Expert Opinion On Pharmacotherapy December 2009, Vol. 10, No. 18, Pages 3015-3031 - 3015-3031.

Review
Pharmacotherapy of actinic keratosis

Brian Berman, Sadegh Amini, Whitney Valins & Samantha Block
1. 2. 3. 4. Introduction Prevention Treatment of actinic keratosis Expert opinion
University of Miami, Miller School of Medicine, Department of Dermatology and Cutaneous Surgery, 1600 NW 10th Ave, RMSB, Room 2023A (R250), Miami, FL 33136, USA
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by HINARI on 04/09/12 For personal use only.
Actinic keratosis (AK) represents the initial intraepidermal manifestation of abnormal keratinocyte proliferation with the potential of progression to squamous cell carcinoma (SCC). When in limited numbers, clinically visible AKs are treated individually with ablative and/or surgical procedures (lesiondirected treatment), while multiple and sublinical AKs are treated with elddirected therapies that use ablative, nonablating and other topically applied treatment modalities. Owing to difculties in predicting which AK will progress to SCC, the general rule is to treat all AKs. The goals of treatment are to eliminate the AKs, minimizing their risk of progression to invasive SCC, while pursuing good cosmetic outcomes. Prevention is the most important treatment modality for AKs. Avoidance of sun and articial sources of ultraviolet light, applying sunscreen and self-examination are among the most effective preventive measures. Chemopreventive modalities such as retinoids, 2-(Diuoromethyl)-dl-ornithine (DFMO), perillyl alcohol, T4 endonuclease V, and DL-a-tocopherol are described. Lesion-directed treatment modalities include cryotherapy, surgery and electrodessication with or without curettage. Field-directed treatment modalities include nonablative and ablative laser resurfacing, dermabrasion, chemical peels, topical immunomodulators (imiquimod, 5-uorouracil and diclofenac) and photodynamic therapy. And, nally, newer and investigational treatment modalities such as ingenol mebutate, resiquimod and betulinic acid are also being discussed.
Keywords: actinic keratosis, eld-directed treatment., lesion-directed treatment, prevention Expert Opin. Pharmacother. (2009) 10(18):3015-3031
1.
Introduction
Several factors should be considered before selecting the appropriate treatment modality for actinic keratoses (AKs). These include risk factors such as history of chronic ultraviolet B (UVB) exposure, which causes mutations on the tumor suppressor gene p53 [1-3]; history of genetic DNA instability or melanin deciency, as seen in cases of autosomal recessive inherited type 1 and 2 albinism and xeroderma pigmentosum respectively [4-7]; older age [8,9]; male gender [10-12]; Fitzpatrick skin phototypes I II; and history of living in lower latitudes (i.e., closer to the equator) [13,14]. Other factors to consider include anatomical distribution, having more than 80% of AKs located on the head and neck, dorsum of forearms, and hands, history of immunossupression particularly in post-transplant patients [15,16] and the number of lesions. Subclinical (nonvisible) AKs are estimated to occur up to 10 times more often than visible AKs, particularly in sun-damaged skin [17]. At the time of treating AKs the clinician has to decide between two approaches: treating only one (or a few) visible lesions (lesion-directed) versus treating multiple (sometimes hundreds) invisible lesions (eld-directed) [18,19]. AKs represent the initial intraepidermal manifestation of abnormal keratinocyte proliferation with the potential of progression to squamous cell carcinoma (SCC). SCC is the second leading cause of skin cancer
10.1517/14656560903382622 2009 Informa UK Ltd ISSN 1465-6566 All rights reserved: reproduction in whole or in part not permitted
3015
deaths in the USA, with 40% of SCC developing from clinically normal skin in the previous year, and 60 65% of SCC arising from previous AKs [20,21]. The risk of progression has been calculated to be between 0.025 and 16% per year [20,22], and the calculated lifetime risk of malignant transformation for a patient with AKs followed up for 10 years is from 6.1 to 10.2% [23]. The rationale behind the controversial recommendation that all AKs should be treated [24,25] is based on the difculty to predict which single AK is going to progress to SCC. Suchniak et al. [26] reported 36% of lesions previously diagnosed clinically as AKs being in fact SCC with 14% being in situ SCC. Ehrig et al. [27] showed that 4% of AKs clinically diagnosed by board-certied dermatologists were in fact SCC and 5% were considered occult early stage of cutaneous malignancy. Moreover, spontaneous regression has been reported in as high as 25.9% of AKs over a 12-month period, although 15% later reappeared [28-30]. The goals of the treatment are to eliminate AKs completely, minimizing their risk of progression to invasive SCC, reducing the potential to metastasize and cause death, while obtaining the best cosmetically acceptable outcomes. Additionally, treatment reduces symptoms like tenderness and pruritus [21]. AKs management options are chosen depending on whether a lesion-directed or a eld-directed therapy is preferred, although combination therapies have also been reported [31]. Lesion-directed therapy includes ablative and surgical procedures reserved for cases where only a few clinically AKs are visible. AKs treated in this manner are usually thick lesions (e.g., hypertrophic or lichen planus-like keratosis) or suspicious AKs (i.e., lesions at increased risk of progression to SCC). Field-directed therapy includes ablative, non-ablating and topical treatments used for patients with multiple clinically visible AKs. It offers the advantage of also treating subclinical lesions that are likely later to become clinically visible AKs. In this review the most reliable evidence-based data from studies available in PUBMED were analyzed particularly focusing on randomized, controlled clinical trials with large numbers of subjects. When comparing study results it is important to consider which measurements were used to evaluate the efcacy and safety end points. Some studies evaluate the patient complete response (CR) rate (the percentage of patients with 100% clearance from baseline), consistent with the FDA standard primary end point. Other FDA-approved secondary end points include partial response (PR) rate (the percentage of patients with 75% clearance from baseline) as well as the percentage reduction on AK lesions in a target treatment area. The percentage reduction may be analyzed as the mean or median percentage change in lesion number from the baseline counts or from the peak numbers of AKs due to detection of previously subclinical lesions. Since the percentages reported by studies may represent different end points, direct percentage comparisons among studies may lead to incorrect conclusions when interpreting the data. For example, if patients from study A had a
3016
mean of four baseline lesions and at the end of the study a mean of two lesions, with the end point dened as the mean percentage change from baseline, the results would show a mean reduction of lesions of 50%. If patients from study B had a mean peak of 100 lesions and at the end of the study a mean of 2 lesions, with the end point dened as the mean percent change from the peak number of lesions, the results would show a mean reduction of lesions of 98%. Directly analyzing the percentages from studies A and B, the reader could incorrectly conclude that treatment from study B seems to be superior to the treatment from study A, when the fact is that these two outcomes cannot be compared as they are calculated in a different way. In regards to safety end points, although many studies focus on local skin reactions (LSRs), the metrics of assessment vary from study to study and, as a rule, none of these tools has been validated. For example, two studies may report scabbing as an LSR. However, different grading scales may be used by each study, making it difcult to compare the studies accurately.
2.
Prevention
Prevention is the most important treatment modality for AKs. [28,32]. Effective measures include avoidance of excessive sun exposure, particularly between 1100 and 1400 h, avoidance of articial sources of ultraviolet (UV) light such as tanning beds [33] or prolonged UV treatments, wearing protective clothing, applying sunscreen with at least 30 SPF three to four times a day over sun-exposed areas, and educating patients regarding self-examination to detect signs of malignant transformation. These measures prevent the development of AKs and accelerate the remission rate of existing lesions [34-36]. A 5-min skin exam is also considered appropriate to screen for the development of AKs, especially in high risk patients [25,28]. The role of chemoprevention in decreasing the development of new SCC was demonstrated in a randomized, double-blind, controlled trial [37] involving 2297 patients with a history of moderate to severe AKs, where daily oral vitamin A (retinol, 25,000 UI) signicantly decreased (32%) the 5-year probability of generating a new SCC with no signicant toxicity. UV is a potent carcinogen capable of inducing the three phases of skin carcinogenesis (initiation, promotion and progression). The most effective and practical approach has been the inhibition of the promotion phase more than treating a developed cancer [38-41]. Tumor promotion includes a long (reversible) period ( 10 years) of clonal expansion of UV-induced DNA-damaged cells which may evolve into premalignant and malignant lesions [38,41]. Current molecular targets of human skin cancer chemoprevention include nuclear retinoid receptors, p53 mutations, and several cellular pathways. These include UV-induced mitogen-activated protein kinase (MAPK) signal transduction pathways, which control genes involved in cell proliferation, differentiation, and tumorigenesis such as the Activator Protein -1 (AP-1) complex, and also the arachidonic acid/clyclooxygenase pathway, polyamine synthesis (ornithine
Expert Opin. Pharmacother. (2009) 10(18)
Berman, Amini, Valins & Block
decarboxylase) pathway, phosphotidylinositol 3-kinase/Akt (PI3K/Akt) pathway, and nuclear factor-kappa B pathway [39,41]. Several compounds for chemoprevention of skin cancer have been evaluated in clinical trials [39,42].
Retinoids Retinoids have consistently been shown to be effective both orally and topically [37,43,44]. Retinoids downregulate the expression of AP-1 responsive genes, activate transrepression of AP-1, arrest growth and induce apoptosis and differentiation [45-47]. Through transrepression of AP-1, retinoids also downregulate the UV-induced overexpression of clyclooxygenase-2 (COX-2), reducing prostaglandins, which are increased in AKs and non-melanoma skin cancers (NMSCs) [48-51]. Isotretinoin at 0.25 0.5 mg/kg/day and acitretin at 10 20 mg/day are the most common systemic retinoids used for skin cancer chemoprevention [42,52]. Routine monitoring for clinical signs of retinoid toxicity and laboratory abnormalities is mandatory. Recommended laboratory tests include lipid panel, liver function tests, creatinine, glucose, complete blood count and bone radiographs. Owing to their teratogenic effect, retinoids should be avoided in women of child-bearing potential. In the rare case that they are prescribed in this population, extensive measures must be taken to prevent pregnancy. A negative pregnancy test is necessary 1 month before starting treatment and the simultaneous use of two different effective contraceptive methods starting 1 month before treatment and for 1 month (isotretinoin) and 3 years (acitretin) after nishing treatment is mandatory. [42,52]. In addition, a written consent must be provided before starting treatment and a negative pregnancy test is required before each prescription is relled. Topical all-trans-retinoic acid (tretinoin) is effective for the treatment of AKs [53-57]. In a double-blind, randomized, clinical trial 25 patients applied tretinoin 0.05% cream or arotinoid methyl sulfone cream twice daily for 16 weeks to opposite sides of the face, resulting in a signicant reduction (30.3 and 37.8%) in the number of AKs respectively compared with baseline (p < 0.01) [58]. Tretinoin cream caused more local adverse events including severe erythema in 50% and severe scaling in 23% of patients. In a double-blind, randomized, placebo-controlled, parallel-group study, 93 patients with AKs on the face, scalp, dorsal forearms and hands were randomized to apply isotretinoin 0.1% cream or vehicle cream twice daily to each area that had at least one AK present at baseline for 24 weeks, resulting in signicant reduction in number of facial AKs in the isotretinoin group compared with placebo (p = 0.001), while no signicant effect was seen on AKs on the scalp or upper extremities [59].
2.1
spermidine and spermine) are necessary for normal cellular proliferation, differentiation and apoptosis [62]. They are upregulated during the promotion phase of chemically and UVB-induced skin carcinogenesis models [39]. In a randomized, placebo-controlled trial [63], DFMO 10% ointment was applied for 6 months on one of the forearms of 48 patients with moderate to severe AKs. Compared with placebo, a 23.5% reduction in the number of AKs (p 0.001) and 26% decrease in spermidine levels (p = 0.04) was found. There was a 4.2% rate of severe and a 10.4% rate of moderate local adverse events requiring treatment modication. In a followup study [64] the skin levels of p53, proliferating cell nuclear antigen (PCNA) and the apoptotic rate were measured after DFMO application. A signicant reduction in p53 expression was reported (22%; p = 0.04), while PCNA levels and apoptotic rate were not signicantly altered. At present, a Phase II, randomized trial is being conducted, comparing the efcacy of DFMO with or without triamcinalone in the prevention of NMSC in patients with AKs [65].
Perillyl alcohol Perillyl alcohol (POH) is another substance that has been shown to have antitumor activity in UV-induced skin carcinogenesis [66]. It is a hydroxylated monoterpene found in essential oils of plants, including citrus peels, mints and celery seeds [67]. POH affects multiple different steps in the carcinogenesis process. It has been shown to induce Ras farnesylation, which therefore inhibits downstream Ras signaling pathways [68]. It also plays a role in the induction of apoptosis. The effect of POH on tumorigenesis was studied [69], showing that POH had an effect on many parameters, including suppression of inammation, oxidative stress, the activity of ornithine decarboxylase, thymidine incorporation into DNA, the Ras pathway, and alteration of the Bax:Bcl-2 ratio in mice skin. A Phase I, double-blind, placebo-controlled, randomized trial [70] studied the toxicity and tolerability of POH cream applied to the forearms of patients with no evidence of sun damage. Thirty-two per cent of subjects (8/25) reported mild adverse events such as small papules. Otherwise, there were no signicant differences between the appearance of the POH-treated versus the placebo-treated areas. A current randomized, double-blind, placebo-controlled, Phase II trial is comparing a high-dose POH cream with a lower dose in the treatment of patients with AKs and/or sun-damaged skin [71] and will provide more information on the use of POH in humans.
2.3
2-(Diuoromethyl)-dl-ornithine (DFMO) Another compound being evaluated is DFMO, an irreversible inhibitor of ornithine decarboxylase, the rate-limiting enzyme in polyamine synthesis [60,61]. Polyamines (e.g., putrescine,
2.2
T4 endonuclease V (T4N5) T4 endonuclease V (T4N5), isolated from Escherichia coli, is an enzyme that repairs UV-induced cyclobutane pyrimidine dimers in DNA. These dimers participate in the generation of mutations leading to the development of AKs and NMSC [72,73]. When T4N5 is integrated into liposomes for topical application, it has been found within the cytoplasm and nucleus of epidermal keratinocytes and Langerhans cells [72]. In a multicenter, double-blind, randomized clinical trial [73],
2.4
3017
30 patients with xeroderma pigmentosum who had all of their AKs and cancerous lesions removed before the study were randomly assigned to apply T4N5 liposome lotion (n = 20) or placebo lotion (n = 10) to the face and arms daily for 1 year. At the end of the study T4N5 liposome lotion reduced the incidence of AKs by more than 68%. A Phase III multicenter, double-blind, randomized trial to evaluate efcacy and safety of T4N5 liposome lotion compared with placebo for the prevention of AKs and other sun-induced damage in patients with xeroderma pigmentosum is now in development [74]. In addition, a Phase IIb, multicenter, randomized, double-blind, placebo-controlled trial is also in development comparing the incidence of NMSC on the sun-exposed skin of renal transplant recipients with a history of NMSC treated with T4N5 liposomal lotion versus placebo [75]. Several in vitro and in vivo animal models have shown that compounds such as NSAIDs, green tea polyphenols (including epigallocatechin-3-gallate; ECGC), apigenin, black tea theaavins, curcumin, resveratol, proanthocyanidins and silymarin may have a role in human skin cancer chemoprevention through modulation of the molecular targets cellular pathways mentioned above [38,39,41,76-79].
2.5 DL-a-tocopherol
DL-a-tocopherol, the biologically active component of vitamin E [80], is a known epidermal antioxidant that is depleted when the skin is exposed to UV radiation [81]. Studies show that topical use of vitamin E prevents skin cancer in mice [82] and decreases UVB-induced inammation and cytokine release [83]. A randomized, placebo-controlled trial [83] evaluated the chemopreventive potential of vitamin E by measuring biomarkers such as p53, PCNA and polyamine concentrations in sun-damaged skin. Subjects were randomly assigned to apply either 12.5% DL-a-tocopherol cream or placebo to each dorsal forearm for 6 months. The results showed that p53 levels and PCNA levels were not signicantly altered, while the levels of polyamines (putrescine, spermidine and spermine) were decreased signicantly. Although the skin levels of DL-atocopherol were highly elevated (p < 0.001), the decline in number of AKs was insignicant in both the placebo and the treatment arms after 6 months.
3.
3.1
Treatment of actinic keratosis

