The prevalence of AK increases with age. Among Caucasians it has been reported that prevalence rates are less than 10 % for individuals in their third decade of life but more than 80 % in their seventh decade [4]. Men are at increased risk for developing AKs, most likely due to occupational and recreational exposure. In the UK, prevalence of AK for individuals between the ages 16 and 49 years was found to be 27 % for males and 13 % for females, a little more than double the prevalence for males. However, in the age group from 50 to 86 years, prevalence was more evenly distributed between sexes, 66 % for males and 56 % for females. In Brazil, a cohort of Japanese-Brazilians were diagnosed with AK at a mean age of 68.9 years [5].

AKs represent one of the top three most frequent reasons for consulting a dermatologist [4]. Between 1990 and 1999, AKs were diagnosed in 47 million visits, or 14 % of all visits to the dermatologist’s office [6]. They are primarily seen in fair-skinned individuals who have had long-term sun exposure. Sun-sensitive cutaneous phenotypes include people who are fair skinned, have light-colored eyes, and have red or blond hair. In addition, the inability to tan, tendency to sunburn easily, and ability to form freckles are consistent with this phenotype [4]. In one study, prevalence rates were reported to be as high as 40–50 % in Australian residents older than 40 years; individuals with fair skin had a relative risk of 14.1 when compared with persons of olive skin color, and individuals with medium skin color had a 6.5-fold relative risk [7]. In the USA, lower prevalence rates have been reported ranging from 11 to 26 % [4]. In darker skinned individuals, AKs are extremely rare. Cumulative ultraviolet radiation is the other major risk factor for AKs. The frequency of AKs is greater in residents of sunny countries closer to the equator and those with outdoor occupations [7, 8]. In fact, one study showed that individuals with maximal occupational UV light exposure had an increase in relative risk of 2.4; those with multiple AKs were 4.3 times as likely to have maximal occupational UV light exposure [4].

Normally, melanin in the epidermis absorbs UV and protects keratinocytes from DNA damage. Overexposure to UV radiation induces a mutation in the p53 tumor-suppressor gene (single-nucleotide substitutions at a dipyrimidine site: C to T, C to A, or T to C). This mutation inhibits the cell’s ability to undergo apoptosis, which leads to atypical proliferation of keratinocytes in the epidermis, and ultimately AK [9].

Protection from UV radiation reduces the risk for developing AK. Patients are commonly recommended to avoid sunlight or seek shade during midday hours when UV exposure is greatest. Patients are also encouraged to use protective clothing, such as hats, long-sleeved clothing, and sunglasses. Importantly, the regular use of sunscreen prevents the development of AKs. In a randomized, controlled trial published in the New England Journal of Medicine it was shown that people 40 years and older who used SPF 17 sunscreen for only 1 month had fewer new AK lesions and more remissions. In fact, the mean number of AKs decreased by 0.6 in the sunscreen group [10].

Because AKs represent the initial stage in the evolution of squamous cell carcinoma, recognition and treatment are important. Treatment is administered based on characteristics and number of lesions, patient preference for the mode and duration of treatment, willingness and ability to comply with self-administered therapies, as well as tolerance of side effects. In older patients with poor vision, memory, or manual dexterity, a caregiver may need to be enlisted to apply topical pharmacotherapy.

One consideration in selecting the treatment modality for AKs is treatment efficacy. Comparison of treatment efficacy across studies should account for follow-up times after treatment across, outcomes assessed, a number of treatment cycles, and severity of disease treated.

The most widely utilized treatment for AKs in the office is liquid nitrogen cryotherapy because it is quick, is easily performed in the office setting, produces excellent cosmetic results, and is well tolerated by patients. It is considered the standard of care and particularly useful when lesions are scattered or few in number [11]. This technique uses liquid nitrogen to freeze and destroy the epidermis containing AK with an efficacy cure rate as high as 98.9 % after 1 year [12]. In a review written for the Cochrane Collaboration, the use of cryotherapy was evaluated against other treatment options for AK. They report that a 1-week course of topical 0.5 % 5-fluorouracil (5-FU) before cryosurgery resulted in significantly less AKs 6 months after treatment than cryosurgery alone. Similarly, combination therapy with imiquimod is more efficacious when compared to cryotherapy alone [13]. One of the drawbacks of using cryotherapy however is the inability to preserve tissue for histologic analysis to rule out other neoplasms such as squamous cell carcinoma. In addition, thick lesions and lesions on the dorsum of hand do not respond as well [14]. The main side effects of cryotherapy include burning and stinging during treatment and possible hypopigmentation following treatment [15]. Pain associated with cryotherapy is usually well tolerated but not insignificant. One study surveying patient response to pain found levels to be higher than deemed appropriate by patients but below levels necessary for additional analgesics; only 30.4 % reported the need for prior analgesia and 69.9 % reported no need for analgesia [16]. In older patients with areas of thinner skin, cryotherapy may be effective with reduced thaw times, although this has not been formally studied.

