Conventional photodynamic therapy (PDT) involves the application of photosensitizing agents (5-aminolevulinic acid [ALA] or methyl aminolevulinate [MAL]) to the region of interest, and use of a light source with a wavelength between 404nm and 420nm (blue light), or 635nm (red light).3 It is the most widely studied treatment in SOTR and according to the findings made so far, it has the highest complete response rate to date (40% to 89%).10 Higher response rates have been reported in patients treated with 2 cycles of PDT. We should mention that response rates are lower for AK on the hands (22% to 40%).11 No comparative trials have ever been performed between ALA and MAL in transplant recipients. The latter offers the advantage of better skin penetration thanks to its lipophilicity and greater specificity in treating neoplastic cells.12 However, in immunocompetent patients, there does not seem to be significant differences between the 2 photosensitizers, and even PDT with ALA may yield better results after a 1-year course of treatment.13,14

Despite the good results obtained, a drawback of this technique is the pain it causes in the region of interest during and after PDT sessions.11,15 This feeling may be greater in transplant recipients, likely due to their larger field cancerization compared to that of immunocompetent patients.11

Daylight photodynamic therapy (dPDT) uses UV radiation to activate the photosensitizer, making it useful to treat a larger field cancerization. Patients treated with dPDT had fewer new-onset AK lesions at the 3-, 9-, 15-, and 21-month follow-up compared to cryotherapy. Additionally, these patients showed a preference for this field treatment.16

Studies have been conducted where ablative laser therapy is used prior to the application of the photosensitizer to improve the efficacy rates. This would lead to better drug absorption, especially in thicker and more hyperkeratotic lesions. Differences in the complete response after 4 months of treatment have been reported, ranging from 75.5% to 64%, respectively, depending on whether laser therapy is previously used or not,17 being these results consistent with those from former studies.18

Imiquimod is a toll-like receptor 7 agonist, which triggers the activation of numerous cellular proteins, being nuclear factor kappa B a notable example. This induces the release of cytokines that will eventually activate the immune system vs antigens expressed in atypical keratinocytes, ultimately leading to their death.3

Despite immunosuppressive therapy in transplant recipients reduces the activity of the immune system and possibly the efficacy profile of the drug,19 complete response rates (between 28% and 62.1%) have been reported 3 months, or 8 weeks, respectively, after completing treatment.15,20

Conflicting data surround sustained responses, being these responses maintained in 7% to 80% of the patients at the 1-year follow-up.21,22 These differences may be due to variations in the therapeutic regimens across the different studies.

The action of 5-FU is based on the inhibition of thymidylate synthase, resulting in the inhibition of DNA synthesis and interference in the formation and function of RNA, which eventually triggers the death of target cells.3

Data on the efficacy profile of 5-FU treatment in immunosuppressed patients are scarce, with varying and difficult-to-compare results due to the different review times involved. Ingham et al. reported a complete response rate of 63% in patients 8 weeks into treatment, and a partial response rate of 71% at 1 year in 8 SOTR.23 Perret et al. compared 5-FU treatment (one 3-week cycle) and MAL-PDT in 7 renal transplant recipients, with complete response rates of 11% at 6 months for 5-FU and 89% for MAL-PDT.24 Recently, Hasan Zu et al. conducted a study that compared 3 cohorts of 40 SOTR treated with 5-FU at 5%, imiquimod, and sunscreen, with 1-year partial response rates of 58%, 29%, and 15%, respectively (the difference between imiquimod and the sunscreen was not significant), and total response rates of 17%, 7%, and 8%, being these differences also nonsignificant.22

Tirbanibulin is a recently approved therapy vs non-hyperkeratotic and non-hypertrophic AK (Olsen I). Tirbanibulin is a synthetic antiproliferative agent which by binding to tubulin, inhibits its polymerization and disrupts Src signaling in actively dividing cells. This mechanism of action leads to cell cycle arrest, abnormal mitosis, and eventually apoptosis.25