Lesion-directed treatment modalities Cryotherapy
3.1.1
Cryotherapy is a destructive modality that is the most-often used treatment for AKs [84]. It has been the therapeutic modality preferred by dermatologists [31] because it is a quick, easy, ofce-based procedure that does not require anesthesia, that can be used for treating few as well as multiple lesions, and that used to be the most cost-effective treatment modality. Although patients now prefer topical agents owing to less discomfort [31], cryotherapy still has a high degree of patient
3018
acceptance, particularly when less than 15 lesions are present [85]. In addition, physicians in some countries like the USA may be inuenced by the current payment system and therefore may have a preference for a destructive modality like cryotherapy over a prescription medication. However, in other countries lacking these economic incentives, cryotherapy remains a popular and inexpensive option for the treatment of AKs among dermatologists. Clearance rates ranging from 39 to 98.8% have been reported with the use of cryotherapy [24,25,86-88]. The most commonly used agent is liquid nitrogen at -195.8 C applied to individual lesions with a cotton-tipped applicator or spray. It causes a nonspecic destruction of normal and atypical keratinocytes. The usual application is in a single freeze-thaw cycle, with the additional freezing of a 1-mm rim of normal skin with freeze times ranging between 5 and 40 s. In a multicenter Australian study [87] evaluating the efcacy of cryotherapy for the treatment of AKs on the face and scalp, of the 89 patients in the intended-to-treat (ITT) population (421 lesions treated), there was a 67.2% lesion response rate per patient. Of interest, CR was obtained in 39% of lesions frozen for < 5 s, 69% of lesions frozen for > 5 s, and 83% of lesions frozen for > 20 s. Cosmetic outcomes graded good and excellent were reported in 94% of the CR lesions. Krawtchenko et al. [89] evaluated 75 patients with at least ve visible and histologically proven AKs in a target area up to 50 cm2 on the head, neck or decollete who were randomly assigned to three treatment groups (cryotherapy, 5-uorouracil (5-FU), or imiquimod). The authors reported a clinical clearance rate of 68% versus a histological clearance rate of 32% with cryotherapy applied for one or two courses at freezing times of 20 40 s per lesion. After 1 year posttreatment, 4% of the patients sustained clinical clearance of the total treatment eld, with a recurrence rate of 72%. The authors concluded that imiquimod was superior to 5-FU and cryotherapy in sustained lesion clearance and cosmetic outcomes in the treatment of AKs. Photodynamic therapy (PDT) was compared with cryotherapy for the treatment of AKs in an open, randomized, controlled study [90] in which a total of 202 patients with 732 AK lesions were evaluated. The anatomical areas treated with PDT or cryotherapy included the face (250 AKs (65.1%) vs 214 AKs (61.5%)), scalp (100 AKs (26.0%) vs 106 AKs (30.5%)), and other locations (34 AKs (8.9%) vs 28 AKs (8.0%)), respectively. CR rate was 69% with PDT and 75% with cryotherapy. Response rates correlated with the lesion thickness, with thinner lesions having a higher response. However, cosmetic outcomes were 96 and 81% respectively. Common adverse events include mild discomfort and the possibility of developing scarring and dyschromia, particularly hypochromia. The use of extensive cryosurgery cryopeeling has been described for the treatment of patients with many AKs [91]. In 373 patients with a total of 34,604 AKs predominately on the face and scalp, liquid nitrogen was applied to each individual
lesion followed by spraying the surrounding skin area. Recurrence rates were 4% at 6 months and 9% at 6 12 months post-treatment. New lesions occurred in 12% of 124/373 patients at 12 18 months of follow-up. Although no direct head-to-head comparison with 5-FU was performed, the author analyzed long-term data (i.e., 1 3 years postoperatively) for both treatments, reporting that cryopeeling was approximately twice as effective as 5-FU.
Surgery Surgical modalities, including full-thickness excision and tangential shave excision, are generally reserved for suspicious lesions that need further histopathological evaluation to exclude SCC. Common clinical signs indicating the progression towards SCC include bleeding, induration, pain, rapid growth or failure to respond to other treatments modalities. Disadvantages of surgical excision include the need for local anesthesia, perioperatory hemostatics and suturing, which may lead to inammation, skin tension and scarring. The advantage of tangential shave excision is that sutures are not required [92,93].
3.1.2
Electrodessication and curettage Electrodessication and curettage are used for thick and hyperkeratotic AKs, or when AKs are refractory to other treatment modalities. Two to three cycles of therapy may be required [88]. With curettage, the atypical tissue is scraped away until healthy tissue is reached. It may be followed by electrodessication, which destroys the residual lesion at the margins, and also is used for postcurettage hemostasis [94]. Like surgical excision, curettage enables tissue samples to be collected for histological evaluation. High cure rates and good cosmetic results have been reported [94]. Experience is required to perform the procedure since it is necessary to perceive the difference between atypical cells and healthy tissue [28]. Disadvantages include the need for local anesthesia and a higher risk of scarring compared with other modalities, including cryotherapy [95]. Electrodessication and curettage should be avoided in recurrent lesions, punch-biopsied lesions and hairbearing sites [28]. They should also be avoided for invasive SCC and tumors that reach the subcutaneous fat because malignant cells extend deeply making their removal difcult. In addition, with electrodesiccation and curettage of invasive SCC there are no margins available for histological evaluation, and therefore the potential risks of recurrence and metastasis are elevated [96,97].
3.1.3 3.2
(58.3%) remained lesion-free after 1 and 2 years respectively post-laser treatment. After a median of 42 months, 50% of patients remained free of AKs, and the other 50% experienced a total of 28 AKs. Overall, this study found a 94% reduction in the number of AKs. Disadvantages of lasers include the importance of adherence to postoperative care, lengthy wound healing and downtime. The most common adverse events include hyper/hypopigmentation, infections, scarring and acne [100]. Thirty-ve patients with photodamage were evaluated at 3, 6 and 12 months following CO2 laser resurfacing of the decollete, periorbital and hairline areas [101]. With 14.3% of patients developing new or recurrent AKs, the authors concluded that CO2 laser resurfacing is not as effective as dermabrasion, chemabrasion and deep chemical peel for the prophylaxis of AKs. CO2 laser results in separation of the dermis and epidermis through thermal induction of subepidermal blister formation and lateral spread of heat. Deeper extensions of the lesional area are identied by the presence of increased vascularity and capillary bleeding, which can be treated with additional passes. The cessation of bleeding is an indication of elimination of the AK. After treatment, collagen formation occurs, leaving the skin with a smooth texture and appearance [99]. Erbium-YAG laser leads to less thermal injury and higher cure rates compared with the CO2 laser [102]. This is due to the lasers greater selectivity for water, leading to reduced tissue damage. In a study by Wollina et al. [103], 29 patients with AKs on photodamaged skin were treated with the Er:YAG laser. A CR in 26/29 (89.7%) patients and a PR in 3/29 (10.3%) patients was obtained, with an average healing time of 7 10 days. Eight patients needed more than one treatment. During a 3-month follow-up, there was no evidence of recurrence, infection, hypo/hyperpigmentation or scarring. Compared with CO2 laser, patients treated with Er:YAG laser experience less pain and faster healing time [104].
Dermabrasion Dermabrasion is a surgical procedure used to treat large areas of photodamage with multiple, thick AKs. It uses quickly rotating diamond fraise or a stainless steel wire brush generating abrasion of skin layers. Dermabrasion is useful in the prophylactic treatment of AKs as demonstrated by a retrospective study [105] that evaluated its use in 23 patients with multiple AKs on the face. Eighty-three per cent and 64% of patients remained lesion-free at 2 and 4 years post-treatment, respectively. The average time before recurrence or appearance of new lesions was 4 years. Necessary preoperatory evaluations include addressing the tendency of developing hypertrophic scarring or keloids, history of completing previous treatment with isotretinoin for at least 12 months, hepatitis testing, HIV antibody screening, and nasal swabbing for patients with a history of impetigo. Herpes virus prophylayxis must be provided 10 14 days before and 7 10 days after the procedure. Re-epithelialization is expected after 7 10 days. Persistent erythema could be present from
3.2.2
3.2.1
Field-directed treatment modalities Nonablative and ablative laser resurfacing
Full face resurfacing can provide long-term prevention of future AKs and SCC. The rst use of CO2 lasers for AKs was introduced by David et al. [98]. A retrospective study [99] of 24 patients with > 30 facial AKs who underwent resurfacing with the CO2 and/or Er:YAG laser at least 1 year before the study showed that 21/24 patients (87.5%) and 14/24 patients
3019
1 2 weeks up to 2 3 months. Sun protection is highly recommended during recovery. Common adverse events include permanent hypopigmentation in 10 20% of patients, particularly in darker skin types, reversible hyperpigmentation, and scarring [106,107].
Deep and medium-depth chemical peels Chemical peeling is a destructive method where caustic agents are applied to the skin, causing necrosis at specic depths. Chemical peels range from supercial to deep, based on the agent used, concentration, time of application and thickness of the skin area to be treated. The efcacy is approximately 75% with recurrence rates of 25 35% [24]. Inammation in the papillary dermis denes a medium depth peel, while inammation in the deeper reticular dermis constitutes a deep chemical peel, inducing the production of new collagen [108]. The most commonly used agent is trichloracetic acid (TCA), which is categorized as a medium-depth peel when used at a concentration of 35% and as a deep peel at concentrations over 50%. Of importance, concentrations greater than 40% have increased risk of scarring [109]. To reduce this risk, several approaches have been taken including the use of combination therapies where a supercial agent (i.e., CO2 ice, Jessners solution, and glycolic acid) is used that disrupts the epidermis before peeling to aid penetration [109]. One type of deep peel, the phenol peel, induces damage to endothelial cells more than keratinocytes [110,111], which may eventually induce ischemic changes and epidermal necrosis [112,113]. Importantly, when phenol is absorbed systemically, it can lead to cardiac, liver and kidney damage and respiratory depression. These adverse events correlate with the amount of skin involved and the duration of the peel [114]. In a pilot study [115] the efcacy of the phenol peel was clinically and histologically assessed in 48 patients with AKs and Bowen disease predominantly on the face and scalp. The results showed that 84.8% (39/48) of patients had a CR after one to eight treatment sessions. Systemic adverse events were not observed in any patients. Among the 39 patients with a CR, 32 showed no recurrences for over 1 year of follow-up. Histological and immunochemical analysis showed that tumor thickness and cyclin A expression were useful markers for determining clinical improvement after the peel. Following chemical peels, skin protection with moisturizing ointment is necessary until the necrotic tissue has peeled away (usually 4 5 days). The earliest complication of dermal peels is an infection (viral, fungal or bacterial). Later, postoperative pigmentary changes may occur, which are more common in patients with Fitzpatrick skin types III or IV. On average, a peel does not need to be repeated for at least 2 years [109].
