month 3.  For grade III lesions, a significant mean thickness reduction of 51 % was observed at month 3.  The erythema score (all lesions) was reduced by 70 %; 4 patients out of 22 (18 %) were completely free of AK lesions at month 3.  No severe side effects were reported.  The authors concluded that in this exploratory trial, a combined treatment with a cream containing piroxicam and sunscreen and a retinoic/glycolic gel was associated with a substantial reduction of both grade II and III AK lesions with good local tolerability.  These preliminary findings need to be validated by well-designed studies.

The authors stated that this study had several drawbacks.  First, this was not a double-blind trial, and lacked a control group.  However, the present study was a pilot proof-of-concept trial.  Further larger prospective controlled studies are needed to examine if this combined therapeutic strategy could be helpful in the management of “difficult” AK lesions such as grade III.  In addition, the lesion thickness and erythema values (secondary outcomes of the present study) were evaluated in an objective manner (computer analysis of standardized acquired images).  Second, the treatment period was relatively short (3 months).  However, the goal of this study was to evaluate the clinical efficacy of this therapeutic approach in the short-term and also as an initial feasible stage in a more articulate multi-step therapeutic AK strategy.

Non-Ablative Fractional Thulium Laser

Weiss and colleagues (2013) noted that AKs are precancerous epidermal proliferations commonly present on chronically sun-damaged skin.  These lesions are among the most often treated dermatologic conditions.  In a prospective clinical trial, these investigators examined the 6-month safety, tolerance, and efficacy of non-ablative 1,927-nm fractional resurfacing of facial AKs.  This trial included 24 individuals with facial photodamage and AKs receiving up to 4 treatments with the fractionated 1,927-nm non-ablative thulium laser.  At 6 months, an 86.6 % reduction in absolute number of lesions was noted by independent physician assessment.  In addition, at this same time-point, patients reported marked or noticeable improvement in overall photodamage.  The authors concluded that the clinical and histologic findings, as well as the reported patient satisfaction and safety, suggested that the treatment of AKs and photodamage with a fractionated 1,927-nm non-ablative thulium laser was a promising new therapeutic option.  The main drawback of this study was that it not provide safety, tolerance, and efficacy data beyond 6 months of follow-up, nor did it identify the precise mechanism of action involved in AKs clearance after 1,927-nm resurfacing.

In a pilot study, Prens and associates (2013) evaluated the efficacy of fractional laser therapy for clearing AKs and improving skin quality.  These investigators compared patient friendliness of the "fractional" therapy with those reported for other field therapeutic modalities.  A total of 10 patients with Fitzpatrick skin type I to III with multiple AKs and extensive sun-damaged skin, received 5 to 10 sessions with a 4-week interval using a 1,550-nm Erbium-Glass Fractionated laser (Sellas, Korea); 4 weeks and 24 weeks following the last treatment the clinical results were evaluated by an independent physician.  The mean degree of improvement, in terms of reduction in the number of AKs and improvement of skin texture, was 54 % on a 4-point Physician's Global Assessment (PGA) scale, and persisted for approximately 6 months.  The biggest advantage of fractional laser treatment, besides the eradication of AKs and a clear rejuvenation effect, was the absence of "downtime".  The authors concluded that fractional non-ablative resurfacing induced significant reduction in the number of AKs and improved the skin quality.  Furthermore, all patients preferred fractional laser therapy above other AK therapeutic modalities.

Furthermore, an UpToDate review on “Treatment of actinic keratosis” (Jorrizo, 2019) states that “A few uncontrolled studies have reported reductions in AKs following treatment with non-ablative fractional lasers; however, a 6-month follow-up with histologic evaluation performed in one of the studies revealed persistence of AKs after treatment”.

