ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد ایتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Treatment of actinic keratosis

Treatment of actinic keratosis
Author:
Brian Berman, MD, PhD
Section Editors:
Robert P Dellavalle, MD, PhD, MSPH
June K Robinson, MD
Deputy Editor:
Rosamaria Corona, MD, DSc
Literature review current through: Jul 2022. | This topic last updated: Jul 13, 2021.

INTRODUCTION — Actinic keratoses (AKs or solar keratoses) are keratotic or scaling macules, papules, or plaques resulting from the intraepidermal proliferation of atypical keratinocytes in response to prolonged exposure to ultraviolet radiation. Although most AKs do not progress to squamous cell carcinoma (SCC), AKs are a concern because the majority of cutaneous SCCs arise from pre-existing AKs, and AKs that will progress to SCC cannot be distinguished from AKs that will spontaneously resolve or persist [1,2]. Because of these factors, most clinicians routinely treat AKs [3]. Improvement in associated symptoms and cosmetic appearance can be additional benefits of treatment.

The treatment of AKs will be reviewed here. The epidemiology, clinical manifestations, and diagnosis of AKs are discussed separately. (See "Epidemiology, natural history, and diagnosis of actinic keratosis".)

OVERVIEW OF TREATMENT OPTIONS — Treatment options for actinic keratosis (AK) include destructive therapies (eg, surgery, cryotherapy, dermabrasion, photodynamic therapy [PDT]), topical medications (eg, topical fluorouracil, imiquimod, ingenol mebutate, diclofenac), and field ablation treatments (eg, chemical peels, laser resurfacing). In general, lesion-directed treatments, such as cryotherapy and surgical procedures, are the primary approach for isolated lesions [3]. Field-directed therapies, such as topical fluorouracil, imiquimod, and PDT, are particularly useful for treating areas with multiple AKs. (See 'Choice of therapy' below.)

Evidence for efficacy of these therapies is derived from multiple randomized trials and meta-analyses [4-8]:

One systematic review and meta-analysis of 83 randomized trials evaluating 24 treatments in over 10,000 patients found sufficient evidence to conclude that topical fluorouracil, imiquimod, ingenol mebutate, and topical diclofenac are superior to placebo for complete clearance of lesions in the treated field in patients with AKs [4]. In addition, this meta-analysis found that PDT performed with aminolevulinic acid (ALA-PDT) with red light or blue light or with methyl aminolevulinate (MAL-PDT) with red light was superior to placebo for the treatment of individual AK lesions [4]. The meta-analysis also found that treatment with imiquimod or PDT generally resulted in better cosmetic outcomes than topical fluorouracil or cryotherapy [4].

A subsequent network meta-analysis of 26 individual or pooled randomized trials evaluated the relative efficacy in inducing complete lesion clearance for eight main interventions for AK [5]. This analysis suggests that topical fluorouracil is the most effective treatment followed by 5-ALA-PDT, topical imiquimod, ingenol mebutate, 5-MAL-PDT, cryotherapy, topical diclofenac with hyaluronic acid, and placebo. However, the ranking of relative efficacies should be interpreted with caution because of the variability in the parameters used to describe the AK severity in the included studies.

CHOICE OF THERAPY — Given the multiple effective treatment options for actinic keratoses (AKs), the choice of therapy is influenced by factors such as the number and distribution of lesions, lesion characteristics, patient preference for the mode of treatment (eg, office based versus home administered, duration of therapy), patient tolerance for side effects (eg, pain, inflammation, hypopigmentation, scarring), and treatment availability and cost.

Our approach is generally consistent with current international guidelines (algorithm 1) [9-13]. Cryotherapy and surgical interventions (eg, tangential excision or curettage followed by electrodesiccation or cryotherapy) are lesion-directed treatments primarily used for isolated lesions. Cryotherapy is most frequently used because it is rapid, inexpensive, and does not require local anesthesia. Surgical interventions are best reserved for hypertrophic or hyperkeratotic lesions and those of uncertain diagnosis. Although photodynamic therapy with 20% aminolevulinic acid solution (ALA-PDT) is approved by the US Food and Drug Administration (FDA) for targeted lesion therapy, in clinical practice, it is almost exclusively used as a field therapy. (See 'Patients with multiple lesions/field cancerization' below.)

Field-directed therapies are indicated for the treatment of multiple AKs and field cancerization [14]. They include topical agents (eg, topical fluorouracil, imiquimod, ingenol mebutate), photodynamic therapy, or field ablation with dermabrasion, chemical peels, and carbon dioxide laser resurfacing [3]. (See 'Patients with multiple lesions/field cancerization' below.)

Topical therapies have many advantages (noninvasive, effective against subclinical lesions, self-administered). However, adherence to these treatments is generally low for patients requiring long duration of therapy or those presenting high frequency of local skin reactions (eg, skin irritation, erosions, ulcerations).

PATIENTS WITH ONE OR FEW DISCRETE LESIONS — Lesion-directed treatment with cryotherapy is most frequently used as a primary approach for patients with one or few isolated lesions because it is rapid, inexpensive, and does not require local anesthesia. Surgical interventions (tangential excision or curettage followed by electrodesiccation or cryotherapy) are best reserved for hyperkeratotic lesions and those of uncertain diagnosis (algorithm 1).

Liquid nitrogen cryotherapy — We suggest liquid nitrogen cryotherapy as first-line therapy for patients with one or a few (two to three or more, depending on the patient's tolerance of treatment) isolated actinic keratoses (AKs) (algorithm 1). The treatment is delivered by either spray or contact with a cryoprobe. The contact technique is particularly useful for treating small lesions in sensitive areas of the face (eg, periocular, perioral). The freezing time varies from 5 to 10 seconds or more, depending upon lesion size and thickness, with the "ice ball" extending at least 1 mm beyond the clinical margin of the lesion. A single freeze-thaw cycle is adequate for thin lesions, while a double freeze-thaw cycle is required for thicker lesions.

Cryotherapy is the most widely utilized treatment for AK. It can be quickly performed in an office-based setting, does not require local anesthesia, is inexpensive, is well tolerated by patients, and in most cases, results in good or excellent cosmetic outcome [15]. Cryotherapy is associated with transient discomfort and can result in hypopigmentation. (See "Minor dermatologic procedures", section on 'Cryotherapy (cryosurgery)'.)

However, since this procedure does not produce a specimen for histologic confirmation, it should only be performed when the clinical diagnosis of AK is relatively certain. If there is doubt about the diagnosis, a biopsy for histologic confirmation is warranted.

The efficacy of liquid nitrogen cryotherapy has been evaluated in a limited number of randomized trials. In a systematic review of eight randomized trials of cryotherapy combined with other topical treatments (ie, imiquimod, topical fluorouracil, ingenol mebutate, diclofenac) versus cryotherapy alone, the response rate for cryotherapy alone ranged from 39 to 76 percent compared with 73 to 89 percent for combination therapy [16]. The included studies were heterogeneous and generally of low methodologic quality. Similar clearance rates for cryotherapy, ranging from 40 to 88 percent, were reported in randomized trials comparing cryotherapy with other treatment modalities [17-24].

The wide variability in the reported clearance rates may be related to differences across studies in cryotherapy administration, such as freeze time, number of freeze-thaw cycles, use of contact versus spray technique, and distance from the spray tip to the AK [25,26].

Other destructive therapies — Shave excision and curettage, with or without electrodesiccation, and laser ablation with carbon dioxide (CO2) or erbium:yttrium aluminum garnet (Er:YAG) lasers can be used for the treatment of isolated, hyperkeratotic AK lesions. None of these therapies has been evaluated in clinical trials, and their use is based upon limited evidence from small, observational studies and clinical experience.

Shave excision and curettage followed by electrodesiccation or cryotherapy are frequently used for AKs, particularly for hyperkeratotic lesions (see 'Patients with hypertrophic or hyperkeratotic lesions' below). Although these techniques can provide tissue for histopathologic evaluation, the specimens are usually not adequate to determine whether a lesion is invasive or intraepidermal.

PATIENTS WITH HYPERTROPHIC OR HYPERKERATOTIC LESIONS

Initial treatment — We suggest liquid nitrogen cryotherapy as the initial treatment for hypertrophic or hyperkeratotic lesions (picture 1 and algorithm 1). Because thick lesions are more resistant to liquid nitrogen, freezing times >10 seconds or repeat applications may be necessary. We typically use two freeze-thaw cycles, allowing time to thaw the lesion's peripheral rim. (See "Minor dermatologic procedures", section on 'Cryotherapy (cryosurgery)'.)