3.2.3 3.2.4
3.2.4.1
Topical immunomodulators Imiquimod
Imiquimod is an imidazolaquinoline that binds intracellular toll-like receptors (TLR) 7 and 8 acting as a topical immunomodulator. It induces cytokines such as interferon-a
3020
(IFN-a), IFN-g, tumor necrosis factor-a (TNF-a), interleukin-1a (IL-1a), IL-6, IL-8 and IL-12 by human peripheral blood mononuclear cells including monocytes, macrophages and TLR-7 bearing plasmocytoid dendritic cells. Imiquimod-induced keratinocytes produce IL-6, IL-8 and IFN-a, resulting in a Th1-dominant response [116-121]. IFN-a induces cellular immunity by stimulating CD4 T-cells to express IL-12 b2 receptor. In addition, IL-12 induces IFN-g to stimulate cytotoxic T-lymphocytes to kill virus infected and tumor cells [32]. It has been demonstrated that suppression of type I IFN signaling proteins is an early event leading to SCC [122] Since imiquimod increases the levels of type I IFN, it may help to improve the responsiveness to endogenous IFN-a, which is typically low in AKs [32,123]. A Phase I, randomized, double-blind, parallel-group, vehicle-controlled study [124] evaluated the nature of the cellular inltrates and cells involved in the cutaneous immune response induced by the application of imiquimod 5% cream or vehicle to ve AK lesions on the scalp, forearm or upper trunk of 18 patients once daily, 3 days a week for up to 16 weeks. Imiquimod signicantly increased tissue biomarker levels for CD3, CD4, CD8, CD11c, CD86, CD11c, CD68, HLA-DR and TUNEL compared with baseline, with no differences obtained in the vehicle group. Imiquimod stimulated a cutaneous immune response characterized by an increase in activated dendritic cells and CD4+ and CD8+ T cells leading to the regression of AKs. The proapoptotic activity of imiquimod was evaluated in vitro [125] in SCC lines, along with the expression of death receptors, caspases and cytochrome c in the apoptotic signaling cascade. Imiquimod bypassed several signal transduction pathways inducing activation of caspase-3 downstream of membrane-bound death receptor activation, and also activated the mitochondrial release of cytochrome c in a Bcl-2dependent fashion, providing evidence of the antineoplastic activity of imiquimod. Overall, CR rates of 45 85% have been obtained with imiquimod for the treatment of AKs [126-132]. Recurrence rates are 10 and 16% within 1 year and 18 months of treatment respectively, and are approximately 20% at 24 months follow-up [126,133]. In an open-label study [134] imiquimod 5% cream was applied to AK lesions on the head three times a week for 4 weeks followed by a 4-week rest and an additional 4 weeks of treatment in case remaining lesions were present. Fifty per cent (30/60) of the patients showed CR and 75% (40/60) showed PR. After 12-months of follow-up, 77% of patients achieving CR remained free of recurrences. In a multicenter, non-controlled study [135], 829 patients (7427 baseline lesions) applied imiquimod 5% cream to AKs on the head, three times a week for 4 weeks followed by a 4-week rest. A second 4-week course was applied in case of remaining lesions. A CR rate of 40.5% after the rst course of treatment and overall clearance rate of 68.9% was reported. Eighty-ve per cent of the total number of lesions was cleared.
Common adverse events included LSRs. In a multicenter, vehicle-controlled, randomized, double-blind study by Alomar et al. [136], using the same treatment schedule, 259 patients (855 AKs) with lesions within a contiguous 25-cm2 treatment area on the face or the balding scalp were randomized to receive imiquimod 5% cream or vehicle with a median number of six and seven baseline AKs, respectively. A CR rate of 37.2% was obtained in the imiquimod group compared with 0.8% in the vehicle group after the rst course of treatment (p < 0.0001). Overall CR rates of 55.0 and 2.3%, respectively, were reported (p < 0.0001). The overall percentage of patients that obtained PR was 65.9% in the imiquimod-treated group and 3.8% in the vehicle-treated group (p < 0.0001). The individual lesion clearance rate after the rst course of treatment and at the end of the study were 61.1 and 75.7% respectively in the imiquimod-treated group, and 11.3 and 18.9% respectively in the vehicle-treated group. Adverse events occurred in 53.5 and 30.8% of the patients, respectively (p < 0.001). The most common adverse events reported by the investigators were LSRs including erythema, aking/scaling/dryness, and scabbing/crusting. The most intense LSRs were signicantly more frequent with imiquimod than with vehicle and included edema, vesicles, erosion/ ulceration and weeping/exudates. No serious adverse events related to imiquimod were reported. Two Phase III, multicenter, randomized, double-blind, parallel-group, vehicle-controlled trials evaluated 492 patients with four to eight AKs in a 25-cm2 treatment area on the face or the balding scalp [137]. Patients received imiquimod 5% cream or placebo once daily, three times a week, for 16 weeks. The CR rate for imiquimod (48.3%) was signicantly higher than placebo (7.2%; p < 0.001). PR rates were 64.0 and 13.6%, respectively (p < 0.001). At 8 weeks follow-up, half of the patients who received imiquimod had at least an 86.6% reduction in the number of AKs versus 14.3% with placebo. Another Phase III, multicenter, randomized, double-blind, parallel-group, vehicle-controlled study [129] evaluated the efcacy of imiquimod 5% cream versus vehicle applied daily, 3 days a week, for 16 weeks in 286 patients with ve to nine visible and histologically conrmed AKs located within a contiguous 25-cm2 treatment area on the face or balding scalp. The CR rate for imiquimod was 57.1% (84/147) versus 2.2% (3/139) for the vehicle (p < 0.001). The PR rate for imiquimod and vehicle groups were 72.1% (106/147) and 4.3% (6/139), respectively (p < 0.001). Two Phase III, multicenter, randomized, double-blind, vehicle-controlled studies [128] evaluated the efcacy of imiquimod 5% cream in the treatment of four to eight AKs located within a contiguous 25-cm2 treatment area on the face and balding scalp. In these studies 436 patients received either imiquimod 5% or vehicle cream once daily, 2 days a week for 16 weeks. A CR rate of 45.1% (97/215) was reported in the imiquimod group and 3.2% (7/221) in the vehicle group (p < 0.001). The PR rates for the imiquimod and vehicle groups were 59.1% (127/215) and 11.8% (26/221),
respectively (p < 0.001). At 8 weeks follow-up half of the patients that were treated with imiquimod had at least an 83.3% reduction in the number of AKs. Comparison between the two treatment regimens used in the above studies shows that applying imiquimod 5% cream three times a week results in a higher clinical response than twice a week. However, this difference was smaller than expected, probably owing to lower rate of CR obtained in one of the studies that evaluated the three times-a-week regimen (40.8%). In addition, the difference can also be attributed to random variation seen with clinical studies. The median percentage of reduction in the number of AKs from baseline was greater than 86% in the studies with three times-a-week application compared with 83.3% in the studies with twice-a-week application. More local skin and application site reactions, more rest periods, and more subjects who discontinued treatment due to LSRs were associated with the three times-a-week regimen [137]. The most common adverse events related to imiquimod were local site reactions including erythema, scabbing/crusting, aking/scaling/dryness, and erosion/ulceration, with the majority resolving by 8 weeks posttreatment [128,129,137]. A split-face, placebo-controlled, double-blind study [138] assessed the efcacy of imiquimod 5% cream applied to a 20-cm2 area on one side of the face, once a week for 6 months to 20 patients with a minimum of six symmetrically distributed AKs. At the end of the study, 7/15 patients (46.7%) had marked improvement with imiquimod compared with 1/15 (6.7%) with placebo. All patients receiving imiquimod reported some degree of improvement, while of those receiving placebo, six patients had no improvement and seven had slight worsening. An average change of +2.20 in the investigator assessment score was recorded for imiquimod, compared with -0.27 for the placebo group (p = 0.0002). A multicenter, randomized, placebo-controlled study [139] evaluated the safety and efcacy of imiquimod 5% cream for the treatment of AKs in post-transplanted patients receiving immunosuppressive therapy within the previous 6 months. Forty-three patients applied imiquimod or vehicle three times a week for 16 weeks to a 100-cm2 contiguous eld containing 4 10 AKs on the face, forehead or balding scalp. Patients receiving imiquimod showed a CR rate of 62.1% (18/29) versus 0% of patients receiving placebo. Histological conrmation was obtained for all patients. The overall clearance rate of individual AKs in the imiquimod group was 73.7% versus -99.1% in the placebo group. Common imiquimod-related adverse events included mild to moderate application site reactions (5/29), fatigue (1/29), headache (1/29), diarrhea (1/29), nausea (1/29), rash (1/29), skin disorder (1/29) and leucopenia (1/29). Of importance, no patient in the study reported transplant rejection. Imiquimod demonstrated to be effective and well-tolerated for the treatment of AKs in post-transplant immunosuppressed patients. In a randomized study [89], 75 patients with at least ve visible and histologically proven AKs in a target area up to
3021
50 cm2 on the head, neck or decollete were assigned to receive one of the three treatments: one or two courses of cryotherapy (20 40 s per lesion), topical 5-FU (twice daily for 4 weeks), or one or two courses of imiquimod 5% cream (three times a week for 4 weeks each). Sixty-eight per cent (17/25), 96% (23/24) and 85% (22/26) of patients had initial clinical clearance with cryotherapy, 5-FU and imiquimod, respectively. However, histological clearance was 32, 67 and 73% respectively. At 12 months post-treatment, sustained clearance of initially cleared AKs was seen in 28% with cryosurgery, 54% with 5-FU and 73% with imiquimod (p < 0.01). Imiquimod achieved the best cosmetic outcomes (p = 0.0001).
5-Fluorouracil Topical 5-uorouracil (5-FU) is a chemotherapeutic agent that interferes with DNA synthesis by inhibiting thymidylate synthetase decreasing cell proliferation, and causing cell death, particularly in fast-growing dysplastic cells [32]. The efcacy of 5-FU treatment has been reported to be 90 98% for the treatment of AKs with minimal scarring [28,140]. In addition, with this therapy, clinically undetectable (subclinical) AKs are also treated [28]. Recurrence rates of up to 55% have been reported [3]. Low treatment compliance, due to adverse events, is associated with 60% failure rates [94]. In a prospective study [141], 20 patients with moderate to severe AKs of the face and scalp were instructed to apply 5-FU 0.5% cream nightly for 4 weeks. Partial to complete response was reported in 53% of patients at week 8. Seventy-nine per cent of patients reported at least one adverse event including tenderness, burning, erythema and blistering. Based on electronic monitoring, adherence to 5-FU therapy ranged from 54 to 100%, with 14 of the patients having a mean adherence over 80% (p < 0.001). A Phase III, double-blind, randomized, vehicle-controlled study [142] evaluated 177 patients with at least ve AKs who applied 5-FU 0.5% cream or vehicle once daily for 1, 2 or 4 weeks. Complete clearance was obtained in 26, 20 and 48% of the patients respectively, compared with 3.4% of patients receiving the vehicle. In a single-blind, randomized study [143], patients with six or more AKs who were treated with 5-FU 0.5% cream once daily and 5-FU 5% cream twice daily on opposite sides of the face for 4 weeks were evaluated. The reduction in the number of AKs was signicantly greater with the 0.5% cream than with the 5% cream (p = 0.044). Both concentrations were equally effective in the percent reduction of AKs compared with baseline (67 and 47%, respectively). In a prospective study, 64 patients with multiple AKs on the face, scalp, upper limbs or legs were treated with a combination of 5% 5-FU cream applied each morning for 1 week and imiquimod 5% cream applied nightly for 6 nights [144]. The treatment regimen consisted of three courses, each separated by a rest period of 3 4 weeks. Combination therapy resulted in a shorter time to obtain an adequate response and fewer adverse events when compared with each individual treatment.
3.2.4.2
This was attributed to the synergistic effect of combining the two different mechanisms of action. A randomized, physician-blinded study [145] compared the efcacy of 5-FU 5% cream applied twice daily for 2 4 weeks to imiquimod 5% cream applied twice daily for 16 weeks in 36 patients with at least four AKs in one 25-cm2 area on the face, forehead and scalp. At week 24 the total AK count was reduced by 94% with 5-FU compared with baseline versus 66% with imiquimod. CR rates at week 24 were 84% versus 24% respectively. 5-FU was more effective in exposing and treating subclinical AKs, reducing the nal count of AKs, and achieving CR. Adverse event proles were similar with both treatments.
Diclofenac Diclofenac is a nonsteroidal anti-inammatory agent that inhibits cyclooxygenase, the rate-limiting enzyme in the synthesis of prostaglandins. Diclofenac has a greater afnity for COX-2 than for COX-1. Expression of COX-2 is increased in AKs, melanoma and NMSC, and other neoplasias. In addition, prostaglandins potentially contribute in the development of UV-induced NMSC [49,146,147]. One of the roles of diclofenac in the treatment of AKs may be based in the inhibition of UV-induced prostaglandins. By the same principle, multiple UV-induced proinammatory cytokines such as IL-1, TNF-a, transforming growth factor-b (TGF-b) also capable of inducing COX-2, may be inhibited by diclofenac. The addition of hyaluronic acid 2.5% vehicle gel decreases the diffusion of diclofenac through the skin, increasing diclofenacs time of exposure to the epidermis and enhancing its delivery to the atypical cells [32]. In a multicenter, randomized, double-blind, placebocontrolled study [148], 195 patients with a minimum of ve AKs contained in up to three 5-cm2 areas on the forehead, central face, scalp or dorsal hands were treated twice daily with 3.0% diclofenac in 2.5% hyaluronan gel or hyaluronan gel alone for 30 or 60 days. Treatment with diclofenac-hyaluronan for 60 days showed more efcacy than the 30-day application or the vehicle. The sequential treatment with diclofenac 3% gel and cryotherapy has also shown to be an effective approach for the management of multiple refractory AKs [149]. A single-center, randomized, bilateral, open-label, evaluatorblinded study compared 5-FU 5% cream and diclofenac 3% gel in 30 patients (n = 251 AKs) with at least three AKs on each side of the face and/or scalp. Diclofenac was randomly assigned to be applied to one side of the face and/or scalp, twice daily for 90 days. At day 62, 5-FU was applied twice daily to the opposite side of the face, for the nal 28 days of the study. Results showed that the efcacies of diclofenac and 5-FU were similar, slightly favoring 5-FU, with more patients reporting adverse events with 5-FU [150]. In a randomized, comparative, open-label study [151] the efcacy of daily diclofenac 3% gel was compared with imiquimod 5% cream three times a week for 12 weeks in 49 patients with at least three AKs on the face and scalp.
3.2.4.3
3022
A CR rate of 12% in the diclofenac group versus 22% in the imiquimod group was reported by investigator assessments, while CRs recorded by patient assessments were 28% versus 23%, respectively. There were no signicant differences between the two groups (p > 0.05), and both treatments were well tolerated.
Photodynamic therapy Photodynamic therapy (PDT) is a noninvasive, effective and tolerable treatment for numerous, thin, nonhyperkeratotic AKs [152,153]. In PDT, aminolevulinic acid (ALA) or methylaminolevulinate (MAL) is topically applied to the target area. Upon absorption these precursors accumulate inside dysplastic and neoplastic cells at a rate up to 10 times higher than in normal cells [90,154-156], where they are converted into photoporphyrin IX, a potent photosensitizer. After an incubation period, the target area is exposed to a light source causing activation of photoporphyrin IX, leading to the formation of reactive oxygen species (ROS), particularly singlet oxygen. The specicity of ALA-PDT depends on the wavelength corresponding to the absorption peak of the photosensitizer and enables the appropriate penetration to the pathologic process being targeted. Genes such as Bcl-2 help regulate PDTs destruction of dysplastic cells. Depending on the dosing and time after treatment, the result may be growth inhibition, necrosis or apoptosis of the targeted cells [32,90,154-157]. The link between the formation of ROS following PDT and the proteolytic events leading to apoptosis remains unknown. Two multicenter, Phase III studies evaluated 243 patients with AKs on the face and scalp, [158] who were treated with ALA-blue light once, or twice (after 8 weeks) if CR was not achieved with one session. At 12 weeks of follow-up, 72% obtained a CR, while 88% cleared at least 75% of the lesions. In a randomized, investigator-blinded, placebo-controlled study [156], 243 patients (1403 AKs on scalp and face) were randomized to receive ALA or vehicle, followed by 14 18 h of incubation and further exposure to blue light. At 8 weeks, 30% of patients who responded partially were retreated. At 12 weeks, CR was reported in 91% of the lesions treated with ALA. In addition, CR was reported in 73% of the patients, while PR was reported in 89% of patients. Discomfort was the most common adverse event. In a randomized study [159], 36 patients with at least four AKs on the face or scalp receiving two sessions of ALA-PDT or ALApulse dye laser (ALA-PDL) using a short incubation time (1 h) separated by 30 days was compared with topical treatment with 5-FU 0.5% cream once or twice daily for 4 weeks. At 1 month post-treatment, the overall individual lesion clearance rates for 5-FU, ALA-PDT, and ALA-PDL were 79, 80 and 50%, respectively. CR rates were 50, 50 and 8%, respectively, and PR rates were 75, 75 and 42%, respectively. ALA-PDT and ALA-PDL were better tolerated than 5-FU. A multicenter, double-blind,randomized, placebo-controlled study [160] evaluated 80 patients with 4 10 AKs on the face and scalp who received two treatment sessions 1 week apart with
3.2.5
either MAL-red light-PDT or placebo (red light alone). CR obtained at 3 months was 89% with MAL-PDT compared with 38% with placebo. More than 90% of patients treated with MAL-PDT reported excellent or good cosmetic result. In a multicenter, randomized, open study involving 211 patients with 413 AKs on the face or scalp [161], the efcacy and safety of different MAL-PDT regimens was evaluated. With one regimen, patients received a single treatment followed by repeat treatment if CR was not achieved by 3 months. With the other regimen, patients received MALPDT given as two treatments 1 week apart. For thin lesions, after single treatment, the CR rate was 93%, but increased to 97% after repeat treatment, while for the two-treatment regimen the CR rate was 89%. For thicker lesions, the CR rate was 70% after single treatment, but improved to 88% after repeat treatment, while for the two-treatment regimen the CR rate was 84%. MAL-PDT single treatment is as effective as two treatments for thin AKs, but repeated treatment is recommended for thicker or nonresponsive lesions. When PDT has been compared with cryotherapy, mixed results have been reported, although cosmetic outcomes have been consistently superior with PDT [90,162]. The efcacies of ALA-PDT and imiquimod were compared in 30 patients with a total of 256 AKs on the dorsal hands and forearms [163]. ALA-PDT (two sessions 15 days apart) or imiquimod 5% cream (once daily 3 days per week for 4 weeks plus 4 weeks of rest, and a second 4-week cycle in case patients had not achieved CR) was applied to a randomly allocated upper extremity (right-left comparison). At 1 month, the CR rate for PDT was 70.16 and 18.26% for imiquimod (p < 0.05). At 6 months CR rates were similar for both treatments (65.32 and 55.65% respectively; p > 0.05). At 6 months, no statistical difference was obtained for investigatorassessed cosmetic outcome, which was excellent in 80% of lesions with PDT versus 75% with imiquimod (p = 0.065). Sixty-nine per cent of patients preferred PDT while 31% preferred imiquimod in regards to the procedure. In terms of efcacy 55% preferred PDT and 45% preferred imiquimod. A randomized, double-blind, vehicle-controlled, split-face study [164] evaluated the efcacy of combination therapy with ALA-PDT and imiquimod 5% cream in patients with more than 10 AKs. Patients received two sessions of ALA-PDT 1 month apart on both sides of the face followed by imiquimod 5% cream and vehicle starting at month 2, randomly assigned to opposite sides of the face. Both imiquimod and vehicle were, applied once daily twice a week for 16 weeks. At month 12, median lesion reduction was 89.9% for PDT + imiquimod versus 74.5% for PDT + vehicle (p = 0.0023). Severe LSRs included erythema and aking/scaling/dryness. The sequential regimen was well tolerated and showed efcacy.
Treatment cost-effectiveness There have not been many studies addressing the relationship between the cost and effectiveness of AK treatments [85]. According to one meta-analysis from the USA [165], treatment
3.3
3023
of patients with more than six AKs with 5-FU 0.5% cream may be more cost-effective than the 1 and 5% concentrations. One study from the UK [166] showed that the cost-effectiveness of MAL-PDT was comparable to 5-FU and imiquimod for the treatment of AKs. Finally, a study from Belgium [167] used a medical decision tree created to simulate all the possible outcomes related to the medical decision. The cost-effectiveness ratio was obtained by calculating the total cost per year and the effects expressed as percentage of patients with a clinical response and an excellent cosmetic outcome, after a period of 1 year. The AK data were based on a large, multicenter, Phase III, randomized, controlled clinical trial that compared MAL-PDT head to head with cryotherapy and placebo [162]. Although MAL-PDT showed to be more expensive than cryotherapy for the treatment of AKs, the cost per full responder was comparable with cryotherapy. The incremental cost per full responder showed that MAL-PDT was statistically more expensive than cryotherapy, and the incremental cost-effectiveness ratio per full responder was not statistically different from current data obtained with cryotherapy.
3.4
higher compared with the vehicle. The median percentage reduction in the number of AKs from baseline with ingenol mebutate ranged from 75 to 100% compared with 0% for the vehicle (p < 0.0001). Ingenol mebutate was well tolerated at all concentrations. At present, several Phase II and Phase III studies are being conducted.
Resiquimod Resiquimod is an imidazoquinolamine and a toll-like receptor 7 and 8 agonist that has comparable stimulatory effects on monocytic cells, although it is 10- to 100-times more potent than imiquimod [172-174]. In addition, it induces interleukin-1 receptor antagonist (IL-1ra), granulocyte colony-stimulating factor, granulocyte/macrophage colony-stimulating factor, macrophage inammatory protein macrophage, inammatory protein-1a, macrophage inammatory protein-1b, and monocyte chemotactic protein (MCP-1) [116,119,174]. A Phase II doseranging study [175] evaluated the efcacy of resiquimod gel in 132 patients with four to eight AKs in a contiguous 25-cm2 area on the face or balding scalp at concentrations of 0.01, 0.03, 0.06 or 0.1% applied daily three times a week for 4 weeks. CR rates after one course of treatment were 40.0, 74.2, 56.3 and 70.6%, respectively. Patients with residual lesions received a second treatment. Efcacy was similar with all resiquimod concentrations, but the lower two concentrations were better tolerated than the higher concentrations.
3.4.2
3.4.1
Newer and investigational treatment modalities Ingenol mebutate
Ingenol mebutate (PEP005) is an extract from the plant Euphorbia peplus (milkweed) that has been used for many years as a traditional treatment for skin conditions including AKs and skin cancers [168,169]. Ingenol mebutate has demonstrated a new mechanism of action for a chemotherapeutic agent initially causing chemoablation by plasma membrane disruption and rapid loss of the mitochondrial membrane potential and subsequent mitochondrial swelling in dysplastic keratinocytes, followed by cell death by primary necrosis within 1 h [169]. Further generation of tumor-specic antibodies, proinammatory cytokines and neutrophil inltration results in antibody-dependent cellular cytotoxicity that eliminates residual cells [170]. A multicenter, randomized, double-blind, vehicle-controlled Phase IIa study [169] was conducted to evaluate safety and efcacy of several concentrations of ingenol mebutate for the treatment of AKs. In a total of 58 patients, ve preselected AKs were treated twice with different concentrations of ingenol mebutate gel either 7 days apart or 1 day apart. A total of 67% of patients using the 0.05% concentration achieved 80% clinical clearance of AKs treated, compared with vehicle (17%; p = 0.0185). This concentration also obtained an individual lesion clearance rate of 71%. All concentrations were well tolerated. A multicenter, randomized, double-blind, vehicle-controlled study [171] evaluated three dosing regimens with ingenol mebutate at concentrations of 0.025% (applied once daily for 3 days) and 0.05% (applied once daily for 2 or 3 days) in 222 patients with four to eight AKs in a contiguous 25-cm2 area on the arm, shoulder, chest, back or scalp. PR rates (56.0 75.4% vs 21.7%) and CR rates (40 54.4% vs 11.7%) obtained by all concentrations were signicantly
3024
Betulinic Acid (Oleogel S-10) Betulin, betulinic acid, oleanolic acid, lupeol and erythrodiol are pentacyclic triterpenes contained in the outer bark of birch (Betula alba cortex). They have antiviral, antimicrobial, hepatoprotective and antitumor effects [176,177]. Besides their anti-inammatory effects, the most important effects of betulins are the promotion of differentiation in normal human keratinocytes and the induction of cytotoxic, antiproliferative and apoptotic effects on tumor cells [178]. In a randomized, comparative, Phase IIa study [178], 45 patients with < 10 AKs mostly located on the face and scalp received treatment with either topical betulin-based oleogel twice daily, cryotherapy or a combination of the two. After 3 months, 100 and 75% clearing rates of the lesions were 64 and 86%, respectively in the betulin-based oleogel group, 79 and 93% with cryotherapy, and 71 and 71% with the combined therapy. Betulin-based oleogel seems to be an effective approach in the topical treatment of AKs.
3.4.3
4.
Expert opinion
Several currently available modalities are the most widely used in clinical practice for the treatment of AKs. These treatments, all of which have shown to be efcacious, include cryotherapy, which has been considered the mainstay of therapy, electrodessication and curettage, chemical peels, imiquimod, 5-uorouracil, diclofenac and photodynamic therapy. Preventive measures, such as sun avoidance, are also crucial
in limiting the development of or the recurrence of AKs, therefore decreasing the risk of progression to SCC. It is important to recognize that a great number of subclinical lesions may exist in the photodamaged areas where most clinically visible lesions are located. Newer treatment modalities that focus on the concept of treating the whole area (eld-directed treatment) are being developed with great success. There have been encouraging results from clinical trials involving investigational drugs, including ingenol mebutate, resiquimod, betulinic acid and several preventive agents such as retinoids, 2-(Diuoromethyl)-dl-ornithine (DFMO), perillyl alcohol (POH), and T4 endonuclease V (T4N5), which may also be considered for treatment. On the contrary, lesion-directed therapies are an alternative for single or few AKs. Using cryotherapy alone, recurrence rates are usually high, permanent adverse events such as scarring and/or pigmentary alterations can occur, and subclinical lesions are not concomitantly treated. The management of AKs requires a combination of therapies usually embracing a lesion-directed modality and a elddirected agent with the goal of increasing efcacy and tolerability, while minimizing adverse events and achieving good cosmetic results. Successful combination regimens that have been reported in recent clinical trials include diclofenac 3% gel followed by cryotherapy, ALA-PDT followed by imiquimod 5% cream, sulindac and hydrogen peroxide gels, and diclofenac 3% gel followed by ALA-PDT. Alternate dosing and new regimens using well-established agents are another area of interest to improve patient compliance and satisfaction, in addition to shortening treatment cycles and downtime, decreasing LSRs and reducing costs. Clinical trials are being conducted to evaluate the efcacy and
tolerability of a newer photosensitizer for PDT, such as topical silicon phthalocyanine 4 (Pc 4), and a new self-adhesive thin ALA patch (PD P 506 A) to facilitate treatment with PDT. ALA-PDT using the long-pulsed pulsed dye laser (LP PDL) (595 nm) is also now being evaluated for the treatment of AKs. Another study is evaluating safety and efcacy of pretreatment of AKs with topical retinoids followed by blue-light therapy with photosensitizing agent. A Phase II III study is now evaluating celecoxib versus placebo in preventing the development of new AKs in patients with existing AKs. A Phase II study is at present evaluating the efcacy and safety of afamelanotide (CUV1647), a chemical analogue of AlphaMelanocyte Stimulating Hormone (a-MSH), which is implanted subcutaneously (16 mg every 60 days), for the reduction in the number of AKs and SCCs in immunocompromised organ-transplant recipients. In an attempt to optimize the use of imiquimod topically, a recent Phase III study evaluated short-course, cyclic regimens of imiquimod cream at two concentrations (3.75 and 2.5%). Daily application of imiquimod 3.75% for two 2-week treatment cycles, separated by a 2-week rest period, maximized tolerance while maintaining efcacy achieved with 5% imiquimod for prolonged 4 months treatment, as measured by median percent reductions in the number of AKs [179]. We await the results of ongoing clinical studies of sequential AK therapy employing eld-therapy with imiquimod 3.75% cycle dosing and lesiontargeted treatment.
Declaration of interest
B Berman is on the advisory Board and Speaker Bureau of Graceway, Peplin and Pharmaderm.
3025
Bibliography
1. Smit NP, Vink AA, Kolb RM, et al. Melanin offers protection against induction of cyclobutane pyrimidine dimers and 6-4 photoproducts by UVB in cultured human melanocytes. Photochem Photobiol 2001;74:424-30 Ortonne JP. Photoprotective properties of skin melanin. Br J Dermatol 2002;146:(Suppl 61):7-10 Lane DP. Cancer. p53, guardian of the genome. Nature 1992;358:15-6 Lookingbill DP, Lookingbill GL, Leppard B. Actinic damage and skin cancer in albinos in northern Tanzania: ndings in 164 patients enrolled in an outreach skin care program. J Am Acad Dermatol 1995;32:653-8 Lehmann AR, Bridges BA. Sunlight-induced cancer: some new aspects and implications of the xeroderma pigmentosum model. Br J Dermatol 1990;122:(Suppl 35):115-19 Lambert WC, Kuo HR, Lambert MW. Xeroderma pigmentosum. Dermatol Clin 1995;13:169-209 Luande J, Henschke CI, Mohammed N. The Tanzanian human albino skin. Natural history. Cancer 1985;55:1823-8 Schwartz RA. The actinic keratosis. A perspective and update. Dermatol Surg 1997;23:1009-19 Helfand M, Gorman AK, Mahon S, et al. Actinic Keratoses Final Report. US Department of Health & Human Services. Available from: http://www.cms.hhs.gov/coverage/ download/8b3-t3.pdf [Last accessed 27 August 2009] Memon AA, Tomenson JA, Bothwell J, Friedmann PS. Prevalence of solar damage and actinic keratosis in a Merseyside population. Br J Dermatol 2000;142:1154-9 Zagula-Mally ZW, Rosenberg EW, Kashgarian M. Frequency of skin cancer and solar keratoses in a rural southern county as determined by population sampling. Cancer 1974;34:345-9 Frost C, Williams G, Green A. High incidence and regression rates of solar keratoses in a queensland community. J Invest Dermatol 2000;115:273-7 Giles GG, Marks R, Foley P. Incidence of non-melanocytic skin cancer treated in 16. Australia. Br Med J (Clin Res Ed) 1988;296:13-7 14. Marks R, Jolley D, Lectsas S, Foley P. The role of childhood exposure to sunlight in the development of solar keratoses and non-melanocytic skin cancer. Med J Aust 1990;152:62-6 Kinlen LJ, Sheil AG, Peto J, Doll R. Collaborative United Kingdom Australasian study of cancer in patients treated with immunosuppressive drugs. Br Med J 1979;2:1461-6 Blohme I, Larko O. Skin lesions in renal transplant patients after 10 23 years of immunosuppressive therapy. Acta Derm Venereol 1990;70:491-4 Jeffes EW III, Tang EH. Actinic keratosis. Current treatment options. Am J Clin Dermatol 2000;1:167-79 Alexiades-Armenakas MR, Geronemus RG. Laser-mediated photodynamic therapy of actinic keratoses. Arch Dermatol 2003;139:1313-20 Leffell D. New advances in treating actinic keratoses. Skin Aging 2002;10:31-2 Marks R, Rennie G, Selwood TS. Malignant transformation of solar keratoses to squamous cell carcinoma. Lancet 1988;1:795-7 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;115:2523-30 Glogau RG. The risk of progression to invasive disease. J Am Acad Dermatol 2000;42:23-4 Salasche SJ. Epidemiology of actinic keratoses and squamous cell carcinoma. J Am Acad Dermatol 2000;42:4-7 Guidelines for the Management of Actinic Keratoses. 2004/2005 European Dermatology Forum. Available from: http://www.euroderm.org/content/ guidelines_keratoses.htm [Last accessed 27 August 2009] Drake LA, Ceilley RI, Cornelison RL, et al. Guidelines of care for actinic keratoses. Committee on Guidelines of Care. J Am Acad Dermatol 1995;32:95-8 Suchniak JM, Baer S, Goldberg LH. High rate of malignant transformation in hyperkeratotic actinic keratoses. J Am Acad Dermatol 1997;37:392-4 38. 35. 32. 29. 27. Ehrig T, Cockerell C, Piacquadio D, Dromgoole S. Actinic keratoses and the incidence of occult squamous cell carcinoma: a clinical-histopathologic correlation. Dermatol Surg 2006;32:1261-5 Berman B, Bienstock L, Kuritzky L, et al; Primary Care Education Consortium; Texas Academy of Family Physicians. Actinic keratoses: sequelae and treatments. Recommendations from a consensus panel. J Fam Pract 2006;55(Suppl):1-8 Quaedvlieg PJ, Tirsi E, Thissen MR, et al. Actinic keratosis: how to differentiate the good from the bad ones? Eur J Dermatol 2006;16:335-9 Marks R, Foley P, Goodman G, et al. Spontaneous remission of solar keratoses: the case for conservative management. Br J Dermatol 1986;115:649-55 Balkrishnan R, Cayce KA, Kulkarni AS, et al. Predictors of treatment choices and associated outcomes in actinic keratoses: results from a national physician survey study. J Dermatolog Treat 2006;17:162-6 Berman B, Villa AM, Ramirez CC. Mechanisms of action of new treatment modalities for actinic keratosis. J Drugs Dermatol 2006;5:167-73 Nora AB, Panarotto D, Lovatto L, et al. Frequency of counseling for skin cancer prevention by the various specialties in Caxias do Sul. Ann Bras Dermantol 2004;79:45-52 Thompson SC, Jolley D, Marks R. Reduction of solar keratoses by regular sunscreen use. N Engl J Med 1993;329:1147-51 Naylor MF, Boyd A, Smith DW, et al. High sun protection factor sunscreens in the suppression of actinic neoplasia. Arch Dermatol 1995;131:170-5 Rigel DS. Photoprotection: a 21st century perspective. Br J Dermatol 2002;146:(Suppl 61):34-7 Moon TE, Levine N, Cartmel B, et al. Effect of retinol in preventing squamous cell skin cancer in moderate-risk subjects: a randomized, double-blind, controlled trial. Southwest Skin Cancer Prevention Study Group. Cancer Epidemiol Biomarkers Prev 1997;6:949-56 Stratton SP, Dorr RT, Alberts DS. The state-of-the-art in chemoprevention of skin cancer. Eur J Cancer 2000;36:1292-7
2.
28.
15.
3. 4.
17.
30.
5.
18.
31.
6.
19. 20.
7.
8.
21.
33.
9.
34.
22.
10.
23.
24.
36.
11.
37.
25.
12.
26.
13.
3026
39.
Einspahr JG, Stratton SP, Bowden GT, Alberts DS. Chemoprevention of human skin cancer. Crit Rev Oncol Hematol 2002;41:269-85 Sporn MB, Suh N. Chemoprevention of cancer. Carcinogenesis 2000;21:525-30 Afaq F, Adhami VM, Mukhtar H. Photochemoprevention of ultraviolet B signaling and photocarcinogenesis. Mutat Res 2005;571:153-73 Campbell RM, DiGiovanna JJ. Skin cancer chemoprevention with systemic retinoids: an adjunct in the management of selected high-risk patients. Dermatol Ther 2006;19:306-14 Evans TR, Kaye SB. Retinoids: present role and future potential. Br J Cancer 1999;80:1-8 Lippman SM, Lotan R. Advances in the development of retinoids as chemopreventive agents. J Nutr 2000;130(2S Suppl):479-82S Niles RM. Recent advances in the use of vitamin A (retinoids) in the prevention and treatment of cancer. Nutrition 2000;16:1084-9 Nicholson RC, Mader S, Nagpal S, et al. Negative regulation of the rat stromelysin gene promoter by retinoic acid is mediated by an AP1 binding site. EMBO J 1990;9:4443-54 Fanjul A, Dawson MI, Hobbs PD, et al. A new class of retinoids with selective inhibition of AP-1 inhibits proliferation. Nature 1994;372:107-11 Pentland AP, Schoggins JW, Scott GA, et al. Reduction of UV-induced skin tumors in hairless mice by selective COX-2 inhibition. Carcinogenesis 1999;20:1939-44 Buckman SY, Gresham A, Hale P, et al. COX-2 expression is induced by UVB exposure in human skin: implications for the development of skin cancer. Carcinogenesis 1998;19:723-9 Muller-Decker K, Reinerth G, Krieg P, et al. Prostaglandin-H-synthase isozyme expression in normal and neoplastic human skin. Int J Cancer 1999;82:648-56 Fischer SM, Lo HH, Gordon GB, et al. Chemopreventive activity of celecoxib, a specic cyclooxygenase-2 inhibitor, and indomethacin against ultraviolet light-induced skin carcinogenesis. Mol Carcinog 1999;25:231-40
52.
40. 41.
Otley CC, Stasko T, Tope WD, Lebwohl M. Chemoprevention of nonmelanoma skin cancer with systemic retinoids: practical dosing and management of adverse effects. Dermatol Surg 2006;32:562-8 Bollag W, Ott F. Retinoic acid: topical treatment of senile or actinic keratoses and basal cell carcinomas. Agents Actions 1970;1:172-5 Barranco VP, Olson RL, Everett MA. Response of actinic keratoses to topical vitamin A acid. Cutis 1970;6:681-5 Bollag W, Ott F. Vitamin A acid in benign and malignant epithelial tumours of the skin. Acta Derm Venereol Suppl (Stockh) 1975;74:163-6 Kurka M, Orfanos CE, Pullmann H. Vitamin A acid for the topical management of epithelial neoplasms. Combination with 5-uorouracil. Hautarzt 1978;29:313-18 Kleinsmith DA, Thomas L. Retinoic acid in the treatment of actinic keratoses. J Dermatol Surg Oncol 1988;14:103 Misiewicz J, Sendagorta E, Golebiowska A, et al. Topical treatment of multiple actinic keratoses of the face with arotinoid methyl sulfone (Ro 14-9706) cream versus tretinoin cream: a double-blind, comparative study. J Am Acad Dermatol 1991;24:448-51 Alirezai M, Dupuy P, Amblard P, et al. Clinical evaluation of topical isotretinoin in the treatment of actinic keratoses. J Am Acad Dermatol 1994;30:447-51 McCann PP, Bitonti, AJ, Pegg AE. Inhibition of polyamine metabolism and the consequent effects on cell proliferation. In: Wattenberg L, editor, Cancer Chemoprevention. Boca Raton, FL: CRC Press; 1992. p. 531-9 Pegg AE. Polyamine metabolism and its importance in neoplastic growth and a target for chemotherapy. Cancer Res 1988;48:759-74 Pegg AE, Madhubala R, Karneji T, et al. Control of ornithine decarboxylase activity in alpha-diuoromethylornithine-resistant L1210 cells by polyamines and synthetic analogues. J Biol Chem 1988;263:11008-14 Alberts DS, Dorr RT, Einspahr JG, et al. Chemoprevention of human actinic keratoses by topical 2-(Diuoromethyl)-dl-ornithine.
Cancer Epidemiol Biomarkers Prev 2000;9:1281-6 64. Einspahr JG, Nelson MA, Saboda K, et al. Modulation of biologic endpoints by topical diuoromethylornithine (DFMO), in subjects at high-risk for nonmelanoma skin cancer. Clin Cancer Res 2002;8:149-55 Alberts DS. Phase IIB randomized, double-blinded, placebo controlled study to evaluate the safety and efcacy of topical diuoromethylornithine (DFMO) with and without a topical corticosteroid cream (triamcinolone 0.1%) in the therapy of actinic keratoses (AK) on the forearms. ClinicalTrials.gov Identier: NCT00021294. Available from: http:// clinicaltrials.gov/ct2/show/NCT00021294 [Last accessed on 27 August 2009] Crowell PL. Prevention and therapy of cancer by dietary monoterpenes. J Nutr 1999;129:775-8S Belanger JT. Perillyl alcohol: applications in oncology. Altern Med Rev 1998;3:448-57 Barthelman M, Chen W, Gensler HL, et al. Inhibitory effects of perillyl alcohol on UVB-induced murine skin cancer and AP-1 transactivation. Cancer Res 1998;58:711-16 Chaudhary SC, Alam MS, Siddiqui MS, Athar M. Perillyl alcohol attenuates Ras-ERK signaling to inhibit murine skin inammation and tumorigenesis. Chem Biol Interact 2009;179:145-53, [Epub 2008 Dec 31] Stratton SP, Saboda KL, Myrdal PB, et al. Phase 1 study of topical perillyl alcohol cream for chemoprevention of skin cancer. Nutr Cancer 2008;60:325-30 Stratton S. Phase 2a randomized, placebo-controlled, double-blind trial of topical perillyl alcohol in sun damaged skin. ClinicalTrials.gov Identier: NCT00608634. Available from: http:// clinicaltrials.gov/ct2/show/NCT00608634 [Last accessed on 27 August 2009] Cafardi JA, Elmets CA. T4 endonuclease V: review and application to dermatology. Expert Opin Biol Ther 2008;8:829-38 Yarosh D, Klein J, OConnor A, et al. Effect of topically applied T4 endonuclease V in liposomes on skin cancer in xeroderma pigmentosum: a randomised study. Xeroderma Pigmentosum Study Group. Lancet 2001;357:926-9
53.
65.
42.
54.
55.
43.
56.
44.
66.
45.
57.
67.
58.
68.
46.
69.
47.
59.
48.
60.
70.
49.
71.
61.
50.
62.
72.
51.
73.
63.
3027
74.
A randomized, double-blind, multicenter clinical study to test the safety and efcacy of T4N5 liposome lotion on patients with xeroderma pigmentosum in the protection against actinic keratosis. ClinicalTrials.gov Identier: NCT00002811. Available from: http://clinicaltrials.gov/ct2/show/ NCT00002811 [Last accessed 27 August 2009] A Phase IIb randomized, double-blind, placebo-controlled clinical trial of topical bacteriophage t4 endonuclease v in renal allograft recipients with a history of non-melanoma skin cancer. ClinicalTrials. gov Identier: NCT00089180. Available from: http://clinicaltrials.gov/ ct2/show/NCT00089180 [Last accessed 27 August 2009] Reagan-Shaw S, Mukhtar H, Ahmad N. Resveratrol imparts photoprotection of normal cells and enhances the efcacy of radiation therapy in cancer cells. Photochem Photobiol 2008;84:415-21 Aziz MH, Reagan-Shaw S, Wu J, et al. Chemoprevention of skin cancer by grape constituent resveratrol: relevance to human disease? FASEB J 2005;19:1193-5 Baliga MS, Katiyar SK. Chemoprevention of photocarcinogenesis by selected dietary botanicals. Photochem Photobiol Sci 2006;5:243-53 Elmets CA, Singh D, Tubesing K, et al. Cutaneous photoprotection from ultraviolet injury by green tea polyphenols. J Am Acad Dermatol 2001;44:425-32 Fryer MJ. Evidence for the photoprotective effects of vitamin E. Photochem Photobiol 1993;58:304-12 Rhie G, Shin MH, Seo JY, et al. Agingand photoaging-dependent changes of enzymic and nonenzymic antioxidants in the epidermis and dermis of human skin in vivo. J Invest Dermatol 2001;117:1212-17 Gensler HL, Magdaleno M. Topical vitamin E inhibition of immunosuppression and tumorigenesis induced by ultraviolet irradiation. Nutr Cancer 1991;15:97-106 Foote JA, Ranger-Moore JR, Einspahr JG, et al. Chemoprevention of human actinic keratoses by topical DL-a-tocopherol. Cancer Prev Res 2009;2:394-400 Halpern AC, Hanson LJ. Awareness of, knowledge of and attitudes to nonmelanoma skin cancer (NMSC) and actinic keratosis (AK) among physicians. Int J Dermatol 2004;43:638-42
85.
Neidecker MV, Davis-Ajami ML, Balkrishnan R, et al. Pharmacoeconomic considerations in treating actinic keratosis. Pharmacoeconomics 2009;27:451-64 Lubritz RR, Smolewski SA. Cryosurgery cure rates of actinic keratosis. J Am Acad Dermatol 1982;7:631-2 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;43:687-92 de Berker D, McGregor JM, Hughes BR, et al. Guidelines for the management of actinic keratoses. Br J Dermatol 2007;156:222-30 Krawtchenko N, Roewert-Huber J, Ulrich M, et al. A randomised study of topical 5% imiquimod vs. topical 5-uorouracil 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):34-40 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;47:258-62 Chiarello SE. Cryopeeling (extensive cryosurgery) for treatment of actinic keratosis: an update and comparison. Dermatol Surg 2000;26:728-32 Emmett AJ, Broadbent GD. Shave excision of supercial solar skin lesions. Plast Reconstr Surg 1987;80:47-54 Moy RL. Clinical presentation of actinic keratoses and squamous cell carcinoma. Am Acad Dermatol 2000;42:8-10 Dinehart SM. The treatment of actinic keratoses. J Am Acad Dermatol 2000;42:25-8 Fu W, Cockerell C. The actinic (solar) keratosis: a 21st-century perspective. Arch Dermatol 2003;139:66-70 An KP, Ratner D. Surgical management of cutaneous malignancies. Clin Dermatol 2001;19:305-20 Geisse JK. Comparison of treatment modalities for squamous cell carcinoma. Clin Dermatol 1995;13:621-6 David LM, Lask GP, Glassberg E, et al. Laser abrasion for cosmetic and medical treatment of facial actinic damage. Cutis 1989;43:583-7
99.
86.
Iyer S, Friedli A, Bowes L, et al. Full face laser resurfacing: therapy and prophylaxis for actinic keratoses and non-melanoma skin cnacer. Lasers Surg Med 2004;34:114-19 Ostertag JU, Quaedvlieg P, Neumann M, Krekels G. Recurrence rates and long-term follow-up after laser resurfacing as a treatment for widespread actinic keratoses in the face and on the scalp. Dermatol Surg 2006;32:261-7 Fulton JE, Rahimi AD, Helton P, et al. Disappointing results following resurfacing of facial skin with CO2 lasers for prophylaxis of keratoses and cancers. Dermatol Surg 1999;25:729-32 Orenstein A, Goldan O, Weissman O, et al. A new modality in the treatment of actinic cheilitis using the Er:YAG laser. J Cosmet Laser Ther 2007;9:23-5 Wollina U, Konrad H, Karamlov T. Treatment of common warts and actinic keratoses by Er: YAG laser. J Cutan Laser Ther 2001;3:63-6 Jiang SB, Levine VJ, Nehal KS, et al. Er: YAG laser for the treatment of actinic keratoses. Dermatol Surg 2000;26:437-40 Coleman WP III, Yarborough JM, Mandy SH. Dermabrasion for prophylaxis and treatment of actinic keratoses. Dermatol Surg 1996;22:17-21 Harmon CB. Dermabrasion. Dermatol Clin 2001;19:439-42, viii Dermabrasion. In: Fewkes JL, Cheney ML, Pollack SV, editors. Illustrated Atlas of Cutaneous Surgery. 1st edition. Philadelphia, PA: J.B. Lippincott Co.; 1992. p. 26.1-26.11 Monheit GD. Medium-depth chemical peels. Dermatol Clin 2001;19:413-25, vii Coleman WP III. Dermal peels. Dermatol Clin 2001;19:405-11 Yamamoto Y, Uede K, Yonei N, et al. Expression of tenascin and human B-1 integrin in the skin peeled with phenol or trichloracetic acid. Aesthetic Dermatol 2003;13:17-24 Yamamoto Y, Uede K, Ueda M, et al. Characterization of monoclonal anti-human skin basal cell antibody 3B 4-6 and its reactivity to the skin peeled with phenol or trichloracetic acid (TCA). Aesthetic Dermatol 2002;12:70-6 Yamamoto Y, Yonei N, Kaminaka C, et al. Effects of phenol peeling on dermal
100.
87.
75.
88.
101.
89.
102.
76.
103.
77.
90.
104.
78.
105.
91.
79.
106. 107.
92.
80.
93.
81.
108. 109. 110.
94.
82.
95.
96.
83.
111.
97.
84.
98.
112.
3028
endothelial cells. J Dermatol Sci 2004;35:158-61 113. Yamamoto Y, Uede K, Otani T, et al. Different apoptotic patterns observed in tissues damaged by phenol and TCA peels. J Dermatol Sci 2006;2(Suppl):75-81 Stuzin JM. Phenol peeling and the history of phenol peeling. Clin Plast Surg 1998;25:1-19 Kaminaka C, Yamamoto Y, Yonei N, et al. Phenol peels as a novel therapeutic approach for actinic keratosis and Bowen disease: prospective pilot trial with assessment of clinical, histologic, and immunohistochemical correlations. J Am Acad Dermatol 2009;60:615-25 Imbertson LM, Beaurline JM, Couture AM, et al. Cytokine induction in hairless mouse and rat skin after topical application of the immune response modiers imiquimod and S-28463. J Invest Dermatol 1998;110:734-9 Wagner TL, Ahonen CL, Couture AM, et al. Modulation of TH1 and TH2 cytokine production with the immune response modiers, R-848 and imiquimod. Cell Immunol 1999;191:10-9 Hemmi H, Kaisho T, Takeuchi O, et al. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol 2002;3:196-200 Hengge UR, Benninghoff B, Ruzicka T, Goos M. Topical immunomodulators progress towards treating inammation, infection, and cancer. Lancet Infect Dis 2001;1:189-98 Kono T, Kondo S, Pastore S, et al. Effects of a novel topical immunomodulator, imiquimod, on keratinocyte cytokine gene expression. Lymphokine Cytokine Res 1994;13:71-6 Arany I, Tyring SK, Stanley MA, et al. Enhancement of the innate and cellular immune response in patients with genital warts treated with topical imiquimod cream 5%. Antiviral Res 1999;43:55-63 Clifford JL, Walch E, Yang X, et al. Suppression of type I interferon signaling proteins is an early event in squamous skin carcinogenesis. Clin Cancer Res 2002;8:2067-72 Tyring S, Conant M, Marini M, et al. Imiquimod; an international update on therapeutic uses in dermatology. Int J Dermatol 2002;41:810-16
124.
Ooi T, Barnetson RS, Zhuang L, et al. Imiquimod-induced regression of actinic keratosis is associated with inltration by T lymphocytes and dendritic cells: a randomized controlled trial. Br J Dermatol 2006;154:72-8 Schon M, Bong AB, Drewniok C, et al. Tumor-selective induction of apoptosis and the small-molecule immune response modier imiquimod. J Natl Cancer Inst 2003;95:1138-49 Stocketh E, Meyer T, Benninghoff B, et al. A randomized, double-blind, vehicle-controlled study to assess 5% imiquimod cream for the treatment of multiple actinic keratoses. Arch Dermatol 2002;138:1498-502 Salasche SJ, Levine N, Morrison L. Cycle therapy of actinic keratoses of the face and scalp with 5% topical imiquimod cream: an open-label trial. J Am Acad Dermatol 2002;47:571-7 Lebwohl M, Dinehart S, Whiting D, et al. Imiquimod 5% cream for the treatment of actinic keratosis: results from two phase III, randomized, double-blind, parallel group, vehicle-controlled trials. J Am Acad Dermatol 2004;50:714-21 Szeimies RM, Gerritsen MJ, Gupta G, et al. Imiquimod 5% cream for the treatment of actinic keratosis: results from a phase III, randomized, double-blind, vehicle-controlled, clinical trial with histology. J Am Acad Dermatol 2004;51:547-55 Gupta AK, Davey V, Mcphail H. Evaluation of the effectiveness of imiquimod and 5-uorouracil for the treatment of actinic keratosis: critical review and meta-analysis of efcacy studies. J Cutan Med Surg 2005;9:209-14 Falagas ME, Angelousi AG, Peppas G. Imiquimod for the treatment of actinic keratosis: a meta-analysis of randomized controlled trials. J Am Acad Dermatol 2006;55:537-8 Hadley G, Derry S, Moore RA. Imiquimod for actinic keratosis: systematic review and meta-analysis. J Invest Dermatol 2006;126:1251-5 Stocketh E, Christophers E, Benninghoff B, Sterry W. Low incidence of new actinic keratoses after topical 5% imiquimod cream treatment: a long-term follow-up study. Arch Dermatol 2004;140:1542
134.
Rivers JK, Rosoph L, Provost N, et al. Open-label study to assess the safety and efcacy of imiquimod 5% cream applied once daily three times per week in cycles for treatment of actinic keratoses on the head. J Cutan Med Surg 2008;12:97-101 Stocketh E, Sterry W, Carey-Yard M, et al. Multicentre, open-label study using imiquimod 5% cream in one or two 4-week courses of treatment for multiple actinic keratoses on the head. Br J Dermatol 2007;157:(Suppl 2):41-6 Alomar A, Bichel J, McRae S. Vehicle-controlled, randomized, double-blind study to assess safety and efcacy of imiquimod 5% cream applied once daily 3 days per week in one or two courses of treatment of actinic keratoses on the head. Br J Dermatol 2007;157:133-41 Korman N, Moy R, Ling M, et al. Dosing with 5% imiquimod cream 3 times per week for the treatment of actinic keratosis: results of two phase 3, randomized, double-blind, parallel-group, vehicle-controlled trials. Arch Dermatol 2005;141:467-73 Zeichner JA, Stern DW, Uliasz A, et al. Placebo-controlled, double-blind, randomized pilot study of imiquimod 5% cream applied once per week for 6 months for the treatment of actinic keratoses. J Am Acad Dermatol 2009;60:59-62 Ulrich C, Bichel J, Euvrard S, et al. Topical immunomodulation under systemic immunosuppression: results of a multicentre, randomized, placebo-controlled safety and efcacy study of imiquimod 5% cream for the treatment of actinic keratoses in kidney, heart, and liver transplant patients. Br J Dermatol 2007;157:(Suppl 2):25-31 Pearlman DL. Weekly pulse dosing: effective and comfortable topical 5-uorouracil treatment of multiple facial actinic keratoses. J Am Acad Dermatol 1991;25:665-7 Yentzer B, Hick J, Williams L, et al. Adherence to a topical regimen of 5-uorouracil, 0.5%, cream for the treatment of actinic keratoses. Arch Dermatol 2009;145:203-5 Weiss J, Menter A, Hevia O, et al. Effective treatment of actinic keratosis with 0.5% uorouracil cream for 1, 2, or 4 weeks. Cutis 2002;70(2 Suppl):22-9 Loven K, Stein L, Furst K, et al. Evaluation of the efcacy and tolerability of 0.5%
114.
125.
135.
115.
126.
136.
116.
127.
137.
117.
128.
138.
118.
129.
119.
139.
130.
120.
131.
140.
121.
132.
141.
122.
133.
142.
123.
143.
3029
uorouracil cream and 5% uorouracil cream applied to each side of the face in patients with actinic keratosis. Clin Ther 2002;24:990-1000 144. Price NM. The treatment of actinic keratoses with a combination of 5-uorouracil and imiquimod creams. J Drugs Dermatol 2007;6:778-81 Tanghetti E, Werschler P. Comparison of 5% 5-uorouracil cream and 5% imiquimod cream in the management of actinic keratoses on the face and scalp. J Drugs Dermatol 2007;6:144-7 An KP, Athar M, Tang X, et al. Cyclooxygenase-2 expression in murine and human nonmelanoma skin cancers: implications for therapeutic approaches. Photochem Photobiol 2002;76:73-80 Denkert C, Kobel M, Berger S, et al. Expression of cyclooxygenase 2 in human malignant melanoma. Cancer Res 2001;61:303-8 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;146:94-100 Mastrolonardo M. Topical diclofenac 3% gel plus cryotherapy for treatment of multiple and recurrent actinic keratoses. Clin Exp Dermatol 2009;34:33-5 Smith SR, Morhenn VB, Piacquadio DJ. Bilateral comparison of the efcacy and tolerability of 3% diclofenac sodium gel and 5% 5-uorouracil cream in the treatment of actinic keratoses of the face and scalp. J Drugs Dermatol 2006;5:156-9 Kose O, Koc E, Erbil AH, et al. Comparison of the efcacy and tolerability of 3% diclofenac sodium gel and 5% imiquimod cream in the treatment of actinic keratosis. J Dermatolog Treat 2008;19:159-63 Buggiani G, Troiano M, Rossi R, et al. Photodynamic therapy: off-label and alternative use in dermatological practice. Photodiagnosis Photodyn Ther 2008;5:134-8 Wang XL, Wang HW, Guo MX, et al. Treatment of skin cancer and pre-cancer using topical ALA-PDT a single hospital experience. Photodiagnosis Photodyn Ther 2008;5:127-33 Touma D, Yaar M, Whitehead S, et al. A trial of short incubation, broad-area photodynamic therapy for facial actinic
keratoses and diffuse photodamage. Arch Dermatol 2004;140:33-40 155. Braathen LR, Szeimies RM, Basset-Seguin N, et al. Guidelines on the use of photodynamic therapy for nonmelanoma skin cancer: an international consensus. International society for photodynamic therapy in dermatology, 2005. J Am Acad Dermatol 2007;56:125-43 Piacquadio DJ, Chen DM, Farber HF, et al. Photodynamic therapy with aminolevulinic acid topical solution and visible blue light in the treatment of multiple actinic keratoses of the face and scalp: investigator-blinded, phase 3, multicenter trials. Arch Dermatol 2004;140:41-6 Tierney E, Barker A, Ahdout J, et al. Photodynamic therapy for the treatment of cutaneous neoplasia, inammatory disorders, and photoaging. Dermatol Surg 2009;35:725-46 Dusa Pharmaceuticals. Levulan Kerastick (aminolevulinic acid HCL) for topical solution, 20%. Product Insert; 2004 Smith S, Piacquadio D, Morhenn V, et al. Short incubation PDT versus 5-FU in treating actinic keratoses. J Drugs Dermatol 2003;2:629-35 Pariser DM, Lowe NJ, Stewart DM, et al. Photodynamic therapy with topical methyl aminolevulinate for actinic keratosis: results of a prospective randomized multicenter trial. J Am Acad Dermatol 2003;48:227-32 Tarstedt M, Rosdahl I, Berne B, et al. A randomized multicenter study to compare two treatment regimens of topical methyl aminolevulinate (Metvix)-PDT in actinic keratosis of the face and scalp. Acta Derm Venereol 2005;85:424-8 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;14:99-106 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;23:1061-5
164.
Shaffelburg M. Treatment of actinic keratoses with sequential use of photodynamic therapy; and imiquimod 5% cream. J Drugs Dermatol 2009;8:35-9 Gupta AK. The management of actinic keratoses in the United States with topical uorouracil: a pharmacoeconomic evaluation. Cutis 2002;70(2 Suppl):30-6 Muston D, Downs A, Rives V. An economic evaluation of topical treatments for actinic keratosis. J Dermatolog Treat 2009:1-10 Caekelbergh K, Annemans L, Lambert J, Roelandts R. Economic evaluation of methyl aminolaevulinate-based photodynamic therapy in the management of actinic keratosis and basal cell carcinoma. Br J Dermatol 2006;155:784-90 Ogbourne SM, Suhrbier A, Jones B, et al. Antitumor activity of 3-ingenyl angelate: plasma membrane and mitochondrial disruption and necrotic cell death. Cancer Res 2004;64:2833-9 Siller G, Gebauer K, Welburn P, et al. PEP005 (ingenol mebutate) gel, a novel agent for the treatment of actinic keratosis: results of a randomized, double-blind, vehicle-controlled, multicentre, phase IIa study. Australas J Dermatol 2009;50:16-22 Challacombe JM, Suhrbier A, Parsons PG, et al. Neutrophils are a key component of the antitumor efcacy of topical chemotherapy with ingenol-3-angelate. J Immunol 2006;177:8123-32 Anderson L, Schmieder GJ, Werschler WP, et al. Randomized, double-blind, double-dummy, vehicle-controlled study of ingenol mebutate gel 0.025% and 0.05% for actinic keratosis. J Am Acad Dermatol 2009;60:934-43 Testerman TL, Gerster JF, Imbertson LM, et al. Cytokine induction by the immunomodulators imiquimod and S-27609. J Leukoc Biol 1995;58:365-72 Tomai MA, Gibson SJ, Imbertson LM, et al. Immunomodulating and antiviral activities of the imidazoquinoline S-28463. Antiviral Res 1995;28:253-64 Jones T. Resiquimod 3M. Curr Opin Investig Drugs 2003;4:214-18 Szeimies RM, Bichel J, Ortonne JP, et al. A phase II dose-ranging study of topical
165.
145.
166.
156.
167.
146.
147.
157.
168.
148.
158.
169.
149.
159.
150.
160.
170.
151.
161.
171.
152.
162.
172.
153.
173.
163.
174. 175.
154.
3030
resiquimod to treat actinic keratosis. Br J Dermatol 2008;159:205-10 176. Jager S, Laszczyk MN, Schefer A. A preliminary pharmacokinetic study of betulin, the main pentacyclic triterpene from extract of outer bark of birch (Betulae alba cortex). Molecules 2008;13:3224-35 Krasutsky PA. Birch bark research and development. Nat Prod Rep 2006;23:919-42 Huyke C, Reuter J, Rodig M, et al. Treatment of actinic keratoses with a novel 179.
betulin-based oleogel. A prospective, randomized, comparative pilot study. J Dtsch Dermatol Ges 2009;7:128-33 Swanson N, Rosen, T Berman B, et al. Optimizing imiquimod for treating actinic keratosis of the full face or balding scalp: imiquimod 2.5% and 3.75% applied daily for two 2-week or 3-week cycles. Poster presented at the 12th World Congress on Cancers of the Skin, 3 6 May 2009, Tel-Aviv, Israel
177.
178.
Brian Berman MDPhD, Sadegh Amini MD, Whitney Valins BS & Samantha Block BS Author for correspondence University of Miami, Miller School of Medicine, Department of Dermatology and Cutaneous Surgery, 1600 NW 10th Ave, RMSB, Room 2023A (R250), Miami, FL 33136, USA Tel: +1 305 243 5620; Fax: +1 305 243 6191; E-mail: bberman@med.miami.edu
Afliation
3031