Thermal Photodynamic Therapy

Willey (2019) stated that warming the skin during the incubation of 5-ALA has the potential to improve the efficacy and efficiency of cutaneous PDT through multiple mechanisms.  In a proof-of-concept study, these investigators examined the efficacy and tolerability of thermal PDT on facial skin and evaluate porphyrin production objectively during the warming period.  Facial skin of 10 subjects was heated during a 20-min incubation with ALA followed by 10 J/cm blue light illumination.  Lesion counts were performed at baseline and 2 months.  Porphyrin images were captured and the intensity of fluorescence was measured.  The mean intensity of fluorescence after incubation with ALA was compared with baseline.  A total of 10 subjects with 363 actinic keratoses completed the study.  The average temperature during incubation with the warming mask was 38 to 42 °C.  Porphyrin intensity increased significantly after the incubation period (p = 0.001).  The average lesion clearance rate was 91.48 %; 5 subjects had complete lesion clearance (50 %).  The authors concluded that this small proof-of-concept study showed that warming facial skin within the range of physiologic tolerability during the incubation of ALA was well-tolerated by patients and that porphyrins were efficiently and effectively produced during this defined time and temperature range.

Ablative Fractional Laser for the Treatment of Actinic Keratosis in Organ Transplant Recipients

Heppt and colleagues (2019) noted that actinic keratosis (AK) in organ transplant recipients (OTRs) has a high risk of progressing to invasive squamous cell carcinoma (SCC) of the skin.  Thus, early and consequent treatment of AKs is warranted in OTRs.  These researchers examined the current evidence for non-systemic treatments of AKs in OTRs.  They carried out a literature search in Medline, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL) and hand-searched pertinent trial registers up to August 22, 2018; RCTs evaluating non-systemic interventions for AKs in OTRs were included.  The risk of bias was estimated using the Cochrane Risk of Bias Tool.  Of 663 records initially identified, 8 RCTs with 242 OTRs were included in a qualitative synthesis.  Most studies evaluated methyl aminolaevulinate photodynamic therapy (MAL-PDT), followed by ablative fractional laser (AFXL) and diclofenac sodium 3 % in hyaluronic acid, imiquimod 5 % cream and 5-fluorouracil 5 % cream (5-FU).  MAL-PDT showed the highest rates of participant complete clearance (40 to 76.4 %), followed by imiquimod (27.5 to 62.1 %), diclofenac (41 %) and 5-FU (11 %).  Similar results were observed for lesion-specific clearance rates.  Treatment with AFXL alone revealed low lesion clearance (5 to 31 %).  Local skin reactions were most intense in participants treated with a combination of AFXL and day-light MAL-PDT.  There were no therapy-related transplant rejections or worsening of graft function in any trial.  The overall risk of bias was high.  The authors concluded that limited evidence was available for the treatment of AKs in OTRs; MAL-PDT is currently the best-studied intervention.  Lesion-specific regimens may not be sufficient to achieve disease control.  Field-directed regimens are preferable in this high-risk population.