Shave removal or curettage followed by electrodesiccation to ensure hemostasis may be used as alternative treatment modalities for thick lesions that do not respond to liquid nitrogen cryotherapy. Lesion specimens should be sent for histopathologic examination to exclude invasive squamous cell carcinoma (SCC). (See 'When to biopsy' below.)

When to biopsy — A skin biopsy for histopathologic examination to exclude or confirm the presence of in situ or invasive SCC should be performed in the following circumstances [27]:

Lesions that appear indurated (a finding that suggests the possibility of SCC)

Painful, ulcerated, or bleeding lesions

Hyperkeratotic or hypertrophic actinic keratoses (AKs) that failed to resolve after standard therapies or recurred rapidly (<3 months)

A low threshold for considering the possibility of SCC is particularly important in immunocompromised patients, since these patients are more likely to have biologically aggressive lesions.

PATIENTS WITH MULTIPLE LESIONS/FIELD CANCERIZATION — Patients with actinic keratosis (AK) often present with multiple lesions and evidence of chronic actinic damage in adjacent areas. This presentation is commonly referred to as "field cancerization." Sun damage indicative of field cancerization is clinically identified by at least two of the following signs: telangiectasia, atrophy, dyspigmentation, and sand paper-like texture [14].

Patients with multiple AKs and clinical evidence of field cancerization have an increased risk of developing a cutaneous squamous cell carcinoma (cSCC). They are best treated with so-called field-directed therapies, which include topical fluorouracil, imiquimod, and photodynamic therapy (PDT), or field-directed treatment in combination with lesion-directed treatment (sequential treatment) (algorithm 1) [28].

First-line therapies

Topical fluorouracil — For patients with multiple thin lesions on the face or scalp, we suggest field treatment with topical fluorouracil cream as a first-line therapy (algorithm 1) [13,29]. Fluorouracil 5% cream is applied once or twice daily for two to four weeks until superficial erosion occurs. To improve a patient's adherence to treatment, some clinicians utilize topical corticosteroids (eg, desonide ointment 0.05%) in combination with topical fluorouracil to reduce the inflammatory response associated with treatment.

For the treatment of facial lesions, a 0.5% preparation applied once daily for up to four weeks may also be used. A 0.5% preparation is available in the United States. Once-daily application is associated with minimal systemic absorption and is better tolerated than higher-strength preparations [30]. Treatment courses of one, two, and four weeks have demonstrated superiority over placebo for the clearance of AKs, with the four-week course demonstrating the greatest benefit [31].

Fluorouracil inhibits thymidylate synthetase, a critical enzyme in the synthesis of DNA, resulting in inhibition of cell proliferation and cell death. Applied to AK lesions, fluorouracil cream causes inflammation and lesion necrosis (picture 2). Inflammation typically subsides approximately two weeks after topical fluorouracil is discontinued. It typically takes four to six weeks (two to four weeks of which are active treatment) for the skin to progress through erythema, blistering, necrosis with erosion, and re-epithelialization. In patients with extensive AK, the treated area may become extremely inflamed. Thus, pretreatment patient information and education must be thorough.

Efficacy — Multiple randomized trials and meta-analyses have documented the efficacy of topical fluorouracil alone or in combination with other topical agents for the treatment of AK [4,5,9,32]. Treatment with topical fluorouracil may also be effective for the long-term control of AKs (see 'Chemoprevention' below):

Topical fluorouracil 5% as monotherapy:

A network meta-analysis including 32 randomized trials evaluated the relative efficacy of aminolevulinic acid (ALA)-PDT, methyl aminolevulinate (MAL)-PDT, imiquimod, cryotherapy, 0.5% and 5% topical fluorouracil, topical diclofenac, and ingenol mebutate for the outcome of "complete patient clearance" [5]. Topical fluorouracil 5% was ranked as the most effective treatment, followed in order by topical fluorouracil 0.5%, ALA-PDT, imiquimod, ingenol mebutate, MAL-PDT, cryotherapy, topical diclofenac, and placebo.

A multicenter randomized trial compared the efficacy at 12 months of 5% fluorouracil cream (twice daily for four weeks), 5% imiquimod cream (once daily, three times per week for four weeks), MAL-PDT, and 0.015% ingenol mebutate gel (once daily for three consecutive days) in 624 patients with AK lesions of any grade [29]. The primary outcome was the proportion of patients who remained free from treatment failure during 12 months of follow-up after the last treatment. In a modified intention-to-treat analysis including 602 patients for whom data on primary outcome were available, the cumulative probability of treatment success (≥75 percent reduction in the number of AKs counted at baseline) for fluorouracil was 74.7 percent (95% CI 66.8-81.0). For imiquimod, MAL-PDT, and ingenol mebutate, these percentages were 53.9 percent (95% CI 45.4-61.6), 37.7 percent (95% CI 30.0-45.3), and 28.9 percent (95% CI 21.8-36.3), respectively. The rates of adverse events, including erythema, edema, erosions, blisters, scabbing, crusting, and pain, were similar in all treatment groups. A cost-effectiveness evaluation performed on data from this trial showed that topical fluorouracil treatment was more effective and less expensive compared with other therapies 12 months post-treatment [33].

Topical fluorouracil 0.5% in salicylic acid 10% – In Europe and Canada, a combination fluorouracil-salicylic acid topical solution (0.5% fluorouracil in 10% salicylic acid) is available for the treatment of slightly palpable or moderately thick, hyperkeratotic AK (grade I/II). The efficacy of this combination has been evaluated in a few randomized trials:

In one trial including 66 patients with an average of eight moderate to severe hyperkeratotic AKs on face or scalp, treatment with 0.5% fluorouracil/10% salicylic acid once daily for six weeks achieved a higher rate of histologic clearance than two cryotherapy treatments administered three weeks apart (62 versus 42 percent) [21]. The recurrence rates of cleared lesions at 14 weeks were 39 percent in the fluorouracil-salicylic acid group and 85 percent in the cryotherapy group. Adverse events, including local erythema, scabbing, and crusting, were more common in the topical fluorouracil-salicylic acid group than in the cryotherapy group (24 versus 6 percent).

In another trial, 166 patients with a 25 cm2 area of face or scalp skin on their face, bald scalp, or forehead that included 4 to 10 clinically confirmed AK lesions were treated with 0.5% fluorouracil/10% salicylic acid or vehicle for 12 weeks. Eight weeks after the end of treatment, more patients in the active treatment group than in the vehicle group achieved complete clinical clearance (69.5 versus 34.6 percent; odds ratio [OR] 4.9, 95% CI 2.3-10.5) [34]. Adverse effects occurred more frequently in the fluorouracil-salicylic acid group than in the vehicle group and included erythema, pain, inflammation, scab, and erosion.

Topical fluorouracil 5% plus calcipotriol (calcipotriene) 0.005% – The addition of calcipotriol (calcipotriene) to topical fluorouracil may enhance the efficacy of topical fluorouracil for the treatment of AKs by inducing thymic stromal lymphopoietin expression and influx of CD4+ T cells in the skin [35]. In a small, randomized trial, 131 patients with 4 to 15 AKs within a 25 cm2 area on the face, scalp, or upper extremities were treated with topical fluorouracil 5% plus 0.005% calcipotriol ointment or topical fluorouracil 5% plus vehicle twice daily for four days [35]. At eight weeks, the mean reduction in the number of AKs in all treated areas was greater in patients treated with topical fluorouracil combined with calcipotriol than in patients treated with topical fluorouracil alone (88 versus 26 percent on the face, 76 versus 6 percent on the scalp, 69 versus 10 percent on the right upper extremity, and 79 versus 16 percent on the left upper extremity).

Imiquimod — Imiquimod is an alternative to topical fluorouracil for the treatment of multiple AKs and field cancerization. Imiquimod 5% cream is typically applied to an involved area of ≤25 cm2 twice weekly for 16 weeks. The cream is applied at night, ideally at least one hour before bedtime, and washed off after eight hours.