In patients with multiple lesions localized in the same area such as on the face or arms, topical pharmacotherapy is an effective alternative to spot treatment with cryotherapy, in part due to their visibility to the patient for applying the medication. A critical concern in older adults who are prescribed topical field therapy is to make sure that patients have adequate visual acuity to identify the target lesion and the manual dexterity to apply the medication to the required site(s). The FDA-approved topical treatments include 5-FU, imiquimod, diclofenac, and ingenol mebutate as well as several off-label options.

Of these, 5-FU is the most widely used. 5-FU works by inhibiting thymidylate synthetase, the enzyme normally responsible for conversion of deoxyuridine 5-monophosphate (DUMP) to thymidine 5-monophosphate (TMP), which ultimately inhibits DNA synthesis [17]. This mode of treatment preferentially targets AKs with minimal effects on normal skin [18]. Inflammation of AK lesions typically occurs within 2 weeks of initiating therapy and serves as visual evidence that lesion destruction is occurring which may cause irritation and discomfort in some patients [19]. It is important to educate patients that inflammation, erythema, blistering, and re-epithelialization are to be expected in order to promote therapy compliance and prevent premature discontinuation of therapy. Lesion response rates were reported to be 87.8 % in one meta-analysis of seven studies [20]. There is ongoing analysis demonstrating that lower dose, once-daily 0.5 % 5-FU may be more tolerable, safer, cost effective, and equally as efficacious as 5 % 5-FU [21, 22]. In a patient population where treatment compliance is low [23], the reduction of irritability and improvement in adverse events may increase adherence to the regimen [19]. In a review of nine studies following standard treatment regimens comparing complete clearance rates, results for 0.5 % and 5 % 5-FU ranged from 16.7 to 57.8 % and 43 to 100 %, respectively [24]. There is a need for additional comparative studies since tolerability rates among studies were unable to be compared. In one study where each patient received both treatments (5 % twice daily and 0.5 % once daily) on each side of their face, both treatments achieved 43 % complete clearance rates [25]. Patients in that trial preferred the lower dose fluorouracil.

Imiquimod is another popular topical pharmacotherapy that works by modulating the immune response. It binds to cell surface receptors such as Toll-like receptor 7 [26] and induces the synthesis of interferon-alpha and other cytokines that have antitumor properties [27]. Therapeutic skin responses include erythema and crusting but therapy is well tolerated [28, 29]. In a study comparing 5-FU and imiquimod, tolerability was similar between the two treatments. Erythema was more prominent in patients receiving 5-FU initially, but by week 16, erythematous lesions became less prominent than those seen with imiquimod therapy [30]. Complete clearance is expected in 50 % of patients [31]. Recent studies investigating the lower doses of imiquimod, 2.5 and 3.75 % versus the traditional 5 % cream, suggest comparable efficacy [32, 33] and potential benefits in tolerability [34].

Ingenol mebutate is the newest addition to the arsenal for the treatment of AK. Derived from the sap of the plant Euphorbia peplus, ingenol mebutate was approved by the FDA in 2012. It is touted to operate via two mechanisms of action: rapid lesion necrosis and specific neutrophil-mediated, antibody-dependent cellular cytotoxicity [35]. Owing to the rapid cytotoxic response and degradation of plasma membrane, the treatment period is 2–3 days. Studies find complete clearance rates in 42.2 % in lesions involving the face and scalp and 34.1 % in lesions involving the trunk and extremities [36]. Side effects including erythema, flaking, and crusting are described to be mild to moderate and resolve in 2 and 4 weeks for the face/scalp and trunk/extremities, respectively [37]. A long-term, 12-month follow-up study found reduction in the number of AKs by 87 % [38].