Micro-Needling

Steeb and colleagues (2020) stated that AKs are pre-malignant lesions in light-skinned individuals with the potential to progress into invasive SCC of the skin; and PDT with ALA or MAL is an effective treatment for multiple AKs or field cancerization.   Several studies have reported augmentation of PDT through mechanical pre-treatment with metal micro-needling (MN).  However, published results have been heterogeneous, and a clear-cut, evidence-based recommendation for combining PDT with MN does not exist.  Thus, these investigators examined if MN plus PDT is superior to monotherapy with PDT.  The protocol for this study was defined a priori.  The systematic search in the data-bases and trial registers identified 1,482 references, and 11 records underwent full-text review.  A total of 5 RCTs with a sample size of n = 213 met the eligibility criteria.  The combination of MN and ALA-PDT was more effective in clearing lesions than ALA-PDT monotherapy based on the mean lesion complete clearance per patient (MD 6.01; 95 % CI: 0.84 to 11.17; I2 = 11 %; p = 0.02; GRADE +---).  There was no significant difference between ALA-PDT combined with MN compared with monotherapy (RR 1.19; 95 % CI: 0.90 to 1.67; I2 = 35 %; p = 0.22; GRADE +---).  Subjects treated with a combination approach showed partial clearance rates similar to those achieved with ALA-PDT only (RR 1.38; 95 % CI: 0.97 to 1.97; p = 0.07; GRADE ++--).  PDT monotherapy was perceived as equally painful as the combination of PDT with MN reported on a visual analog scale (VAS) from 0 (none) to 10 (extreme pain) (MD 0.66; 95 % CI: -0.23 to 1.55; I2 = 86 %; p = 0.15; GRADE +---).  The authors concluded that PDT is especially suitable in combination with other therapeutic approaches because the penetration of the photo-sensitizer is limited, especially in thick and hyper-keratotic lesions.  The combination of MN and PDT showed significant superiority with respect to the mean lesion clearance, which was calculated to 6.0 %, indicating that, on average, 6 % more treated lesions cleared with the combination compared with PDT monotherapy.  The other efficacy end-points also showed a slight trend toward better efficacy of the combination, although the results were not significantly different.  A combination of MN plus PDT did not appear to be associated with a greater degree of painful sensation in any of the studies.  The treatment protocols of the studies were highly heterogeneous, which resulted in indirectness of the comparisons.  These researchers stated that the drawbacks of this work included the high heterogeneity of the included studies and the low quality of the evidence according to the GRADE rating.  Although these investigators included only RCTs in the analysis, the studies were de-valued because of methodologic shortcomings.  The most common reason for this was a small number of patients and a high variability of reported data with wide CIs.  Nevertheless, a combination of MN plus PDT appeared to be slightly more effective than PDT alone.  However, the MN procedure needs to be standardized for use in daily practice.

Furthermore, an UpToDate review on “Treatment of actinic keratosis” (Jorizzo, 2020) does not mention micro-needling plus PDT as one of the combination therapies.

Microwave Therapy

Jackson and colleagues (2020) examined the efficacy and feasibility of microwave therapy as a treatment for AK.  Stage I was a dose-setting study, in which 7 subjects had the dielectric properties of 12 thick and 22 thin AKs assessed for optimization of the microwave dose used for treatment in Stage II.  Stage II was a randomized, internally controlled trial evaluating 179 AKs in 11 subjects (93 treated, 86 untreated controls) on the scalp / fore-head or dorsal hand.  Subjects received 1 treatment initially and a repeat treatment to unresolved AKs at week 4.  The response was evaluated at 6 visits over 4 months.  The primary outcome was partial or complete resolution of the treated AKs.  A significantly higher proportion of treated AK areas responded than untreated (90 % versus 15 %; p < 0·001).  Thin AKs were more responsive than thick AKs.  The site did not affect efficacy.  Pain was severe, but brief (80 % reported pain lasting “a few seconds only”); AEs were minimal (erythema, n = 6; flaking, n = 3; itch, n = 3).  All subjects who would chose microwave therapy over their current treatment cited the shorter discomfort period.  The authors concluded that microwave therapy was a portable, safe and effective treatment for AK.  An easy-to-deliver, acceptable therapy for AK is attractive as a prevention strategy.  These researchers stated that while these results were promising, a larger RCT is needed against an effective comparator to confirm clinical efficacy and patient acceptability.

The authors stated that this study had several drawbacks.  This was a small study with 11 subjects, but analysis was per AK and 179 AKs were assessed, increasing the power.  Subjects were recruited from secondary care so had relatively severe AK.  Sufficient “thick” and “thin” AKs were treated to analyze these subgroups independently.  While the side to receive treatment was randomized, the assessors were not blinded.  Blinding was not feasible as only 2 clinicians were involved in both treatment delivery and follow‐up.  Furthermore, erythema from the treatment and, at later visits, the biopsy scar, would reveal the treatment side.  As a first‐in‐human study, the effects of treatment on AKs were not known.  Due to the lack of overlapping or step-wise treatment over the entire surface of larger AKs, this study may under-estimate the potential for complete resolution.