Preparations containing 2.5% and 3.75% imiquimod are also available for the treatment of the entire face or the entire scalp. These preparations are applied once daily for two, two-week cycles separated by two weeks of no treatment.

Imiquimod is a topical immune response modifier that stimulates local cytokine induction resulting in a local inflammatory reaction characterized by erythema, pruritus, erosion, ulceration, and crusting. Some patients may experience flu-like symptoms, such as fever, chills, myalgia, and malaise. The healing time of lesions treated with imiquimod is approximately two weeks.

Efficacy — The efficacy of imiquimod for the treatment of AK has been evaluated in several randomized trials and meta-analyses [4,29,32,36]:

A meta-analysis of five randomized trials including approximately 1300 patients found that treatment with imiquimod 5% cream (two to three times per week for 12 to 16 weeks) resulted in complete resolution of AKs in 50 percent of patients compared with 5 percent with the control vehicle [36].

In a 2014 network meta-analysis comparing the relative efficacy of several treatments for AK, including three different imiquimod regimens, the absolute complete clearance rate was 63.3 percent (95% CI 45.5-81.1) for imiquimod 5% for 16 weeks, 56.3 percent (95% CI 33.8-78.8) for imiquimod 5% for 4 weeks, and 39.9 percent (95% CI 15.6-64.2) for imiquimod 3.75% for 4 weeks [37].

In a subsequent randomized trial comparing the efficacy of 5% fluorouracil cream, 5% imiquimod cream (once daily, three times per week for four weeks), MAL-PDT, and 0.015% ingenol mebutate gel in 624 patients, treatment success at 12 months for imiquimod, defined as clearance of ≥75 percent of AKs counted at baseline, was 53.9 percent (95% CI 45.4-61.6) [29].

Photodynamic therapy — Photodynamic therapy (PDT) is an effective therapy for patients with multiple AKs, although it is not widely available in office-based dermatology practices (algorithm 1). PDT consists of topical application of a photosensitizer agent (5-ALA or MAL) to the involved area, followed by exposure to a visible wavelength light source. (See "Photodynamic therapy".)

Following PDT, a localized, erythematous reaction similar to sunburn can typically be expected for four to seven days and may be accompanied by a tingling or burning sensation or pain, edema, minute vesicles, or crusting. Skin exfoliation follows the inflammatory reaction for up to a week. The most common complaint during PDT is burning or stinging during light exposure; in addition, there is a small risk of producing pigmentary changes.

Efficacy — Multiple trials and two meta-analyses have compared PDT with other therapies for AK [4,17-20,38-41]:

One meta-analysis of four randomized trials (641 participants with 2170 AKs) comparing PDT with cryotherapy found that PDT had a 14 percent greater likelihood of achieving complete lesion clearance at three months than cryotherapy [41].

In a multicenter randomized trial (624 participants) evaluating the efficacy of topical fluorouracil, imiquimod, PDT, and ingenol mebutate, the cumulative rate of treatment success (≥75 percent reduction in the number of AKs counted at baseline) at 12 months after last treatment was 37.7 percent (95% CI 30.0-45.3) for PDT [29]. All patients also underwent superficial curettage of their lesions prior to the topical field therapy, and patients could be retreated once if they did not achieve >75% clearance of lesions from baseline.

Although data are insufficient for definitive conclusions on comparative efficacy, the cosmetic outcome from PDT appears to be superior to topical fluorouracil and cryotherapy [4,41].

Standard regimens — Multiple PDT regimens have been used for treatment of AK. Depending on the topical photosensitizer used, the incubation times, light sources, and pretreatment regimens have varied across studies, making it difficult to compare outcomes:

Photosensitizers and light sources – A 10% ALA gel is the only PDT product approved by the US Food and Drug Administration (FDA) for both lesion- and field-directed PDT that can be used with narrowband red light illumination [42]. A 20% ALA solution is only used with blue light illuminators. However, blue light activation can also be used effectively and safely with the 10% ALA gel.

In a split-face study, 40 participants were randomized to 10% ALA gel or 20% ALA solution application to contiguous 25 cm2 fields containing four to eight AK lesions on either side of the face or scalp (no curettage, one-hour incubation, no occlusion) followed by blue light exposure (1000 seconds, 417 nm, 10 J/cm2) [43]. Lesions treated with the gel or solution were cleared by 97 and 95 percent, respectively, compared with baseline. Three days after the first and second treatments, more local skin reactions (erythema, crusting, and scaling or dryness) were noted in the areas treated with 20% ALA solution than in the areas treated with the 10% ALA gel.

Incubation time – The incubation time varies, depending on the photosensitizer formulation and the body site to be treated, and is usually determined by the treating clinician. As an example, the recommended incubation time is 3 hours for ALA gel and 14 to 18 hours for the ALA solution. An effect of the length of the incubation on treatment efficacy was illustrated in a randomized trial (n = 149) in which patients were treated with a self-adhesive ALA patch. The trial found that a four-hour incubation period was more effective for complete clearance of AKs than shorter incubation times of 0.5, 1, or 2 hours [44].

The incubation time may also affect the perceived pain intensity associated with the procedure. In an intrapatient-controlled, randomized trial designed to assess pain during the illumination phase of PDT, topical 20% ALA was applied to the entire face or scalp in 23 patients. Then, on one side, blue light was started immediately and continued for either 30, 45, or 60 minutes ("simultaneous PDT"), while on the contralateral side, blue light began one hour after ALA application and lasted 1000 seconds ("conventional PDT") [45]. All patients experienced significantly less pain during simultaneous illumination than with conventional regimen, and at three months post-treatment, lesion clearance was nearly identical on the two sides (58 and 59 percent for simultaneous and conventional PDT, respectively).

Standard and modified PDT regimens for the treatment of AKs are described in greater detail separately. (See "Photodynamic therapy", section on 'Standard photodynamic therapy regimens for actinic keratoses' and "Photodynamic therapy", section on 'Variations on the standard photodynamic therapy regimen'.)

Laser-assisted photodynamic therapy — Pretreatment of the involved area with ablative and nonablative laser devices appears to increase the efficacy of PDT. A meta-analysis of seven small, randomized, intraindividual trials found that laser-assisted PDT was associated with a higher likelihood of lesion clearance than PDT alone (89.5 versus 67.3 percent, respectively; relative risk 1.33, 95% CI 1.24-1.42), without a significant difference in the pain perceived by the patient [46].

Daylight photodynamic therapy — Daylight photodynamic therapy (DLPDT) using topical MAL cream (Metvix) or ALA nanoemulsion-based gel (Ameluz) is an alternative to conventional PDT for the treatment of patients with multiple AKs [47,48]. DLPDT requires dry and warm weather conditions (outside temperature >10°C or 50°F). A high sun protection factor (SPF) broad-spectrum sunscreen that does not contain minerals (zinc oxide and titanium dioxide also filter visible light) is applied 15 minutes before the photosensitizing cream or emulsion. Thirty minutes after the application of the photosensitizer, patients are sent outside for two hours. Advantages of DLPDT include reduced to nearly absent pain, low cost, and ability to treat larger areas. (See "Photodynamic therapy", section on 'Daylight photodynamic therapy'.)

Multiple randomized trials and systematic reviews have shown that lesion clearance rates for DLPDT are similar to those seen with conventional PDT [49-53]. In an intraindividual right-left comparison study, 46 patients with a total of 453 AKs were treated with DLPDT on one side of face or scalp, followed by conventional PDT on the other side [54]. Three months after treatment, the complete response rate was 78 percent for DLPDT versus 81 percent for conventional PDT. At 12 months, the response rate decreased to 72 and 74 percent for DLPDT and conventional PDT, respectively.

Sequential therapies — Patients with multiple thin AKs who also have discrete, hyperkeratotic lesions may benefit from the sequential use of lesion-directed and field-directed therapies (algorithm 1). For these patients, we suggest cryotherapy for the treatment of individual lesions followed by the application of fluorouracil cream to the involved area.

The sequential use of lesion-directed therapies and field-directed therapies can optimize the clearance of visible, discrete lesions as well as subclinical lesions in photodamaged skin [3,4,55,56]. Applying a topical treatment after a lesion-directed approach may reduce the potential of subclinical lesions for progression to visible AKs. Conversely, pretreating areas of AK involvement with topical agents may reveal subclinical lesions that can be treated with destructive methods, such as cryotherapy.

