Diclofenac sodium 3 % gel is a topical nonsteroidal anti-inflammatory drug (NSAID) that works via cyclooxygenase 1 and 2 (COX1, COX2) inhibition. It halts AK development by blocking the formation of angiogenic and tumorigenic factors produced from downstream arachidonic acid metabolites.

The recommended regimen for topical 3 % diclofenac is twice daily application for 60–90 days [100, 101]. Relatively low response rates (40 %) are balanced out by increased tolerability compared to other topical therapies. Side effects include mild pruritus, erythema, dry skin, hyper- and paresthesia, and type IV hypersensitivity reactions. Systemic drug interactions similar to that seen with oral NSAIDs are not expected with topical diclofenac therapy. Studies from the rheumatologic literature report that the maximal plasma concentrations following topical application of diclofenac and NSAIDs to body surface areas greater than 100 cm², but less than 200–300 cm², were less than 15 % of the plasma concentration reported when comparable doses were administered orally [102, 103]. In three clinical trials testing 3 % diclofenac gel to treat AK lesions, serum levels drawn after 105 days of twice daily application to body surface area of up to 75 cm² (slightly smaller than area of one’s face and typical area of treatment in clinical practice) were extremely low, on average ≤20 ng/mL [104]. By comparison, the area under the curve (a measure of systemic absorption used in pharmacokinetic studies) of a single oral 75 mg dose of diclofenac (Voltaren^®) is 1600 ng/h/mL [104]. Topical diclofenac also does not appear to affect renal function. Creatinine elevations were observed in a small fraction of patients (2 of 48) who were treated topical 3 % diclofenac during clinical trials, but this was the same rate as observed in the placebo group (2 of 49) [104].

Topical 5-fluorouracil (5-FU) inhibits thymidylate synthetase and subsequently halts DNA synthesis in cutaneous carcinogenesis. Its therapeutic effects were discovered as a fortuitous side effect; patients receiving intravenous 5-FU as a systemic chemotherapy were noted to have inflammation and resolution of AKs. Twice daily application of topical 5-FU for 2–4 weeks is indicated for the treatment of AKs; a longer course consisting of at least 3–6 weeks is needed for superficial BCCs. Response rates of 90 % have been reported in immunocompetent populations [23, 105]. While response rates are higher than observed with diclofenac, adverse effects (AEs) from 5-FU often lead to early discontinuation; thus, the true response rates are difficult to establish. Significant crusting, redness, erosions, and sometimes pain can be seen during topical 5-FU treatment. Eroded skin may become superinfected, with a great concern for infection with methicillin-resistant Staphylococcus aureus (MRSA). Pharmacokinetic studies have shown that systemic absorption of 5-FU is minimal (2.4 %) [106].

Topical 5-FU can also be used as part of a “chemowrap,” which is a compression bandage that is applied in the office after topical application of 5-FU allowing for prolonged and adequate 5-FU penetration. Chemowraps are commonly employed to treat large areas of skin where it is difficult to apply 5-FU twice daily and/or extensive, severely photodamaged areas amenable to wraps, like the legs. After covering the leg with 5-FU, medicated petrolatum and zinc oxide impregnated gauze are applied. The top layer consists of Coban™, a self-adherent elastic bandage akin to a disposable ACE bandage. “Chemowraps” are replaced every week in the office. Reduction of malignant or premalignant lesions seen 6 weeks following a chemowrap treatment regimen of 4–20 weeks may be maintained for 3 years of follow-up [107, 108]. Chemowraps may also be useful in patients who cannot tolerate surgery.

Imiquimod is a topical cream that is effective for the treatment of AKs, warts, and superficial BCCs in the RTR as well as in the immune competent patient [109, 110]. Imiquimod is a toll-like receptor (TLR) 7 agonist, which triggers a local immune response through upregulation of numerous cytokines including interferon (IFN)-alpha and IFN-gamma [111, 112]. Though it is generally considered safe, its use in SOTRs was initially limited due to concerns that the immunomodulation it would induce might increase systemic IFN levels causing an increase in graft rejection [113]. However, a large randomized trial demonstrated no increase in graft rejection [112]. The defined treatment area for these studies was 100 m², essentially the entire area of a face which is the largest surface area that would be treated in clinical practice at one time [112]. Although imiquimod may be used for field therapy, it is more often used to treat discrete precancerous and cancerous lesions, which limits the possibility of systemic absorption. Efficacy (based on 3–5 times per week application for 16 weeks) is reported to be similar in SOTRs and in nontransplanted populations (~70 %) [112]. Side effects are similar to that of 5-FU (erythema, inflammation, itching, pain) but tend to be milder. Some patients may exhibit exuberant inflammatory response, which may be indicative of good therapeutic effect. Systemic AEs, simulating a flu-like illness, have also been described with imiquimod.

Ingenol mebutate is a newer topical medication recently FDA-approved for AK treatment in immunocompetent patients. It is a biologically active compound extracted from a milkweed plant, Euphorbia peplus. No studies exist on its effectiveness in SOTRs. Unlike other topical field therapies, ingenol mebutate only requires 2–3 days of treatment as compared to several weeks [114]. While current evidence suggests that it may be less efficacious than other topical field therapies, it can provide durable results in a subset of patients who demonstrate a good initial response [115]. Long-term lesion reduction and sustained lesion clearance (~87 %) at 12 months have been reported in this same subset of superior responders.

PDT differs from other field cancerization options as it is an in-office procedure. Upon arrival, patients are pretreated with a topical photosensitizer such as aminolevulinic acid (ALA) or its methyl ester methyl aminolevulinate (MAL). After 1–2 h of incubation patients are exposed to a device with either red light (635 nm) or blue light (410 nm) for ~15 min. The combination of oxygen, the absorbed photosensitizer, and the chemical-specific light wavelength causes cell death in rapidly dividing cells via production of reactive oxygen species (ROS) [70, 113, 116]. While more extensively studied as a treatment for AKs, PDT has similarly excellent rates of clearing BCCs, particularly superficial BCC. Complete clearance rates for superficial BCCs are as high 85–93 % at 3 months [117]. Like other topical field cancerization treatments, depth of penetration is a limiting factor in its effectiveness. PDT is most effective on areas with thinner skin such as the face and neck. In areas with thicker skin, such as the hands or arms, PDT is less effective.

As a chemopreventive modality, studies have shown clearance of AKs for up to 3 months in SOTRs after 2 sequential PDT sessions performed 1–2 weeks apart [113, 118]. Cyclical ALA-PDT (every 4–8 weeks) has also been demonstrated to decrease the incidence of new SCCs by 95 % after 2 years of treatment [119, 120]. Side effects include discomfort and burning during treatment and posttreatment swelling (especially periorbitally), infections, and redness; in addition, herpes simplex virus (HSV) reactivation has been reported [121]. Strict sun avoidance for 48 h after each treatment is required because of prolonged photosensitivity. Since PDT is an in-office procedure, patient compliance is not an issue. However, the time commitment (frequent 2–3 h-long visits over 2 years) proposed for SOTR regimens may be difficult to incorporate into a patient’s schedule.

During field therapy treatment, it is important to biopsy any “ugly duckling” lesion or any lesion that fails to respond to therapy. While field cancerization is useful for most SOTRs, it is not recommended for SOTRs in whom effective chemoprevention (see below) is necessary.