A valuable modality for field treatment in older adults is photodynamic therapy (PDT), because it does not require the patient to self-apply medication to the correct lesions. This is therefore a good choice for older adults with visual, cognitive, or manual dexterity issues. PDT employs the use of topical photosensitization followed by visible light irradiation to the affected area of skin. The ensuing photochemical activation destroys cells [39]. Two commonly used sensitizing agents include 5-aminolevulinic acid (ALA) and methyl aminolevulinate (MAL), the former used widely in the USA. Overall, PDT is highly effective in treating AKs. Three-month complete response rates for MAL-PDT and ALA-PDT are 90 % and 91 %, respectively [40, 41]. One of the disadvantages to PDT is the pain during illumination. In a retrospective study of 24 patients, all patients reported moderate or severe pain (42 % and 58 %, respectively) during photo irradiation [42]. In a study that aimed at identifying important factors of pain during PDT, researchers found that the greater the erythema, the greater the pain reported, but also the better the outcome [43]. In comparison with 5-FU and cryotherapy, ALA/MAL-PDT treatment appears more effective and may result in a better cosmetic outcome [13]. PDT treatment followed by imiquimod achieves significantly better results than either one alone; better tolerance and less intense local reactions are also reported [44]. One study shows that the use of long-pulsed dye laser (LP PDL) following ALA application minimizes pain during light treatment and achieves comparable efficacy [45, 46].

Recently, a systematic review and meta-analysis of four PDT versus cryotherapy studies (all with mean ages of participants exceeding 64 years) demonstrated a 14 % increased likelihood of complete lesion clearance than cryotherapy at 3 months after treatment [47]. Nevertheless, PDT is limited by availability of equipment, trained staff to apply the dye, and willingness of patient to devote time for incubation and subsequent posttreatment avoidance of sun exposure.

Because the data on treatments for AKs is limited by lack of direct comparison between some interventions, a novel network meta-analysis was performed for common treatments that were randomized controlled trials in non-immunosuppressed participants with mean ages all exceeding 59 years [48]. The results showed that efficacy was highest for 5-FU 0.5 or 5 % > ALA-PDT > cryotherapy > diclofenac 3 %/hyaluronic acid > imiquimod 5 % > ingenol 0.15–0.05 %. This study showed that efficacy was independent of anatomic location except for ingenol.

Second-line topical therapies for actinic keratosis include diclofenac and retinoids and can be considered in older patients who declined first-line treatments topical pharmacotherapies outlined above. They can be used between regular visits for cryotherapy.

Diclofenac is a nonsteroidal anti-inflammatory topical cream approved for use on AKs. While the exact mechanism of action is unknown, it is hypothesized that anti-inflammatory COX-2 inhibition, inhibition of angiogenesis, and induction of apoptosis are responsible for its effect [49, 50]. Compared with the aforementioned topical creams, the treatment period for diclofenac is slightly longer, 60–90 days, a potential disadvantage for this mode of therapy. Complete clearance is recorded in only 40 % of patients [51]. Diclofenac is reported to induce milder inflammation compared with 5-FU [52]. A Cochrane collaboration analysis of interventions for AKs published in 2012 reported that among topical pharmacotherapies, the highest number of participants withdrawing from treatment due to adverse events with highest with 3 % diclofenac compared to imiquimod 5 % [13].

Retinoids are synthetic or natural analogues of vitamin A known to have antineoplastic effects [53]. An analysis of double-blind studies at 31 sites for a total of 1,265 patients found significant reductions in lesions treated with tretinoin (56 %) compared to control (41 %) [54]. In contrast, data from the Veterans Affairs Topical Tretinoin Chemoprevention Trial randomizing 1,131 patients to 0.1 % tretinoin or a vehicle found no statistical significant in AK counts [55]. Adapalene, a third-generation synthetic retinoid, exhibits selectivity for the nuclear retinoic acid receptor, resulting in increased anti-inflammatory activity while inducing less irritation [56]. In a randomized trial, patients treated with 0.1 % and 0.3 % adapalene gel experienced a reduction in the mean number of AKs by 0.5 and 2.5, respectively [57].

Other therapies in dermatology have also been studied in the treatment of AKs. These include using CO₂ and Er:YAG ablative resurfacing lasers. A prospective study of 55 patients (mean age 72.8 years) treated with either topical 5-FU or erbium:yttrium-aluminum-garnet (Er:YAG) laser resurfacing found significantly lower rates of recurrence after 1 year [58]. However, increased erythema, edema, and infections were seen in the laser therapy group. Ablative resurfacing with carbon dioxide lasers in the treatment of AKs was compared with fluorouracil and trichloroacetic acid (TCA); all three groups performed significantly better than the control group, resulting in an 83–92 % reduction in AKs [59

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