Examples of sequential treatments that have been evaluated in randomized trials include:

Cryotherapy before or after topical fluorouracil [57,58]

Cryotherapy before or after topical imiquimod [59]

PDT before or after topical fluorouracil [60]

PDT before or after topical imiquimod [60]

A randomized, vehicle-controlled trial compared the efficacy of cryotherapy alone with cryotherapy following topical fluorouracil applications for the treatment of AKs in 144 patients with five or more visible or palpable AKs on the face. After six months, 30 percent of patients treated with combination therapy remained clear of AKs versus 8 percent of those treated with cryotherapy alone [57].

A 2019 meta-analysis of 10 randomized trials (277 patients) evaluating PDT combined with topical therapies, including imiquimod, topical fluorouracil, tazarotene, and ingenol mebutate, found that patients treated with combination therapy had a higher likelihood of complete clearance at the end of treatment (relative risk 1.63, 95% CI 1.15-2.33) [60].

Second-line therapies — Alternative therapies for patients with multiple AKs who respond poorly or cannot tolerate the adverse effects of first-line therapies include ingenol mebutate and topical diclofenac.

Ingenol mebutate — Due to safety concerns regarding a possible increase in the risk of cSCC [61-63], the use of ingenol mebutate for the field treatment of AKs is not recommended. (See 'Skin cancer risk and marketing suspension in Europe and Canada' below.)

Ingenol mebutate, a substance derived from the sap of the Euphorbia peplus plant, is a topical treatment for AK available in the United States, but not in Europe, for the treatment of nonhypertrophic AKs. It is available in two gel formulations: 0.015%, indicated for a three-day treatment course on the face or scalp, and 0.05%, indicated for a two-day treatment course on the trunk or extremities. The treated areas should not exceed 25 cm2.

The mechanism of action of ingenol mebutate involves two stages: initial disruption of cell plasma membranes and mitochondria leading to cell necrosis (chemoablation) followed by the induction of neutrophil-mediated, antibody-dependent cellular cytotoxicity that eliminates remaining tumor cells [64,65].

The efficacy of ingenol mebutate compared with vehicle for the treatment of AK was examined in several randomized trials demonstrating complete clearance rates of approximately 40 percent at eight weeks [66-68]. At 12 months, clearance rates after retreatment of residual lesions were approximately 50 percent.

An even lower clearance rate was found in a multicenter, randomized trial comparing the efficacy at 12 months of 5% fluorouracil cream, 5% imiquimod cream, MAL-PDT, and 0.015% ingenol mebutate gel in 624 patients with AK on the face or scalp [29]. In this trial, the cumulative probability of treatment success was only 28.9 percent (95% CI 21.8-36.3) for ingenol mebutate. For topical fluorouracil, imiquimod, and MAL-PDT, these rates were 74.7 percent (95% CI 66.8-81.0), 53.9 percent (95% CI 45.4-61.6), and 37.7 percent (95% CI 30.0-45.3), respectively.

Common adverse events associated with ingenol mebutate therapy include erythema, scale, crusting, edema, vesiculation, pustulation, and ulceration [69]. Patients may complain of symptoms of pain, pruritus, or irritation.

Rare adverse effects reported to the US FDA include severe allergic reactions (eg, throat tightness, difficulty breathing, swelling of the lips or tongue), herpes zoster, and severe eye injury from accidental transfer of the gel from the hands even after washing [70].

Skin cancer risk and marketing suspension in Europe and Canada — Previous case reports described the development of invasive squamous cell carcinomas (SCCs) as soon as a few weeks after field treatment of AKs with ingenol mebutate [61,62]. It is uncertain whether these lesions represent pre-existing, but clinically inapparent, lesions or rapidly growing tumors induced by ingenol mebutate.

However, the European Medicines Agency's safety committee (Pharmacovigilance Risk Assessment Committee) recommended suspending ingenol mebutate's marketing authorization in Europe as a precaution, based on the results of a three-year study in 484 patients showing a higher incidence of skin malignancy with ingenol mebutate compared with imiquimod (3.3 versus 0.4 percent, respectively) [63]. Moreover, a higher incidence of skin tumors occurred in the ingenol mebutate arm of an eight-week, vehicle-controlled trial in 1262 patients (1 percent in the ingenol mebutate arm versus 0.1 percent in the vehicle arm) [63].

In July 2020, Health Canada conducted a safety review of ingenol mebutate gel and concluded that there may be a link between its use and an increased risk of nonmelanoma skin cancer and that the benefits of treatment do not outweigh the potential risk of skin cancer. As a result, ingenol mebutate gel was withdrawn from the Canadian market at Health Canada's request [71].

Topical diclofenac — Topical diclofenac 3% in 2.5% hyaluronan gel is a therapeutic option for AKs [4,72,73]. However, its use is limited by its low efficacy, compared with other topical treatments, and very long treatment course. Diclofenac is applied twice daily for 60 to 90 days. The most common adverse effects of diclofenac gel are dry skin, pruritus, erythema, and rash at the application site. Twice-daily treatment with diclofenac gel appears to be better tolerated than twice-daily application of topical fluorouracil [74], although topical diclofenac may be less effective than topical fluorouracil and requires a substantially longer treatment time.

The mechanism of action of topical diclofenac, a nonsteroidal anti-inflammatory drug that inhibits both cyclooxygenase and upregulation of the arachidonic acid cascade, is unclear. Because the production of prostaglandins from arachidonic acid may play a role in ultraviolet B-induced skin cancer (eg, basal cell carcinoma, SCC), inhibition of this cascade by diclofenac may explain its efficacy in the treatment of AKs.

The efficacy of topical diclofenac for the treatment of AK has been evaluated in several randomized trials. A meta-analysis of three trials (364 patients) found that treatment with diclofenac gel resulted in complete resolution of AKs in approximately 40 percent of patients versus 12 percent with placebo [75]. The efficacy of diclofenac may be lessened for AKs on sites other than the face [4].

Tirbanibulin — Tirbanibulin, a synthetic inhibitor of tubulin polymerization and Src kinase signaling, is capable of inducing p53 expression, arrest of cell division and mitosis in proliferating cell populations, and apoptosis. In 2020, a formulation of tirbanibulin 1% ointment was approved in the United States for field treatment of AK. Tirbanibulin is applied once daily to up to a 25 cm2 area for five consecutive days.

In two identical, randomized, phase 3 trials, a 25 cm2 contiguous area with four to eight AKs on the face or scalp of 702 adult patients was treated with either topical tirbanibulin 1% ointment or vehicle (placebo) ointment once daily for five consecutive days [76]. In the pooled data of the two trials, at day 57, complete clearance of AK in the treated areas occurred in 174 of 353 patients (49 percent) in the tirbanibulin groups and in 30 of 349 patients (9 percent) in the vehicle groups (difference, 41 percentage points; 95% CI 35-47). Local skin reactions at the site of application in the two trials were mostly mild or moderate erythema, flaking, or scaling, with a mean maximum composite local skin reaction severity score of 4.0 and 4.3 (out of a highest possible score of 18), and resolved by day 29. Of the patients who had achieved clearance of all AKs in the treated area at day 57, 27 percent maintained complete clearance at one year.

Tirbanibulin may be an alternative therapy for patients who do not tolerate the protracted course of treatment and the more severe adverse effects of other topical treatments, such as topical fluorouracil or imiquimod (see 'Topical fluorouracil' above and 'Imiquimod' above). However, studies comparing the safety and long-term efficacy of tirbanibulin with those of other available agents for the field treatment of AK are lacking. The high cost of tirbanibulin may be a concern.

Other therapies

Retinoids — Topical retinoids have been studied for the treatment of AKs. In a nine-month, randomized trial of 90 patients with multiple AKs, adapalene gel (0.1% or 0.3%) applied daily as field therapy for four weeks and twice daily thereafter significantly, but modestly, decreased the number of AKs compared with placebo and also appeared to improve the appearance of photodamaged skin [77]. In contrast, a randomized trial including 1131 patients found that long-term use of topical tretinoin 0.1% cream was ineffective in reducing the number of AKs [78]. Additional studies are necessary to determine the role of topical retinoids in the management of these lesions.

Systemic retinoids have been used in the secondary prevention of AKs in renal transplant recipients. A 12-month study found that low-dose acitretin therapy (20 mg daily) is safe, well tolerated, and partially effective in chemoprophylaxis of nonmelanoma skin cancer [79]. (See "Prevention and management of skin cancer in solid organ transplant recipients", section on 'Chemoprevention for SCC'.)

Field ablation treatments

Dermabrasion — Dermabrasion, or surgical skin planing, may be used for treating large areas (eg, a sun-damaged bald scalp or forehead) when lesions are too large to treat effectively with topical preparations. Dermabrasion is a procedure in which a specialized handheld instrument is used to "sand" the skin to improve skin contour. The surface of the epidermis of the skin (the stratum corneum) is removed, leaving the skin red and raw looking. The procedure can be very painful and usually requires procedural sedation and analgesia.

A retrospective study of 23 patients treated with dermabrasion found that 96 percent remained free of new AKs at one year after treatment. However, the benefits of dermabrasion gradually diminished, with 83 percent clear at two years and 54 percent clear at five years [80].

Chemical peels — A chemical peel is a procedure in which a topically applied wounding agent creates smooth, rejuvenated skin by way of a wound repair process, collagen remodeling, and exfoliation. Usually, this procedure is performed on the face. Medium-depth peels cause injury at the level of the papillary dermis and should be applied by a clinician in a controlled setting. Prior to treatment, patients should be educated about possible complications of a stinging or burning sensation, visible peeling (which usually lasts five to seven days), pigmentary changes, infections, and, rarely, scarring. (See "Chemical peels: Procedures and complications".)

In a nonrandomized, split-face study, Jessner's solution plus 35% trichloroacetic acid (TCA) demonstrated similar efficacy and decreased rates of morbidity when compared with topical fluorouracil, with a reduction of 75 percent in the number of visible AKs for both treatments [81]. TCA 35% peel was compared with ALA-PDT for the treatment of AK in a split-area, randomized trial with 28 patients [82]. At 12 months, complete clearance was noted for 49 percent of AKs treated with TCA compared with 74 percent of those treated with ALA-PDT.

Laser resurfacing — The use of ablative laser resurfacing with carbon dioxide (CO2) and erbium:yttrium aluminum garnet (Er:YAG) lasers and nonablative fractional lasers has been reported in a few small, randomized trials and uncontrolled studies with variable results [83-87]. In one study including 24 patients with facial photodamage and AKs treated with up to four treatments with a fractionated 1927 nm nonablative thulium laser, the number of AKs was reduced by 87 percent at six months [83]. (See "Ablative laser resurfacing for skin rejuvenation".)

SPECIAL BODY SITES

Periocular area — The use of topical agents (eg, topical fluorouracil, imiquimod) is generally avoided for the treatment of actinic keratoses (AKs) on the eyelids and periorbital area due to the high risk of conjunctival injury. Cautious cryotherapy, sometimes applied with a cotton swab, may be a safer approach.

Dorsal hands/forearm/legs — AK lesions in these areas are generally thick and more treatment resistant. For AKs on the dorsum of the hands, cryotherapy followed by topical therapies (eg, topical fluorouracil, imiquimod) or photodynamic therapy is often used [88-90]. (See 'Sequential therapies' above.)

SOLID ORGAN TRANSPLANT RECIPIENTS — Local destructive therapies, such as cryotherapy, curettage, or carbon dioxide laser, can be used for the management of individual actinic keratoses (AKs) in solid organ transplant recipients [91]. Field-directed therapies, such as photodynamic therapy (PDT), imiquimod, and topical fluorouracil, are often preferred treatment options for patients with numerous lesions. Because these patients often have an inadequate response to therapy, repeated treatment is often necessary. Lesions that do not respond to multiple treatments should be excised and sent for histopathologic evaluation to exclude malignancy. (See "Prevention and management of skin cancer in solid organ transplant recipients".)

Limited evidence from a small number of randomized trials favors the use of PDT over other treatment modalities in this patient population:

A 2019 systematic review of eight small, randomized trials including 242 solid organ transplant recipients found that methyl aminolevulinate (MAL)-PDT was generally associated with a higher clearance rate compared with imiquimod 5% cream or topical fluorouracil 5% cream [92]. The complete clearance rates at three to four months after the last treatment varied across studies, ranging from 40 to 76 percent for MAL-PDT and 28 to 62 percent for imiquimod. The studies were heterogeneous and generally of poor methodologic quality. In one included trial comparing MAL-PDT with topical 5% fluorouracil in eight patients, the clearance rates at three months for MAL-PDT and topical fluorouracil were 89 and 11 percent, respectively [93].

Similar results were provided by a meta-analysis of five split-side, randomized trials that included 86 participants [94]. The complete response rate in the PDT groups (ranging from 74 to 89 percent) was higher than in the control groups (imiquimod, ablative fractional laser, topical fluorouracil, or placebo), with a pooled risk difference of 0.77 (95% CI 0.6-0.94) and 0.5 (95% CI 0.22-0.79) in predivided lesional areas and number of lesions, respectively.

FOLLOW-UP — Ongoing monitoring for lesion recurrence and cutaneous malignancies is required in all patients with a history of actinic keratoses. (See "Cutaneous squamous cell carcinoma: Primary and secondary prevention" and "Prevention and management of skin cancer in solid organ transplant recipients", section on 'Follow-up'.)

PREVENTION

Sun protection — Sun avoidance, especially during the peak hours in spring and summer, use of protective clothing, and regular use of broad-spectrum sunscreens are of key importance for the prevention of actinic keratoses (AKs). (See "Selection of sunscreen and sun-protective measures".)

The efficacy of sunscreens in reducing the development of AKs has been demonstrated by several randomized trials [95-97]. Daily sunscreen use may also decrease the risk of AK and squamous cell carcinoma (SCC) in immunosuppressed organ transplant recipients [98].

Chemoprevention — Treatment with topical fluorouracil or imiquimod may be effective for the long-term control of AKs:

In a randomized trial, 932 participants with a mean total count of 11 AKs on the face and ears were treated with 5% fluorouracil cream or vehicle twice daily for four weeks and followed up for an average time of 2.6 years [99]. At six months, the number of AKs on the face or ears was reduced to 3 (73 percent reduction) and 8.1 (24 percent reduction) per participant in the treatment and control group, respectively. The complete clearance rate at six months was 38 percent in the topical fluorouracil group and 17 percent in the control group. Compared with the control group, the topical fluorouracil group was less likely to receive any spot treatment for AKs during the follow-up period and had fewer AKs at 42 months (4.3 versus 5.7).

A subsequent subgroup analysis showed that fewer individuals in the topical fluorouracil group than in the placebo group had one or more new AKs for up to 24 months after randomization and that the number of new AKs per person was significantly lower in the topical fluorouracil group compared with the placebo group at 24 months (2.18 versus 3.68) [100].

A pooled analysis of two randomized trials that included a total of 479 immunocompetent patients with 5 to 10 typical, visible AK lesions in one contiguous area of up to 50 cm2 on the face or scalp evaluated the long-term efficacy of diclofenac applied twice daily for 12 weeks compared with two, four-week cycles of imiquimod administered four weeks apart [101]. The primary efficacy endpoint (histologic change to a higher histologic grade of AK or development of invasive SCC) in the treated area was observed in more patients in the diclofenac group than in the imiquimod group up to month 36 post-treatment (11 versus 5.4 percent, respectively; absolute risk difference -5.6 percent, 95% CI -10.7 to -0.7).

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Actinic keratosis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Actinic keratosis (The Basics)")

SUMMARY AND RECOMMENDATIONS

Treatment options for actinic keratosis (AK) include lesion-directed, destructive therapies (eg, surgery, cryotherapy, dermabrasion) and field-directed therapies with topical medications (eg, fluorouracil, imiquimod, ingenol mebutate) or photodynamic therapy (PDT) (algorithm 1). Field-directed therapies are indicated for the treatment of areas with multiple AKs, subclinical lesions that are not detected by visual inspection or palpation, and field cancerization (presence of genetically altered cells at risk of malignant transformation in clinically normal skin).

For patients with few isolated AKs, we suggest treatment with liquid nitrogen cryotherapy rather than other destructive treatments (Grade 2C). A freezing time of 5 to 10 seconds is usually sufficient. Cryotherapy can be quickly performed in an office-based setting, is inexpensive, does not require local anesthesia, is generally well tolerated by patients, and, in most cases, results in good or excellent cosmetic outcome. (See 'Patients with one or few discrete lesions' above and 'Patients with hypertrophic or hyperkeratotic lesions' above.)

For hyperkeratotic or hypertrophic lesions (picture 1), we suggest liquid nitrogen cryotherapy as the initial treatment (Grade 2C). As thick lesions are more resistant to liquid nitrogen, freezing times >10 seconds or repeat applications may be necessary. We typically use two freeze-thaw cycles. Shave removal or curettage may be used as alternative treatment modalities, particularly for suspicious lesions requiring histopathologic examination (eg, indurated lesions, painful or ulcerated lesions, lesions recurring in <3 months). (See 'Patients with hypertrophic or hyperkeratotic lesions' above and 'When to biopsy' above.)

For patients with multiple thin lesions on the face and/or scalp, we suggest field treatment with 5% topical fluorouracil (Grade 2B). Alternative therapies include imiquimod, tirbanibulin, or PDT. However, based on available data, these modalities appear to be less effective. (See 'Patients with multiple lesions/field cancerization' above.)

Patients with multiple AKs who also have hyperkeratotic or hypertrophic lesions (picture 1) may benefit from the sequential use of lesion-directed and field-directed therapies. For these patients, we suggest liquid nitrogen cryotherapy for the treatment of hyperkeratotic or hypertrophic lesions followed by the application of fluorouracil cream on the involved area. (See 'Sequential therapies' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Joseph Jorizzo, MD, who contributed to an earlier version of this topic review.

  1. Criscione VD, Weinstock MA, Naylor MF, et al. Actinic keratoses: Natural history and risk of malignant transformation in the Veterans Affairs Topical Tretinoin Chemoprevention Trial. Cancer 2009; 115:2523.
  2. Marks R, Rennie G, Selwood TS. Malignant transformation of solar keratoses to squamous cell carcinoma. Lancet 1988; 1:795.
  3. Ceilley RI, Jorizzo JL. Current issues in the management of actinic keratosis. J Am Acad Dermatol 2013; 68:S28.
  4. Gupta AK, Paquet M, Villanueva E, Brintnell W. Interventions for actinic keratoses. Cochrane Database Syst Rev 2012; 12:CD004415.
  5. Gupta AK, Paquet M. Network meta-analysis of the outcome 'participant complete clearance' in nonimmunosuppressed participants of eight interventions for actinic keratosis: a follow-up on a Cochrane review. Br J Dermatol 2013; 169:250.
  6. Nashan D, Meiss F, Müller M. Therapeutic strategies for actinic keratoses--a systematic review. Eur J Dermatol 2013; 23:14.
  7. Rahvar M, Lamel SA, Maibach HI. Randomized, vehicle-controlled trials of topical 5-fluorouracil therapy for actinic keratosis treatment: an overview. Immunotherapy 2012; 4:939.
  8. Askew DA, Mickan SM, Soyer HP, Wilkinson D. Effectiveness of 5-fluorouracil treatment for actinic keratosis--a systematic review of randomized controlled trials. Int J Dermatol 2009; 48:453.
  9. Werner RN, Stockfleth E, Connolly SM, et al. Evidence- and consensus-based (S3) Guidelines for the Treatment of Actinic Keratosis - International League of Dermatological Societies in cooperation with the European Dermatology Forum - Short version. J Eur Acad Dermatol Venereol 2015; 29:2069.
  10. de Berker D, McGregor JM, Mohd Mustapa MF, et al. British Association of Dermatologists' guidelines for the care of patients with actinic keratosis 2017. Br J Dermatol 2017; 176:20.
  11. Poulin Y, Lynde CW, Barber K, et al. Non-melanoma Skin Cancer in Canada Chapter 3: Management of Actinic Keratoses. J Cutan Med Surg 2015; 19:227.
  12. Heppt MV, Leiter U, Steeb T, et al. S3 guideline for actinic keratosis and cutaneous squamous cell carcinoma - short version, part 1: diagnosis, interventions for actinic keratoses, care structures and quality-of-care indicators. J Dtsch Dermatol Ges 2020; 18:275.
  13. Eisen DB, Asgari MM, Bennett DD, et al. Guidelines of care for the management of actinic keratosis. J Am Acad Dermatol 2021; 85:e209.
  14. Figueras Nart I, Cerio R, Dirschka T, et al. Defining the actinic keratosis field: a literature review and discussion. J Eur Acad Dermatol Venereol 2018; 32:544.
  15. Noels EC, Hollestein LM, van Egmond S, et al. Healthcare utilization and management of actinic keratosis in primary and secondary care: a complementary database analysis. Br J Dermatol 2019; 181:544.
  16. Heppt MV, Steeb T, Ruzicka T, Berking C. Cryosurgery combined with topical interventions for actinic keratosis: a systematic review and meta-analysis. Br J Dermatol 2019; 180:740.
  17. Morton C, Campbell S, Gupta G, et al. Intraindividual, right-left comparison of topical methyl aminolaevulinate-photodynamic therapy and cryotherapy in subjects with actinic keratoses: a multicentre, randomized controlled study. Br J Dermatol 2006; 155:1029.
  18. Szeimies RM, Karrer S, Radakovic-Fijan S, et al. Photodynamic therapy using topical methyl 5-aminolevulinate compared with cryotherapy for actinic keratosis: A prospective, randomized study. J Am Acad Dermatol 2002; 47:258.
  19. Freeman M, Vinciullo C, Francis D, et al. A comparison of photodynamic therapy using topical methyl aminolevulinate (Metvix) with single cycle cryotherapy in patients with actinic keratosis: a prospective, randomized study. J Dermatolog Treat 2003; 14:99.
  20. Kaufmann R, Spelman L, Weightman W, et al. Multicentre intraindividual randomized trial of topical methyl aminolaevulinate-photodynamic therapy vs. cryotherapy for multiple actinic keratoses on the extremities. Br J Dermatol 2008; 158:994.
  21. Simon JC, Dominicus R, Karl L, et al. A prospective randomized exploratory study comparing the efficacy of once-daily topical 0.5% 5-fluorouracil in combination with 10.0% salicylic acid (5-FU/SA) vs. cryosurgery for the treatment of hyperkeratotic actinic keratosis. J Eur Acad Dermatol Venereol 2015; 29:881.
  22. Foley P, Merlin K, Cumming S, et al. A comparison of cryotherapy and imiquimod for treatment of actinic keratoses: lesion clearance, safety, and skin quality outcomes. J Drugs Dermatol 2011; 10:1432.
  23. Krawtchenko N, Roewert-Huber J, Ulrich M, et al. A randomised study of topical 5% imiquimod vs. topical 5-fluorouracil vs. cryosurgery in immunocompetent patients with actinic keratoses: a comparison of clinical and histological outcomes including 1-year follow-up. Br J Dermatol 2007; 157 Suppl 2:34.
  24. Zane C, Facchinetti E, Rossi MT, et al. Cryotherapy is preferable to ablative CO2 laser for the treatment of isolated actinic keratoses of the face and scalp: a randomized clinical trial. Br J Dermatol 2014; 170:1114.
  25. Thai KE, Fergin P, Freeman M, et al. A prospective study of the use of cryosurgery for the treatment of actinic keratoses. Int J Dermatol 2004; 43:687.
  26. Berman B, Shabbir AQ, MacNeil T, Knudsen KM. Variables in Cryosurgery Technique Associated With Clearance of Actinic Keratosis. Dermatol Surg 2017; 43:424.
  27. Dréno B, Amici JM, Basset-Seguin N, et al. Management of actinic keratosis: a practical report and treatment algorithm from AKTeam™ expert clinicians. J Eur Acad Dermatol Venereol 2014; 28:1141.
  28. Cornejo CM, Jambusaria-Pahlajani A, Willenbrink TJ, et al. Field cancerization: Treatment. J Am Acad Dermatol 2020; 83:719.
  29. Jansen MHE, Kessels JPHM, Nelemans PJ, et al. Randomized Trial of Four Treatment Approaches for Actinic Keratosis. N Engl J Med 2019; 380:935.
  30. Levy S, Furst K, Chern W. A pharmacokinetic evaluation of 0.5% and 5% fluorouracil topical cream in patients with actinic keratosis. Clin Ther 2001; 23:908.
  31. Weiss J, Menter A, Hevia O, et al. Effective treatment of actinic keratosis with 0.5% fluorouracil cream for 1, 2, or 4 weeks. Cutis 2002; 70:22.
  32. Gupta AK, Davey V, Mcphail H. Evaluation of the effectiveness of imiquimod and 5-fluorouracil for the treatment of actinic keratosis: Critical review and meta-analysis of efficacy studies. J Cutan Med Surg 2005; 9:209.
  33. Jansen MHE, Kessels JPHM, Merks I, et al. A trial-based cost-effectiveness analysis of topical 5-fluorouracil vs. imiquimod vs. ingenol mebutate vs. methyl aminolaevulinate conventional photodynamic therapy for the treatment of actinic keratosis in the head and neck area performed in the Netherlands. Br J Dermatol 2020; 183:738.
  34. Stockfleth E, von Kiedrowski R, Dominicus R, et al. Efficacy and Safety of 5-Fluorouracil 0.5%/Salicylic Acid 10% in the Field-Directed Treatment of Actinic Keratosis: A Phase III, Randomized, Double-Blind, Vehicle-Controlled Trial. Dermatol Ther (Heidelb) 2017; 7:81.
  35. Cunningham TJ, Tabacchi M, Eliane JP, et al. Randomized trial of calcipotriol combined with 5-fluorouracil for skin cancer precursor immunotherapy. J Clin Invest 2017; 127:106.
  36. Hadley G, Derry S, Moore RA. Imiquimod for actinic keratosis: systematic review and meta-analysis. J Invest Dermatol 2006; 126:1251.
  37. Vegter S, Tolley K. A network meta-analysis of the relative efficacy of treatments for actinic keratosis of the face or scalp in Europe. PLoS One 2014; 9:e96829.
  38. Serra-Guillén C, Nagore E, Hueso L, et al. A randomized pilot comparative study of topical methyl aminolevulinate photodynamic therapy versus imiquimod 5% versus sequential application of both therapies in immunocompetent patients with actinic keratosis: clinical and histologic outcomes. J Am Acad Dermatol 2012; 66:e131.
  39. Hadley J, Tristani-Firouzi P, Hull C, et al. Results of an investigator-initiated single-blind split-face comparison of photodynamic therapy and 5% imiquimod cream for the treatment of actinic keratoses. Dermatol Surg 2012; 38:722.
  40. Sotiriou E, Apalla Z, Maliamani F, et al. Intraindividual, right-left comparison of topical 5-aminolevulinic acid photodynamic therapy vs. 5% imiquimod cream for actinic keratoses on the upper extremities. J Eur Acad Dermatol Venereol 2009; 23:1061.
  41. Patel G, Armstrong AW, Eisen DB. Efficacy of photodynamic therapy vs other interventions in randomized clinical trials for the treatment of actinic keratoses: a systematic review and meta-analysis. JAMA Dermatol 2014; 150:1281.
  42. Ameluz [prescribing information]. Wakefield, MA: Biofrontera Inc.; 2016.
  43. Nestor MS, Berman B, Patel J, Lawson A. Safety and Efficacy of Aminolevulinic Acid 10% Topical Gel versus Aminolevulinic Acid 20% Topical Solution Followed by Blue-light Photodynamic Therapy for the Treatment of Actinic Keratosis on the Face and Scalp: A Randomized, Double-blind Study. J Clin Aesthet Dermatol 2019; 12:32.
  44. Hauschild A, Popp G, Stockfleth E, et al. Effective photodynamic therapy of actinic keratoses on the head and face with a novel, self-adhesive 5-aminolaevulinic acid patch. Exp Dermatol 2009; 18:116.
  45. Kaw U, Ilyas M, Bullock T, et al. A regimen to minimize pain during blue light photodynamic therapy of actinic keratoses: Bilaterally controlled, randomized trial of simultaneous versus conventional illumination. J Am Acad Dermatol 2020; 82:862.
  46. Steeb T, Schlager JG, Kohl C, et al. Laser-assisted photodynamic therapy for actinic keratosis: A systematic review and meta-analysis. J Am Acad Dermatol 2019; 80:947.
  47. Wulf HC. Photodynamic Therapy in Daylight for Actinic Keratoses. JAMA Dermatol 2016; 152:631.
  48. Dirschka T, Ekanayake-Bohlig S, Dominicus R, et al. A randomized, intraindividual, non-inferiority, Phase III study comparing daylight photodynamic therapy with BF-200 ALA gel and MAL cream for the treatment of actinic keratosis. J Eur Acad Dermatol Venereol 2019; 33:288.
  49. Rubel DM, Spelman L, Murrell DF, et al. Daylight photodynamic therapy with methyl aminolevulinate cream as a convenient, similarly effective, nearly painless alternative to conventional photodynamic therapy in actinic keratosis treatment: a randomized controlled trial. Br J Dermatol 2014; 171:1164.