Expert Opinion On Pharmacotherapy December 2009, Vol. 10, No. 18, Pages 3015-3031 - 3015-3031.

Enviado por

Dados do documento

Descrição original:

Título original

Direitos autorais

Formatos disponíveis

Compartilhar este documento

Compartilhar ou incorporar documento

Opções de compartilhamento

Você considera este documento útil?

Este conteúdo é inapropriado?

Direitos autorais:

Formatos disponíveis

Expert Opinion On Pharmacotherapy December 2009, Vol. 10, No. 18, Pages 3015-3031 - 3015-3031.

Enviado por

Direitos autorais:

Formatos disponíveis

Review

Pharmacotherapy of actinic keratosis

Pharmacotherapy of actinic keratosis

Expert Opin. Pharmacother. (2009) 10(18)

Berman, Amini, Valins & Block

Expert Opin. Pharmacother. (2009) 10(18)

Pharmacotherapy of actinic keratosis

Treatment of actinic keratosis

Expert Opin. Pharmacother. (2009) 10(18)

Berman, Amini, Valins & Block

Field-directed treatment modalities Nonablative and ablative laser resurfacing

Expert Opin. Pharmacother. (2009) 10(18)

Pharmacotherapy of actinic keratosis

Topical immunomodulators Imiquimod

Expert Opin. Pharmacother. (2009) 10(18)

Berman, Amini, Valins & Block

Expert Opin. Pharmacother. (2009) 10(18)

Pharmacotherapy of actinic keratosis

Expert Opin. Pharmacother. (2009) 10(18)

Berman, Amini, Valins & Block

Expert Opin. Pharmacother. (2009) 10(18)

Pharmacotherapy of actinic keratosis

Newer and investigational treatment modalities Ingenol mebutate

Expert Opin. Pharmacother. (2009) 10(18)

Berman, Amini, Valins & Block

Expert Opin. Pharmacother. (2009) 10(18)

Pharmacotherapy of actinic keratosis

Expert Opin. Pharmacother. (2009) 10(18)

Berman, Amini, Valins & Block

Expert Opin. Pharmacother. (2009) 10(18)

Pharmacotherapy of actinic keratosis

108. 109. 110.

Expert Opin. Pharmacother. (2009) 10(18)

Berman, Amini, Valins & Block

Expert Opin. Pharmacother. (2009) 10(18)

Pharmacotherapy of actinic keratosis

Expert Opin. Pharmacother. (2009) 10(18)

Berman, Amini, Valins & Block

Expert Opin. Pharmacother. (2009) 10(18)

Você também pode gostar