Furthermore, an UpToDate review on “Treatment of actinic keratosis” (Jorizzo, 2020) does not mention microwave therapy as a therapeutic option.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
CPT codes covered if selection criteria are met:
11300	Shaving of epidermal or dermal lesion, single lesion, trunk, arms or leg; lesion diameter 0.5 cm or less
11301	lesion diameter 0.6 to 1.0 cm
11302	lesion diameter 1.1 to 2.0 cm
11303	lesion diameter over 2.0 cm
11305	Shaving of epidermal or dermal lesion, single lesion, scalp, neck, hands, feet, genitalia; lesion diameter 0.5 cm or less
11306	lesion diameter 0.6 to 1.0 cm
11307	lesion diameter 1.1 to 2.0 cm
11308	lesion diameter over 2.0 cm
11310	Shaving of epidermal or dermal lesion, single lesion, face, ears, eyelids, nose, lips, mucous membrane; lesion diameter 0.5 cm or less
11311	lesion diameter 0.6 to 1.0 cm
11312	lesion diameter 1.1 to 2.0 cm
11313	lesion diameter over 2.0 cm
11400	Excision, benign lesion including margins, except skin tag (unless listed elsewhere), trunk, arms or legs; excised diameter 0.5 cm or less
11401	excised diameter 0.6 to 1.0 cm
11402	excised diameter 1.1 to 2.0 cm
11403	excised diameter 2.1 to 3.0 cm
11404	excised diameter 3.1 to 4.0 cm
11406	excised diameter over 4.0 cm
11420	Excision, benign lesion including margins, except skin tag (unless listed elsewhere), scalp, neck, hands, feet, genitalia; excised diameter 0.5 cm or less
11421	excised diameter 0.6 to 1.0 cm
11422	excised diameter 1.1 to 2.0 cm
11423	excised diameter 2.1 to 3.0 cm
11424	excised diameter 3.1 to 4.0 cm
11426	excised diameter over 4.0 cm
11440	Excision, other benign lesion including margins, except skin tag (unless listed elsewhere), face, ears, eyelids, nose, lips, mucous membrane; excised diameter 0.5 cm or less
11441	excised diameter 0.6 to 1.0 cm
11442	excised diameter 1.1 to 2.0 cm
11443	excised diameter 2.1 to 3.0 cm
11444	excised diameter 3.1 to 4.0 cm
11446	excised diameter over 4.0 cm
15780	Dermabrasion; total face (e.g., for acne scarring, fine wrinkling, rhytids, general keratosis)
15781	segmental, face
15782	regional other than face
15783	superficial, any site (e.g., tattoo removal)
15786	Abrasion; single lesion (e.g., keratosis, scar)
+ 15787	each additional four lesions or less (List separately in addition to code for primary procedure)
15789	Chemical peel, facial; dermal
15793	Chemical peel, nonfacial; dermal
17000	Destruction (e.g., laser surgery, electrosurgery, cryosurgery, chemosurgery, surgical curettement), pre-malignant lesions (e.g., actinic keratoses); first lesion
+ 17003	second through 14 lesions, each (List separately in addition to code for first lesion)
17004	Destruction (e.g., laser surgery, electrosurgery, cryosurgery, chemosurgery, surgical curettement), pre-malignant lesions (e.g., actinic keratoses);15 or more lesions
96567	Photodynamic therapy by external application of light to destroy pre-malignant and/or malignant lesions of the skin and adjacent mucosa (e.g., lip) by activation of photosensitive drug(s), each phototherapy exposure session [red light]
96573	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 [red light]
CPT codes not covered for indications listed in the CPB:
Thermal photodynamic therapy, intense pulsed light, non-ablative fractional thulium laser, micro-needling, microwave therapy - no specific code:
HCPCS codes covered if selection criteria are met:
J7308	Aminolevulinic acid HCL for topical administration, 20%, single unit dosage form (354 mg)
J7345	Aminolevulinic acid hcl for topical administration, 10% gel, 10 mg
HCPCS codes not covered for indications listed in the CPB:
Cream containing sunscreen, piroxicam and a retinoic/glycolic gel, topical calcipotriol, topical vitamin D and analogs, lapatinib - no specific code:
J7309	Methyl aminolevulinate (MAL) for topical administration, 16.8%, 1 gram [discontinued]
ICD-10 codes covered if selection criteria are met:
L57.0	Actinic keratosis

The above policy is based on the following references: