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

8/2/2019 Expert Opinion on Pharmacotherapy December 2009, Vol. 10, No. 18, Pages 3015-3031- 3015-3031.

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1. Introduction

2. Prevention

3. Treatment of actinic keratosis

4. Expert opinion

Review

Pharmacotherapy of actinickeratosisBrian Berman, Sadegh Amini, Whitney Valins & Samantha Block

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

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 (lesion-

directed treatment), while multiple and sublinical AKs are treated with field-

directed therapies that use ablative, nonablating and other topically applied

treatment modalities. Owing to difficulties in predicting which AK will prog-

ress 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 treat-

ment modality for AKs. Avoidance of sun and artificial sources of ultraviolet

light, applying sunscreen and self-examination are among the most effective

preventive measures. Chemopreventive modalities such as retinoids,

2-(Difluoromethyl)-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 curet-

tage. Field-directed treatment modalities include nonablative and ablative

laser resurfacing, dermabrasion, chemical peels, topical immunomodulators

(imiquimod, 5-fluorouracil and diclofenac) and photodynamic therapy. And,

finally, newer and investigational treatment modalities such as ingenol

mebutate, resiquimod and betulinic acid are also being discussed.

Keywords: actinic keratosis, field-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 treatmentmodality for actinic keratoses (AKs). These include risk factors such as history ofchronic ultraviolet B (UVB) exposure, which causes mutations on the tumorsuppressor gene p53 [1-3]; history of genetic DNA instability or melanin deficiency,as seen in cases of autosomal recessive inherited type 1 and 2 albinism and xerodermapigmentosum respectively [4-7]; older age [8,9]; male gender [10-12]; Fitzpatrick skinphototypes I II; and history of living in lower latitudes (i.e., closer to the

equator) [13,14]. Other factors to consider include anatomical distribution, havingmore than 80% of AKs located on the head and neck, dorsum of forearms, andhands, 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 oftenthan visible AKs, particularly in sun-damaged skin [17]. At the time of treating AKsthe clinician has to decide between two approaches: treating only one (or a few)visible lesions (lesion-directed) versus treating multiple (sometimes hundreds)invisible lesions (field-directed) [18,19]. AKs represent the initial intraepidermalmanifestation of abnormal keratinocyte proliferation with the potential of progressionto squamous cell carcinoma (SCC). SCC is the second leading cause of skin cancer

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deaths in the USA, with 40% of SCC developing fromclinically normal skin in the previous year, and 60 65%of SCC arising from previous AKs [20,21]. The risk of pro-gression has been calculated to be between 0.025 and 16% peryear [20,22], and the calculated lifetime risk of malignanttransformation 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 difficulty topredict which single AK is going to progress to SCC. Suchniaket al. [26] reported 36% of lesions previously diagnosedclinically as AKs being in fact SCC with 14% being in situSCC. Ehrig et al. [27] showed that 4% of AKs clinicallydiagnosed by board-certified dermatologists were in factSCC and 5% were considered occult early stage of cutaneousmalignancy. Moreover, spontaneous regression has beenreported in as high as 25.9% of AKs over a 12-month period,although 15% later reappeared [28-30]. The goals of thetreatment are to eliminate AKs completely, minimizing theirrisk of progression to invasive SCC, reducing the potential tometastasize and cause death, while obtaining the best cosmet-ically acceptable outcomes. Additionally, treatment reducessymptoms like tenderness and pruritus [21].

AKs management options are chosen depending onwhether a lesion-directed or a field-directed therapy is pre-ferred, although combination therapies have also beenreported [31]. Lesion-directed therapy includes ablative andsurgical procedures reserved for cases where only a fewclinically AKs are visible. AKs treated in this manner areusually thick lesions (e.g., hypertrophic or lichen planus-likekeratosis) 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 withmultiple clinically visible AKs. It offers the advantage of alsotreating subclinical lesions that are likely later to becomeclinically visible AKs.

In this review the most reliable evidence-based data fromstudies available in PUBMED were analyzed particularly focus-ing on randomized, controlledclinical trials with large numbersof subjects. When comparing study results it is important toconsider which measurements were used to evaluate the efficacyand safety end points. Some studies evaluate the patient com-plete response (CR) rate (the percentage of patients with 100%clearance from baseline), consistent with the FDA standard

primary end point. Other FDA-approvedsecondary end pointsinclude partial response (PR) rate (the percentage of patientswith 75% clearance from baseline) as well as the percentagereduction on AK lesions in a target treatment area. The per-centage reduction may be analyzed as the mean or medianpercentage change in lesion number from the baseline countsor from the peaknumbers ofAKs due to detection of previouslysubclinical lesions. Since the percentages reported by studiesmay represent different end points, direct percentage compar-isons among studies may lead to incorrect conclusions wheninterpretingthedata.Forexample,ifpatientsfromstudyAhada

meanoffourbaselinelesionsandattheendofthestudyameanoftwo lesions, with the end point defined as the mean percentagechange from baseline, the results would show a mean reductionof lesions of 50%. If patients from study B had a mean peak of100 lesions and at the end ofthe study a mean of2 lesions, withthe end point defined asthe mean percentchange fromthe peak

number of lesions, the results would show a mean reduction oflesions of 98%. Directly analyzing the percentages fromstudies A and B, the reader could incorrectly conclude thattreatment from study B seems to be superior to the treatmentfromstudyA,whenthefactisthatthesetwooutcomescannotbecompared as they are calculated in a different way.

In regards to safety end points, although many studies focuson local skin reactions (LSRs), the metrics of assessment varyfrom study to study and, as a rule, none of these tools has beenvalidated. For example, two studies may report scabbing as anLSR. However, different grading scales may be used by eachstudy, making it difficult to compare the studies accurately.

2. Prevention

Prevention is the most important treatment modality forAKs. [28,32]. Effective measures include avoidance of excessivesun exposure, particularly between 1100 and 1400 h, avoidanceof artificial sources of ultraviolet (UV) light such as tanningbeds [33] or prolonged UV treatments, wearing protective cloth-ing, applying sunscreenwith at least 30 SPFthreeto four times aday over sun-exposed areas, and educating patients regardingself-examination to detect signs of malignant transformation.These measures prevent the development of AKs and acceleratetheremission rate of existing lesions[34-36].A5-minskinexamisalso 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 ofmoderate to severe AKs, where daily oral vitamin A (retinol,25,000 UI) significantlydecreased (32%)the 5-yearprobabilityof generating a new SCC with no significant toxicity.

UV is a potent carcinogen capable of inducing the threephases of skin carcinogenesis (initiation, promotion andprogression). The most effective and practical approach hasbeen the inhibition of the promotion phase more than treatinga developed cancer [38-41]. Tumor promotion includes a long

(reversible) period ( 10 years) of clonal expansion ofUV-induced DNA-damaged cells which may evolve intopremalignant and malignant lesions [38,41].

Current molecular targets of human skin cancer chemo-prevention include nuclear retinoid receptors, p53 mutations,and several cellular pathways. These include UV-inducedmitogen-activated protein kinase (MAPK) signal transductionpathways, which control genes involved in cell proliferation,differentiation, and tumorigenesis such as the ActivatorProtein -1 (AP-1) complex, and also the arachidonicacid/clyclooxygenase pathway, polyamine synthesis (ornithine

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decarboxylase) pathway, phosphotidylinositol 3-kinase/Akt(PI3K/Akt) pathway, and nuclear factor-kappa B path-way [39,41]. Several compounds for chemoprevention of skincancer have been evaluated in clinical trials [39,42].

2.1 Retinoids

Retinoids have consistently been shown to be effective bothorally and topically [37,43,44]. Retinoids downregulate theexpression of AP-1 responsive genes, activate transrepressionof AP-1, arrest growth and induce apoptosis and differenti-ation [45-47]. Through transrepression of AP-1, retinoidsalso downregulate the UV-induced overexpression ofclyclooxygenase-2 (COX-2), reducing prostaglandins, whichare increased in AKs and non-melanoma skin cancers(NMSCs) [48-51]. Isotretinoin at 0.25 0.5 mg/kg/day andacitretin at 10 20 mg/day are the most common systemicretinoids used for skin cancer chemoprevention [42,52].

Routine monitoring for clinical signs of retinoid toxicity

and laboratory abnormalities is mandatory. Recommendedlaboratory tests include lipid panel, liver function tests, cre-atinine, glucose, complete blood count and bone radiographs.Owing to their teratogenic effect, retinoids should be avoidedin women of child-bearing potential. In the rare case that theyare prescribed in this population, extensive measures must betaken to prevent pregnancy. A negative pregnancy test isnecessary 1 month before starting treatment and the simul-taneous use of two different effective contraceptive methodsstarting 1 month before treatment and for 1 month(isotretinoin) and 3 years (acitretin) after finishing treatmentis mandatory. [42,52]. In addition, a written consent must beprovided before starting treatment and a negative pregnancy

test is required before each prescription is refilled.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 orarotinoid methyl sulfone cream twice daily for 16 weeks toopposite sides of the face, resulting in a significant reduction(30.3 and 37.8%) in the number of AKs respectively com-pared with baseline (p < 0.01) [58]. Tretinoin cream causedmore 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 forearmsand hands were randomized to apply isotretinoin 0.1% cream

or vehicle cream twice daily to each area that had at least oneAK present at baseline for 24 weeks, resulting in significantreduction in number of facial AKs in the isotretinoin groupcompared with placebo (p = 0.001), while no significant effectwas seen on AKs on the scalp or upper extremities [59].

2.2 2-(Difluoromethyl)-dl-ornithine (DFMO)

Another compound being evaluated is DFMO, an irreversibleinhibitor of ornithine decarboxylase, the rate-limiting enzymein polyamine synthesis [60,61]. Polyamines (e.g., putrescine,

spermidine and spermine) are necessary for normal cellularproliferation, differentiation and apoptosis [62]. They areupregulated during the promotion phase of chemically andUVB-induced skin carcinogenesis models [39]. In a random-ized, placebo-controlled trial [63], DFMO 10% ointment wasapplied for 6 months on one of the forearms of 48 patients

with moderate to severe AKs. Compared with placebo, a23.5% reduction in the number of AKs (p 0.001) and26% decrease in spermidine levels (p = 0.04) was found. Therewas a 4.2% rate of severe and a 10.4% rate of moderate localadverse events requiring treatment modification. In a follow-up study [64] the skin levels of p53, proliferating cell nuclearantigen (PCNA) and the apoptotic rate were measured afterDFMO application. A significant reduction in p53 expressionwas reported (22%; p = 0.04), while PCNA levels andapoptotic rate were not significantly altered. At present, aPhase II, randomized trial is being conducted, comparing theefficacy of DFMO with or without triamcinalone in theprevention of NMSC in patients with AKs [65].

2.3 Perillyl alcohol

Perillyl alcohol (POH)is another substancethat hasbeenshownto have antitumor activity in UV-induced skin carcinogene-sis [66].Itisahydroxylatedmonoterpenefoundinessentialoilsofplants, including citrus peels, mints and celery seeds [67]. POHaffects multiple different steps in the carcinogenesis process. Ithas been shown to induce Ras farnesylation, which thereforeinhibits downstream Ras signaling pathways [68]. It also plays arole in the induction of apoptosis. The effect of POH ontumorigenesis was studied [69], showing that POH had an effecton many parameters, including suppression of inflammation,oxidative stress, the activity of ornithine decarboxylase, thymi-dine incorporation into DNA, the Ras pathway, and alterationof the Bax:Bcl-2 ratio in mice skin. A Phase I, double-blind,placebo-controlled,randomizedtrial [70] studiedthetoxicityandtolerability of POH cream applied to the forearms of patientswith no evidence of sundamage. Thirty-two percent of subjects(8/25) reported mild adverse events such as small papules.Otherwise, there were no significant differences between theappearanceofthePOH-treatedversustheplacebo-treatedareas.

A current randomized, double-blind, placebo-controlled, PhaseIItrialiscomparingahigh-dosePOHcreamwithalowerdoseinthetreatment of patients with AKsand/or sun-damaged skin [71]and will provide more information on the use of POH in

humans.

2.4 T4 endonuclease V (T4N5)

T4 endonuclease V (T4N5), isolated from Escherichia coli,isanenzyme that repairs UV-induced cyclobutane pyrimidinedimers in DNA. These dimers participate in the generationof mutations leading to the development of AKs andNMSC [72,73]. When T4N5 is integrated into liposomes fortopical application, it has been found within the cytoplasm andnucleusofepidermalkeratinocytesandLangerhanscells [72].Inamulticenter, double-blind, randomized clinical trial [73],

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30 patients with xeroderma pigmentosum who had all of theirAKs and cancerous lesions removed before the study wererandomly assigned to apply T4N5 liposome lotion (n = 20)orplacebolotion(n=10)tothefaceandarmsdailyfor1year.Atthe end of the study T4N5 liposome lotion reduced the inci-dence of AKs by more than 68%. A Phase III multicenter,

double-blind, randomized trial to evaluate efficacy and safety ofT4N5 liposome lotion compared with placebo for the preven-tion of AKs and other sun-induced damage in patients withxeroderma pigmentosum is now in development [74]. In addi-tion, a Phase IIb, multicenter, randomized, double-blind, pla-cebo-controlled trial is also in development comparing theincidence of NMSC on the sun-exposed skin of renal transplantrecipientswithahistoryofNMSCtreatedwithT4N5liposomallotion versus placebo [75].

Several in vitro and in vivo animal models have shown thatcompounds such as NSAIDs, green tea polyphenols (includ-ing epigallocatechin-3-gallate; ECGC), apigenin, black teatheaflavins, curcumin, resveratol, proanthocyanidins and sily-marin may have a role in human skin cancer chemopreventionthrough modulation of the molecular targets cellular pathwaysmentioned above [38,39,41,76-79].

2.5 DL-a-tocopherol

DL-a-tocopherol, the biologically active component of vitaminE [80], is a known epidermal antioxidant that is depleted whenthe skin is exposed to UV radiation [81]. Studies show thattopical use of vitamin E prevents skin cancer in mice [82] anddecreases UVB-induced inflammation and cytokine release [83].

A randomized, placebo-controlled trial [83] evaluated thechemopreventive potential of vitamin E by measuring bio-

markers such as p53, PCNA and polyamine concentrations insun-damaged skin. Subjects were randomly assigned to applyeither 12.5% DL-a-tocopherol cream or placebo to each dorsalforearm for 6 months. The results showed that p53 levels andPCNA levels were not significantly altered, while the levels ofpolyamines (putrescine, spermidine and spermine) weredecreased significantly. Although the skin levels of DL-a-tocopherol were highly elevated (p < 0.001), the decline innumber of AKs was insignificant in both the placebo and thetreatment arms after 6 months.

3. Treatment of actinic keratosis

3.1 Lesion-directed treatment modalities

3.1.1 Cryotherapy

Cryotherapy is a destructive modality that is the most-oftenused treatment for AKs [84]. It has been the therapeuticmodality preferred by dermatologists [31] because it is a quick,easy, office-based procedure that does not require anesthesia,that can be used for treating few as well as multiple lesions, andthat used to be the most cost-effective treatment modality.

Although patients now prefer topical agents owing to lessdiscomfort [31], cryotherapy still has a high degree of patient

acceptance, particularly when less than 15 lesions are pres-ent [85]. In addition, physicians in some countries like the USAmay be influenced by the current payment system and there-fore may have a preference for a destructive modality likecryotherapy over a prescription medication. However, in othercountries lacking these economic incentives, cryotherapy

remains a popular and inexpensive option for the treatmentof AKs among dermatologists.

Clearance rates ranging from 39 to 98.8% have beenreported with the use of cryotherapy [24,25,86-88]. The mostcommonly used agent is liquid nitrogen at -195.8C appliedto individual lesions with a cotton-tipped applicator or spray.It causes a nonspecific destruction of normal and atypicalkeratinocytes. The usual application is in a single freeze-thawcycle, with the additional freezing of a 1-mm rim of normalskin with freeze times ranging between 5 and 40 s. In amulticenter Australian study [87] evaluating the efficacy ofcryotherapy for the treatment of AKs on the face and scalp, ofthe 89 patients in the intended-to-treat (ITT) population (421lesions treated), there was a 67.2% lesion response rate perpatient. Of interest, CR was obtained in 39% of lesions frozenfor < 5 s, 69% of lesions frozen for > 5 s, and 83% of lesionsfrozen for > 20 s. Cosmetic outcomes graded goodand excellent were reported in 94% of the CR lesions.Krawtchenko et al. [89] evaluated 75 patients with at leastfive visible and histologically proven AKs in a target area up to50 cm2 on the head, neck or decollete who were randomlyassigned to three treatment groups (cryotherapy, 5-fluoroura-cil (5-FU), or imiquimod). The authors reported a clinicalclearance rate of 68% versus a histological clearance rate of32% with cryotherapy applied for one or two courses at

freezing times of 20 40 s per lesion. After 1 year post-treatment, 4% of the patients sustained clinical clearance ofthe total treatment field, with a recurrence rate of 72%. Theauthors concluded that imiquimod was superior to 5-FU andcryotherapy in sustained lesion clearance and cosmetic out-comes in the treatment of AKs.