  50. Lacour JP, Ulrich C, Gilaberte Y, et al. Daylight photodynamic therapy with methyl aminolevulinate cream is effective and nearly painless in treating actinic keratoses: a randomised, investigator-blinded, controlled, phase III study throughout Europe. J Eur Acad Dermatol Venereol 2015; 29:2342.
  51. Zhao W, Guan M, Nong X, et al. The safety and efficacy of daylight photodynamic therapy in the treatment of actinic keratoses: a systematic review and meta-analysis. Int J Dermatol 2019; 58:159.
  52. Tomás-Velázquez A, Redondo P. Switching From Conventional Photodynamic Therapy to Daylight Photodynamic Therapy For Actinic Keratoses: Systematic Review and Meta-analysis. Actas Dermosifiliogr 2017; 108:282.
  53. Mei X, Wang L, Zhang R, Zhong S. Daylight versus conventional photodynamic therapy for the treatment of actinic keratosis: A meta-analysis of randomized controlled trials. Photodiagnosis Photodyn Ther 2019; 25:23.
  54. Sotiriou E, Evangelou G, Papadavid E, et al. Conventional vs. daylight photodynamic therapy for patients with actinic keratosis on face and scalp: 12-month follow-up results of a randomized, intra-individual comparative analysis. J Eur Acad Dermatol Venereol 2018; 32:595.
  55. Martin GM. Impact of interval and combination therapies on the management of actinic keratosis: review and clinical considerations. J Dermatolog Treat 2011; 22:288.
  56. Stockfleth E. The paradigm shift in treating actinic keratosis: a comprehensive strategy. J Drugs Dermatol 2012; 11:1462.
  57. Jorizzo J, Weiss J, Furst K, et al. Effect of a 1-week treatment with 0.5% topical fluorouracil on occurrence of actinic keratosis after cryosurgery: a randomized, vehicle-controlled clinical trial. Arch Dermatol 2004; 140:813.
  58. Jorizzo J, Weiss J, Vamvakias G. One-week treatment with 0.5% fluorouracil cream prior to cryosurgery in patients with actinic keratoses: a double-blind, vehicle-controlled, long-term study. J Drugs Dermatol 2006; 5:133.
  59. Tan JK, Thomas DR, Poulin Y, et al. Efficacy of imiquimod as an adjunct to cryotherapy for actinic keratoses. J Cutan Med Surg 2007; 11:195.
  60. Heppt MV, Steeb T, Leiter U, Berking C. Efficacy of photodynamic therapy combined with topical interventions for the treatment of actinic keratosis: a meta-analysis. J Eur Acad Dermatol Venereol 2019; 33:863.
  61. Moreno Romero JA, Campoy A, Perez N, et al. Rapidly-growing squamous cell carcinoma shortly after treatment with ingenol mebutate for actinic keratoses: report of two cases. Br J Dermatol 2015; 173:1514.
  62. Bettencourt MS. Effect of Field Treatment of Actinic Keratosis With Ingenol Mebutate Gel on the Identification of Lesions for Biopsy. J Drugs Dermatol 2015; 14:813.
  63. https://www.ema.europa.eu/en/news/ema-suspends-picato-precaution-while-review-skin-cancer-risk-continues (Accessed on May 12, 2020).
  64. Ogbourne SM, Hampson P, Lord JM, et al. Proceedings of the First International Conference on PEP005. Anticancer Drugs 2007; 18:357.
  65. Rosen RH, Gupta AK, Tyring SK. Dual mechanism of action of ingenol mebutate gel for topical treatment of actinic keratoses: rapid lesion necrosis followed by lesion-specific immune response. J Am Acad Dermatol 2012; 66:486.
  66. Lebwohl M, Swanson N, Anderson LL, et al. Ingenol mebutate gel for actinic keratosis. N Engl J Med 2012; 366:1010.
  67. Garbe C, Basset-Seguin N, Poulin Y, et al. Efficacy and safety of follow-up field treatment of actinic keratosis with ingenol mebutate 0·015% gel: a randomized, controlled 12-month study. Br J Dermatol 2016; 174:505.
  68. Ulrich M, Reinhold U, Skov T, et al. Histological examination confirms clinical clearance of actinic keratoses following treatment with ingenol mebutate 0·05% gel. Br J Dermatol 2017; 176:71.
  69. Martin G, Swanson N. Clinical findings using ingenol mebutate gel to treat actinic keratoses. J Am Acad Dermatol 2013; 68:S39.
  70. www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm459311.htm (Accessed on August 25, 2015).
  71. https://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2020/74193a-eng.php (Accessed on October 29, 2020).
  72. Rivers JK, Arlette J, Shear N, et al. Topical treatment of actinic keratoses with 3.0% diclofenac in 2.5% hyaluronan gel. Br J Dermatol 2002; 146:94.
  73. Wolf JE Jr, Taylor JR, Tschen E, Kang S. Topical 3.0% diclofenac in 2.5% hyaluronan gel in the treatment of actinic keratoses. Int J Dermatol 2001; 40:709.
  74. Smith SR, Morhenn VB, Piacquadio DJ. Bilateral comparison of the efficacy and tolerability of 3% diclofenac sodium gel and 5% 5-fluorouracil cream in the treatment of actinic keratoses of the face and scalp. J Drugs Dermatol 2006; 5:156.
  75. Pirard D, Vereecken P, Mélot C, Heenen M. Three percent diclofenac in 2.5% hyaluronan gel in the treatment of actinic keratoses: a meta-analysis of the recent studies. Arch Dermatol Res 2005; 297:185.
  76. Blauvelt A, Kempers S, Lain E, et al. Phase 3 Trials of Tirbanibulin Ointment for Actinic Keratosis. N Engl J Med 2021; 384:512.
  77. Kang S, Goldfarb MT, Weiss JS, et al. Assessment of adapalene gel for the treatment of actinic keratoses and lentigines: a randomized trial. J Am Acad Dermatol 2003; 49:83.
  78. Weinstock MA, Bingham SF, VATTC Trial Group. High-dose topical tretinoin for reducing multiplicity of actinic keratoses (abstract). J Invest Dermatol 2010; 130 Suppl 1:S63.
  79. Carneiro RV, Sotto MN, Azevedo LS, et al. Acitretin and skin cancer in kidney transplanted patients. Clinical and histological evaluation and immunohistochemical analysis of lymphocytes, natural killer cells and Langerhans' cells in sun exposed and sun protected skin. Clin Transplant 2005; 19:115.
  80. Coleman WP 3rd, Yarborough JM, Mandy SH. Dermabrasion for prophylaxis and treatment of actinic keratoses. Dermatol Surg 1996; 22:17.
  81. Lawrence N, Cox SE, Cockerell CJ, et al. A comparison of the efficacy and safety of Jessner's solution and 35% trichloroacetic acid vs 5% fluorouracil in the treatment of widespread facial actinic keratoses. Arch Dermatol 1995; 131:176.
  82. Holzer G, Pinkowicz A, Radakovic S, et al. Randomized controlled trial comparing 35% trichloroacetic acid peel and 5-aminolaevulinic acid photodynamic therapy for treating multiple actinic keratosis. Br J Dermatol 2017; 176:1155.
  83. Weiss ET, Brauer JA, Anolik R, et al. 1927-nm fractional resurfacing of facial actinic keratoses: a promising new therapeutic option. J Am Acad Dermatol 2013; 68:98.
  84. Hantash BM, Stewart DB, Cooper ZA, et al. Facial resurfacing for nonmelanoma skin cancer prophylaxis. Arch Dermatol 2006; 142:976.
  85. Ostertag JU, Quaedvlieg PJ, van der Geer S, et al. A clinical comparison and long-term follow-up of topical 5-fluorouracil versus laser resurfacing in the treatment of widespread actinic keratoses. Lasers Surg Med 2006; 38:731.
  86. Katz TM, Goldberg LH, Marquez D, et al. Nonablative fractional photothermolysis for facial actinic keratoses: 6-month follow-up with histologic evaluation. J Am Acad Dermatol 2011; 65:349.
  87. Prens SP, de Vries K, Neumann HA, Prens EP. Non-ablative fractional resurfacing in combination with topical tretinoin cream as a field treatment modality for multiple actinic keratosis: a pilot study and a review of other field treatment modalities. J Dermatolog Treat 2013; 24:227.
  88. Hashim PW, Nia JK, Singer S, Goldenberg G. An Investigator-initiated Study to Assess the Safety and Efficacy of Ingenol Mebutate 0.05% Gel When Used After Cryosurgery in the Treatment of Hypertrophic Actinic Keratosis on Dorsal Hands. J Clin Aesthet Dermatol 2016; 9:16.
  89. Kohl E, Popp C, Zeman F, et al. Photodynamic therapy using intense pulsed light for treating actinic keratoses and photoaged skin of the dorsal hands: a randomized placebo-controlled study. Br J Dermatol 2017; 176:352.
  90. Richard MA, Amici JM, Basset-Seguin N, et al. Management of actinic keratosis at specific body sites in patients at high risk of carcinoma lesions: expert consensus from the AKTeam™ of expert clinicians. J Eur Acad Dermatol Venereol 2018; 32:339.
  91. Ritchie SA, Patel MJ, Miller SJ. Therapeutic options to decrease actinic keratosis and squamous cell carcinoma incidence and progression in solid organ transplant recipients: a practical approach. Dermatol Surg 2012; 38:1604.
  92. Heppt MV, Steeb T, Niesert AC, et al. Local interventions for actinic keratosis in organ transplant recipients: a systematic review. Br J Dermatol 2019; 180:43.
  93. Perrett CM, McGregor JM, Warwick J, et al. Treatment of post-transplant premalignant skin disease: a randomized intrapatient comparative study of 5-fluorouracil cream and topical photodynamic therapy. Br J Dermatol 2007; 156:320.
  94. Liew YCC, De Souza NNA, Sultana RG, Oh CC. Photodynamic therapy for the prevention and treatment of actinic keratosis/squamous cell carcinoma in solid organ transplant recipients: a systematic review and meta-analysis. J Eur Acad Dermatol Venereol 2020; 34:251.
  95. Naylor MF, Boyd A, Smith DW, et al. High sun protection factor sunscreens in the suppression of actinic neoplasia. Arch Dermatol 1995; 131:170.
  96. Thompson SC, Jolley D, Marks R. Reduction of solar keratoses by regular sunscreen use. N Engl J Med 1993; 329:1147.
  97. Darlington S, Williams G, Neale R, et al. A randomized controlled trial to assess sunscreen application and beta carotene supplementation in the prevention of solar keratoses. Arch Dermatol 2003; 139:451.
  98. Ulrich C, Jürgensen JS, Degen A, et al. Prevention of non-melanoma skin cancer in organ transplant patients by regular use of a sunscreen: a 24 months, prospective, case-control study. Br J Dermatol 2009; 161 Suppl 3:78.
  99. Pomerantz H, Hogan D, Eilers D, et al. Long-term Efficacy of Topical Fluorouracil Cream, 5%, for Treating Actinic Keratosis: A Randomized Clinical Trial. JAMA Dermatol 2015; 151:952.
  100. Walker JL, Siegel JA, Sachar M, et al. 5-Fluorouracil for Actinic Keratosis Treatment and Chemoprevention: A Randomized Controlled Trial. J Invest Dermatol 2017; 137:1367.
  101. Gollnick H, Dirschka T, Ostendorf R, et al. Long-term clinical outcomes of imiquimod 5% cream vs. diclofenac 3% gel for actinic keratosis on the face or scalp: a pooled analysis of two randomized controlled trials. J Eur Acad Dermatol Venereol 2020; 34:82.
Topic 5336 Version 48.0

References