Photodynamic therapy (PDT) was compared with cryo-therapy 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 withPDT or cryotherapy included the face (250 AKs (65.1%) vs214 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 lesionthickness, with thinner lesions having a higher response.However, cosmetic outcomes were 96 and 81% respectively.Common adverse events include mild discomfort and thepossibility of developing scarring and dyschromia, particularlyhypochromia.

The use of extensive cryosurgery cryopeeling has beendescribed for the treatment of patients with many AKs [91]. In373 patients with a total of 34,604 AKs predominately on theface and scalp, liquid nitrogen was applied to each individual




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lesion followed by spraying the surrounding skin area. Recur-rence rates were 4% at 6 months and 9% at 6 12 monthspost-treatment. New lesions occurred in 12% of 124/373patients at 12 18 months of follow-up. Although no directhead-to-head comparison with 5-FU was performed, theauthor analyzed long-term data (i.e., 1 3 years postopera-

tively) for both treatments, reporting that cryopeeling wasapproximately twice as effective as 5-FU.

3.1.2 Surgery

Surgical modalities, including full-thickness excision andtangential shave excision, are generally reserved for suspiciouslesions that need further histopathological evaluation toexclude SCC. Common clinical signs indicating the progres-sion towards SCC include bleeding, induration, pain, rapidgrowth or failure to respond to other treatments modalities.Disadvantages of surgical excision include the need for localanesthesia, perioperatory hemostatics and suturing, whichmay lead to inflammation, skin tension and scarring. The

advantage of tangential shave excision is that sutures are notrequired [92,93].

3.1.3 Electrodessication and curettage

Electrodessication and curettage are used for thick and hyper-keratotic AKs, or when AKs are refractory to other treatmentmodalities. Two to three cycles of therapy may be required [88].

With curettage, the atypical tissue is scraped away untilhealthy tissue is reached. It may be followed by electrodessica-tion, which destroys the residual lesion at the margins, andalso is used for postcurettage hemostasis [94]. Like surgicalexcision, curettage enables tissue samples to be collected forhistological evaluation. High cure rates and good cosmeticresults have been reported [94]. Experience is required toperform the procedure since it is necessary to perceive thedifference between atypical cells and healthy tissue [28]. Dis-advantages include the need for local anesthesia and a higherrisk of scarring compared with other modalities, includingcryotherapy [95]. Electrodessication and curettage should beavoided in recurrent lesions, punch-biopsied lesions and hair-bearing sites [28]. They should also be avoided for invasiveSCC and tumors that reach the subcutaneous fat becausemalignant cells extend deeply making their removal difficult.In addition, with electrodesiccation and curettage of invasiveSCC there are no margins available for histological evaluation,

and therefore the potential risks of recurrence and metastasisare elevated [96,97].

3.2 Field-directed treatment modalities

3.2.1 Nonablative and ablative laser resurfacing

Full face resurfacing can provide long-term prevention offuture AKs and SCC. The first use of CO2 lasers for AKswas introduced by David et al. [98]. A retrospective study[99] of24 patients with > 30 facial AKs who underwent resurfacingwith the CO2 and/or Er:YAG laser at least 1 year before thestudy showed that 21/24 patients (87.5%) and 14/24 patients

(58.3%) remained lesion-free after 1 and 2 years respectivelypost-laser treatment. After a median of 42 months, 50% ofpatients remained free of AKs, and the other 50% experienceda total of 28 AKs. Overall, this study found a 94% reductionin the number of AKs. Disadvantages of lasers include theimportance of adherence to postoperative care, lengthy wound

healing and downtime. The most common adverse eventsinclude hyper/hypopigmentation, infections, scarring andacne [100]. Thirty-five patients with photodamage were eval-uated at 3, 6 and 12 months following CO2 laser resurfacingof the decollete, periorbital and hairline areas [101]. With14.3% of patients developing new or recurrent AKs, theauthors concluded that CO2 laser resurfacing is not as effectiveas dermabrasion, chemabrasion and deep chemical peel for theprophylaxis of AKs.

CO2 laser results in separation of the dermis and epidermisthrough thermal induction of subepidermal blister formationand lateral spread of heat. Deeper extensions of the lesionalarea are identified by the presence of increased vascularity andcapillary bleeding, which can be treated with additional passes.The cessation of bleeding is an indication of elimination ofthe AK. After treatment, collagen formation occurs, leavingthe skin with a smooth texture and appearance [99].

Erbium-YAG laser leads to less thermal injury and highercure rates compared with the CO2 laser [102]. This is due to thelasers greater selectivity for water, leading to reduced tissuedamage. In a study by Wollinaet al. [103], 29 patients with AKson 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 10days. Eight patients needed more than one treatment. During

a 3-month follow-up, there was no evidence of recurrence,infection, hypo/hyperpigmentation or scarring. Comparedwith CO2 laser, patients treated with Er:YAG laser experienceless pain and faster healing time [104].

3.2.2 Dermabrasion

Dermabrasion is a surgical procedure used to treat large areasof photodamage with multiple, thick AKs. It uses quicklyrotating diamond fraise or a stainless steel wire brush gener-ating abrasion of skin layers. Dermabrasion is useful in theprophylactic treatment of AKs as demonstrated by a retro-spective study [105] that evaluated its use in 23 patients withmultiple 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 appearanceof new lesions was 4 years.

Necessary preoperatory evaluations include addressing thetendency of developinghypertrophicscarring or keloids, historyofcompletingprevioustreatmentwithisotretinoinforatleast12months, hepatitis testing, HIV antibody screening, and nasalswabbing for patients with a history of impetigo. Herpes virusprophylayxis must be provided 10 14 days before and 7 10days after the procedure. Re-epithelialization is expectedafter 7 10 days. Persistent erythema could be present from




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1 2 weeks up to 2 3 months. Sun protection is highlyrecommended during recovery. Common adverse eventsinclude permanent hypopigmentation in 10 20% of patients,particularly in darker skin types, reversible hyperpigmentation,and scarring[106,107].

3.2.3 Deep and medium-depth chemical peelsChemical peeling is a destructive method where caustic agentsare applied to the skin, causing necrosis at specific depths.Chemical peels range from superficial to deep, based on theagent used, concentration, time of application and thickness ofthe skin area to be treated. The efficacy is approximately 75%with recurrence rates of 25 35% [24]. Inflammation in thepapillary dermis defines a medium depth peel, while inflam-mation in the deeper reticular dermis constitutes a deepchemical 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 aconcentration of 35% and as a deep peel at concentrationsover 50%. Of importance, concentrations greater than 40%have increased risk of scarring[109]. To reduce this risk, severalapproaches have been taken including the use of combinationtherapies where a superficial agent (i.e., CO2 ice, Jessnerssolution, and glycolic acid) is used that disrupts the epidermisbefore peeling to aid penetration [109].

One type of deep peel, the phenol peel, induces damage toendothelial cells more than keratinocytes [110,111], which mayeventually induce ischemic changes and epidermal necro-sis [112,113]. Importantly, when phenol is absorbed systemically,it can lead to cardiac, liver and kidney damage and respiratorydepression. These adverse events correlate with the amount of

skin involved and the duration of the peel [114]. In a pilotstudy [115] the efficacy of the phenol peel was clinically andhistologically assessed in 48 patients with AKs and Bowendisease predominantly on the face and scalp. The resultsshowed that 84.8% (39/48) of patients had a CR after oneto eight treatment sessions. Systemic adverse events were notobserved in any patients. Among the 39 patients with a CR, 32showed no recurrences for over 1 year of follow-up. Histo-logical and immunochemical analysis showed that tumorthickness and cyclin A expression were useful markers fordetermining clinical improvement after the peel.

Following chemical peels, skin protection with moisturizingointment is necessary until the necrotic tissue has peeled away

(usually 4 5 days). The earliest complication of dermal peelsis an infection (viral, fungal or bacterial). Later, postoperativepigmentary changes may occur, which are more common inpatients with Fitzpatrick skin types III or IV. On average, apeel does not need to be repeated for at least 2 years [109].

3.2.4 Topical immunomodulators

3.2.4.1 Imiquimod

Imiquimod is an imidazolaquinoline that binds intracellulartoll-like receptors (TLR) 7 and 8 acting as a topicalimmunomodulator. It induces cytokines such as interferon-a

(IFN-a), IFN-g, tumor necrosis factor-a (TNF-a),interleukin-1a (IL-1a), IL-6, IL-8 and IL-12 by humanperipheral blood mononuclear cells including monocytes,macrophages and TLR-7 bearing plasmocytoid dendritic cells.Imiquimod-induced keratinocytes produce IL-6, IL-8 andIFN-a, resulting in a Th1-dominant response [116-121].

IFN-a induces cellular immunity by stimulating CD4 T-cellsto express IL-12 b2 receptor. In addition, IL-12 inducesIFN-g to stimulate cytotoxic T-lymphocytes to kill virusinfected and tumor cells [32]. It has been demonstrated thatsuppression of type I IFN signaling proteins is an early eventleading to SCC [122] Since imiquimod increases the levels oftype I IFN, it may help to improve the responsiveness toendogenous IFN-a, which is typically low in AKs [32,123].

A Phase I, randomized, double-blind, parallel-group, vehi-cle-controlled study [124] evaluated the nature of the cellularinfiltrates and cells involved in the cutaneous immuneresponse induced by the application of imiquimod 5% creamor vehicle to five AK lesions on the scalp, forearm or uppertrunk of 18 patients once daily, 3 days a week for up to 16weeks. Imiquimod significantly increased tissue biomarkerlevels for CD3, CD4, CD8, CD11c, CD86, CD11c,CD68, HLA-DR and TUNEL compared with baseline,with no differences obtained in the vehicle group. Imiquimodstimulated a cutaneous immune response characterized by anincrease 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 deathreceptors, caspases and cytochrome c in the apoptotic signal-ing cascade. Imiquimod bypassed several signal transduction

pathways inducing activation of caspase-3 downstream ofmembrane-bound death receptor activation, and also activatedthe mitochondrial release of cytochrome c in a Bcl-2-dependent fashion, providing evidence of the antineoplasticactivity of imiquimod.

Overall, CR rates of 45 85% have been obtained withimiquimod for the treatment of AKs [126-132]. Recurrence ratesare 10 and 16% within 1 year and 18 months of treatmentrespectively, and are approximately 20% at 24 monthsfollow-up [126,133].

In an open-label study [134] imiquimod 5% cream wasapplied to AK lesions on the head three times a week for 4weeks followed by a 4-week rest and an additional 4 weeks of

treatment in case remaining lesions were present. Fifty percent (30/60) of the patients showed CR and 75% (40/60)showed PR. After 12-months of follow-up, 77% of patientsachieving CR remained free of recurrences.

In a multicenter, non-controlled study [135], 829 patients(7427 baseline lesions) applied imiquimod 5% cream to AKson the head, three times a week for 4 weeks followed by a4-week rest. A second 4-week course was applied in case ofremaining lesions. A CR rate of 40.5% after the first course oftreatment and overall clearance rate of 68.9% was reported.Eighty-five per cent of the total number of lesions was cleared.




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Common adverse events included LSRs. In a multicenter,vehicle-controlled, randomized, double-blind study by

Alomar et al. [136], using the same treatment schedule, 259patients (855 AKs) with lesions within a contiguous 25-cm2

treatment area on the face or the balding scalp were random-ized to receive imiquimod 5% cream or vehicle with a median

number of six and seven baseline AKs, respectively. A CR rateof 37.2% was obtained in the imiquimod group comparedwith 0.8% in the vehicle group after the first course oftreatment (p < 0.0001). Overall CR rates of 55.0 and2.3%, respectively, were reported (p < 0.0001). The overallpercentage of patients that obtained PR was 65.9% in theimiquimod-treated group and 3.8% in the vehicle-treatedgroup (p < 0.0001). The individual lesion clearance rate afterthe first course of treatment and at the end of the study were61.1 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 eventsreported by the investigators were LSRs including erythema,flaking/scaling/dryness, and scabbing/crusting. The mostintense LSRs were significantly more frequent with imiqui-mod than with vehicle and included edema, vesicles, erosion/ulceration and weeping/exudates. No serious adverse eventsrelated to imiquimod were reported.

Two Phase III, multicenter, randomized, double-blind,parallel-group, vehicle-controlled trials evaluated 492 patientswith four to eight AKs in a 25-cm2 treatment area on the faceor 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 significantly higher

than placebo (7.2%; p < 0.001). PR rates were 64.0 and13.6%, respectively (p < 0.001). At 8 weeks follow-up, half ofthe 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 theefficacy of imiquimod 5% cream versus vehicle applied daily,3 days a week, for 16 weeks in 286 patients with five to ninevisible and histologically confirmed AKs located within acontiguous 25-cm2 treatment area on the face or baldingscalp. The CR rate for imiquimod was 57.1% (84/147) versus2.2% (3/139) for the vehicle (p < 0.001). The PR rate forimiquimod 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 efficacy of imi-quimod 5% cream in the treatment of four to eight AKslocated within a contiguous 25-cm2 treatment area on the faceand balding scalp. In these studies 436 patients received eitherimiquimod 5% or vehicle cream once daily, 2 days a week for16 weeks. A CR rate of 45.1% (97/215) was reported in theimiquimod group and 3.2% (7/221) in the vehicle group(p < 0.001). The PR rates for the imiquimod and vehiclegroups were 59.1% (127/215) and 11.8% (26/221),

respectively (p < 0.001). At 8 weeks follow-up half of thepatients that were treated with imiquimod had at least an83.3% reduction in the number of AKs.

Comparison between the two treatment regimens used inthe above studies shows that applying imiquimod 5% creamthree times a week results in a higher clinical response than

twice a week. However, this difference was smaller thanexpected, probably owing to lower rate of CR obtained inone of the studies that evaluated the three times-a-weekregimen (40.8%). In addition, the difference can also beattributed to random variation seen with clinical studies.The median percentage of reduction in the number of AKsfrom baseline was greater than 86% in the studies with threetimes-a-week application compared with 83.3% in the studieswith twice-a-week application. More local skin and applica-tion site reactions, more rest periods, and more subjects whodiscontinued treatment due to LSRs were associated with thethree times-a-week regimen [137]. The most common adverseevents related to imiquimod were local site reactions includingerythema, scabbing/crusting, flaking/scaling/dryness, and ero-sion/ulceration, with the majority resolving by 8 weeks post-treatment [128,129,137].

A split-face, placebo-controlled, double-blind study [138]assessed the efficacy of imiquimod 5% cream applied to a20-cm2 area on one side of the face, once a week for 6 monthsto 20 patients with a minimum of six symmetrically distrib-uted AKs. At the end of the study, 7/15 patients (46.7%) hadmarked improvement with imiquimod compared with 1/15(6.7%) with placebo. All patients receiving imiquimodreported some degree of improvement, while of those receiv-ing placebo, six patients had no improvement and seven had

slight worsening. An average change of +2.20 in the investi-gator assessment score was recorded for imiquimod, comparedwith -0.27 for the placebo group (p = 0.0002).

A multicenter, randomized, placebo-controlled study [139]evaluated the safety and efficacy of imiquimod 5% cream forthe treatment of AKs in post-transplanted patients receivingimmunosuppressive therapy within the previous 6 months.Forty-three patients applied imiquimod or vehicle three timesa week for 16 weeks to a 100-cm2 contiguous field containing4 10 AKs on the face, forehead or balding scalp. Patientsreceiving imiquimod showed a CR rate of 62.1% (18/29)versus 0% of patients receiving placebo. Histological confir-mation 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.

Commonimiquimod-relatedadverseeventsincludedmildtomoderate application sitereactions (5/29), fatigue (1/29), head-ache (1/29), diarrhea (1/29), nausea (1/29), rash (1/29), skindisorder (1/29) and leucopenia (1/29). Of importance, nopatient in the study reported transplant rejection. Imiquimoddemonstratedtobeeffectiveandwell-toleratedforthetreatmentof AKs in post-transplant immunosuppressed patients.

In a randomized study [89], 75 patients with at least fivevisible and histologically proven AKs in a target area up to




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50 cm2 on the head, neck or decollete were assigned to receiveone 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 aweek 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% respec-tively. At 12 months post-treatment, sustained clearance ofinitially cleared AKs was seen in 28% with cryosurgery, 54%with 5-FU and 73% with imiquimod (p < 0.01). Imiquimodachieved the best cosmetic outcomes (p = 0.0001).

3.2.4.2 5-Fluorouracil

Topical 5-fluorouracil (5-FU) is a chemotherapeutic agentthat interferes with DNA synthesis by inhibiting thymidylatesynthetase decreasing cell proliferation, and causing cell death,particularly in fast-growing dysplastic cells [32]. The efficacy of5-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 arealso treated [28]. Recurrence rates of up to 55% have beenreported [3]. Low treatment compliance, due to adverse events,is associated with 60% failure rates [94]. In a prospectivestudy [141], 20 patients with moderate to severe AKs of theface and scalp were instructed to apply 5-FU 0.5% creamnightly for 4 weeks. Partial to complete response was reportedin 53% of patients at week 8. Seventy-nine per cent of patientsreported at least one adverse event including tenderness,burning, erythema and blistering. Based on electronic mon-itoring, 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-controlledstudy [142] evaluated 177 patients with at least five AKs whoapplied 5-FU 0.5% cream or vehicle once daily for 1, 2 or4 weeks. Complete clearance was obtained in 26, 20 and 48%of the patients respectively, compared with 3.4% of patientsreceiving the vehicle.

In a single-blind, randomized study [143], patients with sixor more AKs who were treated with 5-FU 0.5% cream oncedaily and 5-FU 5% cream twice daily on opposite sides of theface for 4 weeks were evaluated. The reduction in the numberof AKs was significantly greater with the 0.5% cream than

with the 5% cream (p = 0.044). Both concentrations wereequally effective in the percent reduction of AKs comparedwith baseline (67 and 47%, respectively).

In a prospective study, 64 patients with multiple AKs on theface, scalp, upper limbs or legs were treated with a combina-tion of 5% 5-FU cream applied each morning for 1 week andimiquimod 5% cream applied nightly for 6 nights [144]. Thetreatment regimen consisted of three courses, each separatedby a rest period of 3 4 weeks. Combination therapy resultedin a shorter time to obtain an adequate response and feweradverse events when compared with each individual treatment.

This was attributed to the synergistic effect of combining thetwo different mechanisms of action.

A randomized, physician-blinded study[145] compared theefficacy of 5-FU 5% cream applied twice daily for 2 4 weeksto imiquimod 5% cream applied twice daily for 16 weeks in36 patients with at least four AKs in one 25-cm2 area on the

face, forehead and scalp. At week 24 the total AK count wasreduced by 94% with 5-FU compared with baseline versus66% with imiquimod. CR rates at week 24 were 84% versus24% respectively. 5-FU was more effective in exposing andtreating subclinical AKs, reducing the final count of AKs, andachieving CR. Adverse event profiles were similar with bothtreatments.

3.2.4.3 Diclofenac

Diclofenac is a nonsteroidal anti-inflammatory agent thatinhibits cyclooxygenase, the rate-limiting enzyme in the syn-thesis of prostaglandins. Diclofenac has a greater affinity forCOX-2 than for COX-1. Expression of COX-2 is increased in

AKs, melanoma and NMSC, and other neoplasias. In addi-tion, prostaglandins potentially contribute in the developmentof UV-induced NMSC [49,146,147]. One of the roles of diclo-fenac in the treatment of AKs may be based in the inhibitionof UV-induced prostaglandins. By the same principle, mul-tiple UV-induced proinflammatory cytokines such as IL-1,TNF-a, transforming growth factor-b (TGF-b) also capableof inducing COX-2, may be inhibited by diclofenac. Theaddition of hyaluronic acid 2.5% vehicle gel decreases thediffusion of diclofenac through the skin, increasingdiclofenacs time of exposure to the epidermis and enhancingits delivery to the atypical cells [32].

In a multicenter, randomized, double-blind, placebo-controlled study [148], 195 patients with a minimum of five

AKs contained in up to three 5-cm2 areas on the forehead,central face, scalp or dorsal hands were treated twice daily with3.0% diclofenac in 2.5% hyaluronan gel or hyaluronan gelalone for 30 or 60 days. Treatment with diclofenac-hyaluronanfor60 days showedmore efficacy than the 30-dayapplication orthe vehicle. The sequential treatment with diclofenac 3% geland cryotherapy has also shown to be an effective approach forthe management of multiple refractory AKs [149].

A single-center, randomized, bilateral, open-label, evaluator-blinded study compared 5-FU 5% cream and diclofenac3% gel in 30 patients (n = 251 AKs) with at least three

AKs on each side of the face and/or scalp. Diclofenac wasrandomly assigned to be applied to one side of the face and/orscalp, twice daily for 90 days. At day 62, 5-FU was appliedtwice daily to the opposite side of the face, for the final 28 daysof the study. Results showed that the efficacies of diclofenacand 5-FU were similar, slightly favoring 5-FU, with morepatients reporting adverse events with 5-FU [150].

In a randomized, comparative, open-label study [151] theefficacy of daily diclofenac 3% gel was compared with imi-quimod 5% cream three times a week for 12 weeks in49 patients with at least three AKs on the face and scalp.




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A CR rate of 12% in the diclofenac group versus 22% in theimiquimod group was reported by investigator assessments,while CRs recorded by patient assessments were 28% versus23%, respectively. There were no significant differencesbetween the two groups (p > 0.05), and both treatmentswere well tolerated.

3.2.5 Photodynamic therapy

Photodynamic therapy (PDT) is a noninvasive, effective andtolerable treatment for numerous, thin, nonhyperkeratotic

AKs [152,153]. In PDT, aminolevulinic acid (ALA) or methyl-aminolevulinate (MAL) is topically applied to the target area.Upon absorption these precursors accumulate inside dysplasticand neoplastic cells at a rate up to 10 times higher than innormal cells [90,154-156], where they are converted intophotoporphyrin IX, a potent photosensitizer. After an incuba-tion period, the target area is exposed to a light source causingactivation of photoporphyrin IX, leading to the formation ofreactive oxygen species (ROS), particularly singlet oxygen. The

specificityofALA-PDTdependsonthewavelengthcorrespond-ing to theabsorption peak of thephotosensitizer andenables theappropriate penetration to the pathologic process being tar-geted. Genes such as Bcl-2 help regulate PDTs destruction ofdysplastic cells. Depending on the dosing and time after treat-ment, theresult may be growthinhibition, necrosis or apoptosisofthetargetedcells [32,90,154-157].Thelinkbetweentheformationof ROS following PDT and the proteolytic events leading toapoptosis remains unknown.

Two multicenter, Phase III studies evaluated 243 patientswith AKs on the face and scalp, [158] who were treated with

ALA-blue light once, or twice (after 8 weeks) if CR was notachieved 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-controlledstudy [156], 243 patients (1403 AKs on scalp and face) wererandomized to receive ALA or vehicle, followed by 14 18 hof incubation and further exposure to blue light. At 8 weeks,30% of patients who responded partially were retreated. At12 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 themost common adverse event.

In a randomizedstudy[159], 36 patients with at least fourAKson the face or scalp receiving twosessions of ALA-PDT or ALA-

pulse dye laser (ALA-PDL) using a short incubation time (1 h)separated by 30 days was compared with topical treatment with5-FU 0.5% cream once or twice daily for 4 weeks. At 1 monthpost-treatment, the overall individual lesion clearance rates for5-FU, ALA-PDT, andALA-PDL were 79, 80 and50%, respec-tively. CR rates were 50, 50 and 8%, respectively, and PR rateswere 75, 75 and 42%, respectively. ALA-PDT and ALA-PDLwere better tolerated than 5-FU.

Amulticenter,double-blind, randomized, placebo-controlledstudy[160] evaluated 80 patients with 4 10 AKs on the face andscalp who received two treatment sessions 1 week apart with

either MAL-red light-PDT or placebo (red light alone). CRobtained at 3 months was 89% with MAL-PDT comparedwith 38% with placebo. More than 90% of patients treatedwith MAL-PDT reported excellent or good cosmetic result.

In a multicenter, randomized, open study involving 211patients with 413 AKs on the face or scalp [161], the efficacy

and safety of different MAL-PDT regimens was evaluated.With one regimen, patients received a single treatment fol-lowed by repeat treatment if CR was not achieved by 3months. With the other regimen, patients received MAL-PDT given as two treatments 1 week apart. For thin lesions,after single treatment, the CR rate was 93%, but increased to97% after repeat treatment, while for the two-treatmentregimen the CR rate was 89%. For thicker lesions, the CRrate was 70% after single treatment, but improved to 88%after repeat treatment, while for the two-treatment regimenthe CR rate was 84%. MAL-PDT single treatment is aseffective as two treatments for thin AKs, but repeated treat-ment is recommended for thicker or nonresponsive lesions.

When PDT has been compared with cryotherapy, mixedresults have been reported, although cosmetic outcomes havebeen consistently superior with PDT [90,162].

The efficacies of ALA-PDT and imiquimod were comparedin 30 patients with a total of 256 AKs on the dorsal hands andforearms [163]. ALA-PDT (two sessions 15 days apart) orimiquimod 5% cream (once daily 3 days per week for 4weeks plus 4 weeks of rest, and a second 4-week cycle in casepatients had not achieved CR) was applied to a randomlyallocated 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 6months, no statistical difference was obtained for investigator-assessed cosmetic outcome, which was excellent in 80% oflesions 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 ofefficacy 55% preferred PDT and 45% preferred imiquimod.

A randomized, double-blind, vehicle-controlled, split-facestudy [164] evaluated the efficacy of combination therapy with

ALA-PDTand imiquimod5%cream in patients withmorethan10 AKs. Patients received two sessions of ALA-PDT 1 monthapartonbothsidesofthefacefollowedbyimiquimod5%creamand vehicle starting at month 2, randomly assigned to opposite

sidesof theface.Bothimiquimodand vehiclewere, applied oncedaily twice a week for 16 weeks. At month 12, median lesionreduction was 89.9% for PDT + imiquimod versus 74.5% forPDT + vehicle (p = 0.0023). Severe LSRs included erythemaand flaking/scaling/dryness. The sequential regimen was welltolerated and showed efficacy.

3.3 Treatment cost-effectiveness

There have not been many studies addressing the relationshipbetween the cost and effectiveness of AK treatments [85].

According to one meta-analysis from the USA [165], treatment




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of patients with more than six AKs with 5-FU 0.5% cream maybe more cost-effective than the 1 and 5% concentrations. Onestudy from the UK [166] showed that the cost-effectiveness ofMAL-PDT was comparable to 5-FU and imiquimod for thetreatment of AKs. Finally, a study from Belgium [167] used amedical decision tree created to simulate all the possible

outcomes related to the medical decision. The cost-effectivenessratio was obtained by calculating the total cost per year and theeffects expressed as percentage of patients with a clinicalresponse and an excellent cosmetic outcome, after a periodof 1 year. The AK data were based on a large, multicenter,Phase III, randomized, controlled clinical trial that comparedMAL-PDT head to head with cryotherapy and placebo [162].

Although MAL-PDT showed to be more expensive thancryotherapy for the treatment of AKs, the cost per fullresponder was comparable with cryotherapy. The incrementalcost per full responder showed that MAL-PDT was statisti-cally more expensive than cryotherapy, and the incrementalcost-effectiveness ratio per full responder was not statisticallydifferent from current data obtained with cryotherapy.

3.4 Newer and investigational treatment modalities

3.4.1 Ingenol mebutate

Ingenol mebutate (PEP005) is an extract from the plantEuphorbia peplus (milkweed) that has been used for manyyears as a traditional treatment for skin conditions including

AKs and skin cancers [168,169]. Ingenol mebutate has demon-strated a new mechanism of action for a chemotherapeuticagent initially causing chemoablation by plasma membranedisruption and rapid loss of the mitochondrial membranepotential and subsequent mitochondrial swelling in dysplastickeratinocytes, followed by cell death by primary necrosiswithin 1 h [169]. Further generation of tumor-specific anti-bodies, proinflammatory cytokines and neutrophil infiltrationresults in antibody-dependent cellular cytotoxicity thateliminates residual cells [170].

A multicenter, randomized, double-blind, vehicle-con-trolled Phase IIa study [169] was conducted to evaluate safetyand efficacy of several concentrations of ingenol mebutate forthe treatment of AKs. In a total of 58 patients, five preselected

AKs were treated twice with different concentrations ofingenol mebutate gel either 7 days apart or 1 day apart.

A total of 67% of patients using the 0.05% concentrationachieved 80% clinical clearance of AKs treated, compared

with vehicle (17%; p = 0.0185). This concentration alsoobtained an individual lesion clearance rate of 71%. Allconcentrations were well tolerated.

A multicenter, randomized, double-blind, vehicle-con-trolled study [171] evaluated three dosing regimens with inge-nol mebutate at concentrations of 0.025% (applied once dailyfor 3 days) and 0.05% (applied once daily for 2 or 3 days) in222 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% vs11.7%) obtained by all concentrations were significantly

higher compared with the vehicle. The median percentagereduction in the number of AKs from baseline with ingenolmebutate ranged from 75 to 100% compared with 0% for thevehicle (p < 0.0001). Ingenol mebutate was well tolerated at allconcentrations. At present, several Phase II and Phase IIIstudies are being conducted.

3.4.2 Resiquimod

Resiquimod is an imidazoquinolamine and a toll-like receptor7 and 8 agonist that has comparable stimulatory effects onmonocytic cells, although it is 10- to 100-times more potentthan imiquimod [172-174]. In addition, it induces interleukin-1receptor antagonist (IL-1ra), granulocyte colony-stimulatingfactor, granulocyte/macrophage colony-stimulating factor,macrophage inflammatory protein macrophage, inflammatoryprotein-1a, macrophage inflammatory protein-1b, and mono-cyte chemotactic protein (MCP-1) [116,119,174]. A Phase II dose-ranging study [175] evaluated the efficacy of resiquimod gel in132 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 for4 weeks. CR rates after one course of treatment were 40.0,74.2, 56.3 and 70.6%, respectively. Patients with residuallesions received a second treatment. Efficacy was similar withall resiquimod concentrations, but the lower two concentrationswere better tolerated than the higher concentrations.

3.4.3 Betulinic Acid (Oleogel S-10)

Betulin, betulinic acid, oleanolic acid, lupeol and erythrodiolare 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-inflammatory effects, the most importanteffects of betulins are the promotion of differentiation innormal human keratinocytes and the induction of cytotoxic,antiproliferative and apoptotic effects on tumor cells [178]. In arandomized, comparative, Phase IIa study [178], 45 patientswith < 10 AKs mostly located on the face and scalp receivedtreatment with either topical betulin-based oleogel twice daily,cryotherapy or a combination of the two. After 3 months, 100and 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 combinedtherapy. Betulin-based oleogel seems to be an effective

approach in the topical treatment of AKs.

4. Expert opinion

Several currently available modalities are the most widely usedin clinical practice for the treatment of AKs. These treatments,all of which have shown to be efficacious, include cryotherapy,which has been considered the mainstay of therapy, elec-trodessication and curettage, chemical peels, imiquimod,5-fluorouracil, diclofenac and photodynamic therapy.Preventive measures, such as sun avoidance, are also crucial




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in limiting the development of or the recurrence of AKs,therefore decreasing the risk of progression to SCC. It isimportant to recognize that a great number of subclinicallesions may exist in the photodamaged areas where mostclinically visible lesions are located. Newer treatment modal-ities that focus on the concept of treating the whole area

(field-directed treatment) are being developed with greatsuccess. There have been encouraging results from clinicaltrials involving investigational drugs, including ingenolmebutate, resiquimod, betulinic acid and several preventiveagents such as retinoids, 2-(Difluoromethyl)-dl-ornithine(DFMO), perillyl alcohol (POH), and T4 endonuclease V(T4N5), which may also be considered for treatment. On thecontrary, lesion-directed therapies are an alternative forsingle or few AKs. Using cryotherapy alone, recurrence ratesare usually high, permanent adverse events such as scarringand/or pigmentary alterations can occur, and subclinicallesions are not concomitantly treated.

The management of AKs requires a combination of ther-apies usually embracing a lesion-directed modality and a field-directed agent with the goal of increasing efficacy and toler-ability, while minimizing adverse events and achieving goodcosmetic results. Successful combination regimens that havebeen reported in recent clinical trials include diclofenac 3% gelfollowed by cryotherapy, ALA-PDT followed by imiquimod5% cream, sulindac and hydrogen peroxide gels, anddiclofenac 3% gel followed by ALA-PDT.

Alternate dosing and new regimens using well-establishedagents are another area of interest to improve patient com-pliance and satisfaction, in addition to shortening treatmentcycles and downtime, decreasing LSRs and reducing costs.

Clinical trials are being conducted to evaluate the efficacy and

tolerability of a newer photosensitizer for PDT, such as topicalsilicon 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 efficacy of pretreatment

of AKs with topical retinoids followed by blue-light therapywith photosensitizing agent. A Phase II III study is nowevaluating celecoxib versus placebo in preventing the devel-opment of new AKs in patients with existing AKs. A Phase IIstudy is at present evaluating the efficacy and safety ofafamelanotide (CUV1647), a chemical analogue of Alpha-Melanocyte Stimulating Hormone (a-MSH), which isimplanted subcutaneously (16 mg every 60 days), for thereduction in the number of AKs and SCCs in immuno-compromised organ-transplant recipients. In an attempt tooptimize the use of imiquimod topically, a recent Phase IIIstudy evaluated short-course, cyclic regimens of imiquimodcream at two concentrations (3.75 and 2.5%). Daily appli-cation of imiquimod 3.75% for two 2-week treatment cycles,separated by a 2-week rest period, maximized tolerance whilemaintaining efficacy achieved with 5% imiquimod for pro-longed 4 months treatment, as measured by median percentreductions in the number of AKs [179]. We await the results ofongoing clinical studies of sequential AK therapy employingfield-therapy with imiquimod 3.75% cycle dosing and lesion-targeted treatment.

Declaration of interest

B Berman is on the advisory Board and Speaker Bureau of

Graceway, Peplin and Pharmaderm.




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Bibliography1. 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;74:424-302. Ortonne JP. Photoprotective properties of

skin melanin. Br J Dermatol

2002;146:(Suppl 61):7-10

3. Lane DP. Cancer. p53, guardian of the

genome. Nature 1992;358:15-6

4. Lookingbill DP, Lookingbill GL,

Leppard B. Actinic damage and skin cancer

in albinos in northern Tanzania: findings

in 164 patients enrolled in an outreach skin

care program. J Am Acad Dermatol

1995;32:653-8

5. Lehmann AR, Bridges BA.

Sunlight-induced cancer: some new aspectsand implications of the xeroderma

pigmentosum model. Br J Dermatol

1990;122:(Suppl 35):115-19

6. Lambert WC, Kuo HR, Lambert MW.

Xeroderma pigmentosum. Dermatol Clin

1995;13:169-209

7. Luande J, Henschke CI, Mohammed N.

The Tanzanian human albino skin.

Natural history. Cancer 1985;55:1823-8

8. Schwartz RA. The actinic keratosis.

A perspective and update. Dermatol Surg

1997;23:1009-19

9. 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]

10. 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

11. 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

12. 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

13. Giles GG, Marks R, Foley P. Incidence of

non-melanocytic skin cancer treated in

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 Aust1990;152:62-6

15. 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

16. Blohme I, Larko O. Skin lesions in renal

transplant patients after 10 23 years of

immunosuppressive therapy.

Acta Derm Venereol 1990;70:491-4

17. Jeffes EW III, Tang EH. Actinic keratosis.

Current treatment options.

Am J Clin Dermatol 2000;1:167-7918. Alexiades-Armenakas MR,

Geronemus RG. Laser-mediated

photodynamic therapy of actinic keratoses.

Arch Dermatol 2003;139:1313-20

19. Leffell D. New advances in treating actinic

keratoses. Skin Aging 2002;10:31-2

20. Marks R, Rennie G, Selwood TS.

Malignant transformation of solar

keratoses to squamous cell carcinoma.

Lancet 1988;1:795-7

21. Criscione VD, Weinstock MA,

Naylor MF, et al. Actinic keratoses: natural

history and risk of malignanttransformation in the Veterans Affairs

Topical Tretinoin Chemoprevention Trial.

Cancer 2009;115:2523-30

22. Glogau RG. The risk of progression to

invasive disease. J Am Acad Dermatol

2000;42:23-4

23. Salasche SJ. Epidemiology of actinic

keratoses and squamous cell carcinoma.

J Am Acad Dermatol 2000;42:4-7

24. Guidelines for the Management of

Actinic Keratoses. 2004/2005 European

Dermatology Forum. Available from:

http://www.euroderm.org/content/guidelines_keratoses.htm


25. 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

26. Suchniak JM, Baer S, Goldberg LH. High

rate of malignant transformation in

hyperkeratotic actinic keratoses. J Am


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;32:1261-528. 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

29. 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

30. 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

31. 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

32. Berman B, Villa AM, Ramirez CC.

Mechanisms of action of new treatment

modalities for actinic keratosis.

J Drugs Dermatol 2006;5:167-73

33. 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

34. Thompson SC, Jolley D, Marks R.

Reduction of solar keratoses by regular

sunscreen use. N Engl J Med

1993;329:1147-51

35. Naylor MF, Boyd A, Smith DW, et al.

High sun protection factor sunscreens in

the suppression of actinic neoplasia.


36. Rigel DS. Photoprotection: a 21st century

perspective. Br J Dermatol

2002;146:(Suppl 61):34-7

37. 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

38. Stratton SP, Dorr RT, Alberts DS. The

state-of-the-art in chemoprevention of skin

cancer. Eur J Cancer 2000;36:1292-7




13/17

39. Einspahr JG, Stratton SP, Bowden GT,

Alberts DS. Chemoprevention of human

skin cancer. Crit Rev Oncol Hematol

2002;41:269-85

40. Sporn MB, Suh N. Chemoprevention of

cancer. Carcinogenesis 2000;21:525-30

41. Afaq F, Adhami VM, Mukhtar H.Photochemoprevention of ultraviolet B

signaling and photocarcinogenesis.

Mutat Res 2005;571:153-73

42. 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

43. Evans TR, Kaye SB. Retinoids: present role

and future potential. Br J Cancer

1999;80:1-8

44. Lippman SM, Lotan R. Advances in the

development of retinoids aschemopreventive agents. J Nutr

2000;130(2S Suppl):479-82S

45. Niles RM. Recent advances in the use of

vitamin A (retinoids) in the prevention and

treatment of cancer. Nutrition

2000;16:1084-9

46. 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

47. Fanjul A, Dawson MI, Hobbs PD, et al. A

new class of retinoids with selectiveinhibition of AP-1 inhibits proliferation.

Nature 1994;372:107-11

48. 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

49. 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

50. 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

51. Fischer SM, Lo HH, Gordon GB, et al.

Chemopreventive activity of celecoxib, a

specific cyclooxygenase-2 inhibitor, and

indomethacin against ultraviolet

light-induced skin carcinogenesis.

Mol Carcinog 1999;25:231-40

52. 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

53. Bollag W, Ott F. Retinoic acid: topicaltreatment of senile or actinic keratoses and

basal cell carcinomas. Agents Actions

1970;1:172-5

54. Barranco VP, Olson RL, Everett MA.

Response of actinic keratoses to topical

vitamin A acid. Cutis 1970;6:681-5

55. 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

56. Kurka M, Orfanos CE, Pullmann H.

Vitamin A acid for the topical

management of epithelial neoplasms.Combination with 5-fluorouracil.

Hautarzt 1978;29:313-18

57. Kleinsmith DA, Thomas L. Retinoic acid

in the treatment of actinic keratoses.

J Dermatol Surg Oncol 1988;14:103

58. 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

59. Alirezai M, Dupuy P, Amblard P, et al.

Clinical evaluation of topical isotretinoin

in the treatment of actinic keratoses. J Am


60. 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

61. Pegg AE. Polyamine metabolism and its

importance in neoplastic growth and a

target for chemotherapy. Cancer Res

1988;48:759-74

62. Pegg AE, Madhubala R, Karneji T, et al.

Control of ornithine decarboxylase activity

in alpha-difluoromethylornithine-resistant

L1210 cells by polyamines and synthetic

analogues. J Biol Chem

1988;263:11008-14

63. Alberts DS, Dorr RT, Einspahr JG, et al.

Chemoprevention of human actinic

keratoses by topical

2-(Difluoromethyl)-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 difluoromethylornithine (DFMO),

in subjects at high-risk for nonmelanoma

skin cancer. Clin Cancer Res2002;8:149-55

65. Alberts DS. Phase IIB randomized,

double-blinded, placebo controlled study

to evaluate the safety and efficacy of topical

difluoromethylornithine (DFMO) with

and without a topical corticosteroid cream

(triamcinolone 0.1%) in the therapy of

actinic keratoses (AK) on the forearms.

ClinicalTrials.gov Identifier:

NCT00021294. Available from: http://

clinicaltrials.gov/ct2/show/NCT00021294

[Last accessed on 27 August 2009]

66. Crowell PL. Prevention and therapy of

cancer by dietary monoterpenes. J Nutr

1999;129:775-8S

67. Belanger JT. Perillyl alcohol: applications

in oncology. Altern Med Rev

1998;3:448-57

68. 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

69. Chaudhary SC, Alam MS, Siddiqui MS,

Athar M. Perillyl alcohol attenuates

Ras-ERK signaling to inhibit murine skin

inflammation and tumorigenesis.

Chem Biol Interact 2009;179:145-53,

[Epub 2008 Dec 31]

70. 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

71. Stratton S. Phase 2a randomized,

placebo-controlled, double-blind trial of

topical perillyl alcohol in sun damaged

skin. ClinicalTrials.gov Identifier:

NCT00608634. Available from: http://

clinicaltrials.gov/ct2/show/NCT00608634

[Last accessed on 27 August 2009]72. Cafardi JA, Elmets CA. T4 endonuclease

V: review and application to dermatology.

Expert Opin Biol Ther 2008;8:829-38

73. 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




14/17

74. A randomized, double-blind, multicenter

clinical study to test the safety and efficacy

of T4N5 liposome lotion on patients with

xeroderma pigmentosum in the protection

against actinic keratosis. ClinicalTrials.gov

Identifier: NCT00002811. Available from:

http://clinicaltrials.gov/ct2/show/

NCT00002811


75. 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 Identifier: NCT00089180.

Available from: http://clinicaltrials.gov/

ct2/show/NCT00089180


76. Reagan-Shaw S, Mukhtar H, Ahmad N.

Resveratrol imparts photoprotection of

normal cells and enhances the efficacy ofradiation therapy in cancer cells.

Photochem Photobiol 2008;84:415-21

77. 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

78. Baliga MS, Katiyar SK. Chemoprevention

of photocarcinogenesis by selected dietary

botanicals. Photochem Photobiol Sci

2006;5:243-53

79. 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

80. Fryer MJ. Evidence for the photoprotective

effects of vitamin E. Photochem Photobiol

1993;58:304-12

81. Rhie G, Shin MH, Seo JY, et al. Aging-

and 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

82. Gensler HL, Magdaleno M. Topical

vitamin E inhibition of

immunosuppression and tumorigenesis

induced by ultraviolet irradiation.Nutr Cancer 1991;15:97-106

83. 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

84. 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

86. Lubritz RR, Smolewski SA. Cryosurgery

cure rates of actinic keratosis. J Am

Acad Dermatol 1982;7:631-287. Thai KE, Fergin P, Freeman M, et al. A

prospective study of the use of cryosurgery

for the treatment of actinic keratoses.


88. de Berker D, McGregor JM, Hughes BR,

et al. Guidelines for the management of

actinic keratoses. Br J Dermatol

2007;156:222-30

89. Krawtchenko N, Roewert-Huber J,

Ulrich M, et al. A randomised study of

topical 5% imiquimod vs. topical

5-fluorouracil vs. cryosurgery in

immunocompetent patients with actinickeratoses: a comparison of clinical and

histological outcomes including 1-year

follow-up. Br J Dermatol

2007;157:(Suppl 2):34-40

90. 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


91. Chiarello SE. Cryopeeling (extensive

cryosurgery) for treatment of actinic

keratosis: an update and comparison.


92. Emmett AJ, Broadbent GD. Shave

excision of superficial solar skin lesions.

Plast Reconstr Surg 1987;80:47-54

93. Moy RL. Clinical presentation of actinic

keratoses and squamous cell carcinoma.

Am Acad Dermatol 2000;42:8-10

94. Dinehart SM. The treatment of actinic

keratoses. J Am Acad Dermatol

2000;42:25-8

95. Fu W, Cockerell C. The actinic (solar)

keratosis: a 21st-century perspective.


96. An KP, Ratner D. Surgical management of

cutaneous malignancies. Clin Dermatol

2001;19:305-20

97. Geisse JK. Comparison of treatment

modalities for squamous cell carcinoma.

Clin Dermatol 1995;13:621-6

98. 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. 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

100. Ostertag JU, Quaedvlieg P, Neumann M,

Krekels G. Recurrence rates and long-termfollow-up after laser resurfacing as a

treatment for widespread actinic keratoses

in the face and on the scalp. Dermatol Surg

2006;32:261-7

101. Fulton JE, Rahimi AD, Helton P, et al.

Disappointing results following resurfacing

of facial skin with CO2 lasers for

prophylaxis of keratoses and cancers.


102. 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

103. Wollina U, Konrad H, Karamfilov T.

Treatment of common warts and actinic

keratoses by Er: YAG laser. J Cutan

Laser Ther 2001;3:63-6

104. Jiang SB, Levine VJ, Nehal KS, et al.

Er: YAG laser for the treatment of actinic

keratoses. Dermatol Surg 2000;26:437-40

105. Coleman WP III, Yarborough JM,

Mandy SH. Dermabrasion for prophylaxis

and treatment of actinic keratoses.


106. Harmon CB. Dermabrasion.

Dermatol Clin 2001;19:439-42, viii

107. Dermabrasion. In: Fewkes JL, CheneyML,

Pollack SV, editors. Illustrated Atlas of

Cutaneous Surgery. 1st edition.

Philadelphia, PA: J.B. Lippincott Co.;

1992. p. 26.1-26.11

108. Monheit GD. Medium-depth chemical

peels. Dermatol Clin 2001;19:413-25, vii

109. Coleman WP III. Dermal peels.

Dermatol Clin 2001;19:405-11

110. 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 Dermatol2003;13:17-24

111. 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

112. Yamamoto Y, Yonei N, Kaminaka C, et al.

Effects of phenol peeling on dermal




15/17

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

114. Stuzin JM. Phenol peeling and the historyof phenol peeling. Clin Plast Surg

1998;25:1-19

115. 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


116. Imbertson LM, Beaurline JM,

Couture AM, et al. Cytokine induction in

hairless mouse and rat skin after topical

application of the immune responsemodifiers imiquimod and S-28463.

J Invest Dermatol 1998;110:734-9

117. Wagner TL, Ahonen CL, Couture AM,

et al. Modulation of TH1 and TH2

cytokine production with the immune

response modifiers, R-848 and imiquimod.

Cell Immunol 1999;191:10-9

118. 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

119. Hengge UR, Benninghoff B, Ruzicka T,

Goos M. Topical

immunomodulators progress towards

treating inflammation, infection, and

cancer. Lancet Infect Dis 2001;1:189-98

120. 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

121. 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

122. 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

123. Tyring S, Conant M, Marini M, et al.

Imiquimod; an international update on

therapeutic uses in dermatology.


124. Ooi T, Barnetson RS, Zhuang L, et al.

Imiquimod-induced regression of actinic

keratosis is associated with infiltration by T

lymphocytes and dendritic cells: a

randomized controlled trial. Br J Dermatol

2006;154:72-8

125. Schon M, Bong AB, Drewniok C, et al.Tumor-selective induction of apoptosis

and the small-molecule immune response

modifier imiquimod. J Natl Cancer Inst

2003;95:1138-49

126. Stockfleth 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

127. 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

128. Lebwohl M, Dinehart S, Whiting D, et al.

Imiquimod 5% cream for the treatment of

actinic keratosis: results from two phase III,

randomi

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