No data have been published to this date on the efficacy and safety profile of tirbanibulin therapy in immunosuppressed patients. To date, only 2 stage III clinical trials have been conducted in immunocompetent patients, achieving a nearly 50% complete response on day 57, with 53% of them remaining recurrence-free at the 1-year follow-up.26

The most common side effects are local and transient, being redness and scaling notable and happening after completing therapy.26

Diclofenac is a non-steroidal anti-inflammatory drug that inhibits cyclooxygenase-2 and the synthesis of prostaglandins. The exact mechanism by which diclofenac acts in the management of AK remains unclear. However, it is believed to be due to its anti-inflammatory and antiangiogenic properties, leading to antiproliferative and apoptotic effects.3

Only 1 clinical trial has ever been conducted in SOTR comparing diclofenac at 3% in hyaluronic acid vs a vehicle. In the trial, on week 20, the complete response rate reported was 41% in patients on a 16-week course of diclofenac, a response that was maintained in 45% of patients at the 2-year follow-up.27

There are numerous studies on the management of AK among immunocompetent patients. However, evidence on the most effective therapy to treat AK and field cancerization in SOTR is still scarce. Therefore, there is uncertainty on what the best practices are for different patients. However, recommendations have been made based on expert dermatologist consensus on the management of AK in SOTR based on the presence of actinic damage and the past medical history of non-melanoma skin tumors.28

Based on these recommendations, the treatment of choice for isolated AK is cryotherapy, being necessary to treat field cancerization when AK appears clustered in a certain anatomical area. Field cancerization-directed therapies can be challenging due to patient compliance issues. Given the higher incidence and recurrence of AK in SOTR, they are more likely to require multiple cycles, and a combination of different therapeutic alternatives.

We should mention the need to make regular follow-up appointments with the dermatologist to screen for new-onset lesions, at least, every 6 to 12 months.29

The primary goal of AK prevention techniques is to avoid and reduce the number of these lesions and, consequently, the risk of SCC. Primary prevention through patient education and the use of sunscreen should be recommended for all SOTR. Regarding secondary and tertiary prevention, different options are advised for high-risk patients only.

Sun exposure is the most important modifiable risk factor for the development of AK and SCC in SOTR. However, routine use of sunscreen in this population is simply not enough.1 Significant differences have been reported in the occurrence of AK and SCC when comparing the regular and the intermittent use of sunscreen over a 2-year span.30

Some sunscreens have been specifically designed for chronic sun damage to prevent the appearance of premalignant and malignant skin lesions. Supplementation with DNA repair enzymes helps protect against the damage caused by UV light. These enzymes include photolyase, T4 endonuclease V, UV endonuclease, and OGG1 endonuclease.31

The incidence of low levels of vitamin D in SOTR should also be taken into consideration following the recommendation of avoiding sun exposure, and using glucocorticoids in some patients. Glucocorticoids can increase the breakdown of 25-hydroxyvitamin D. Therefore, lab tests should be conducted among this population, and supplementation administered when necessary, as it is safe and effective to do so.1

The immunosuppression used in SOTR promotes the development of new AK and SCC. The most widely used drugs are calcineurin inhibitors (tacrolimus and cyclosporine), antiproliferatives (azathioprine, mycophenolate mofetil), and recently, mTOR inhibitors (sirolimus and everolimus). In addition to the differences reported in the intensity and duration of immunosuppression, not all immunosuppressants carry the same risk.1 Tacrolimus and azathioprine are 2 immunosuppressants most commonly associated with the development of SCC.1,28 In contrast, mTOR inhibitors have proven capable of reducing the number of non-melanoma skin cancers in SOTR when added to, or in lieu of older immunosuppressants.1,32,33 Additionally, it has been reported that sirolimus delays the development of AK, and even induces regression and slows down the incidence of new SCC.34,35 These can often start right after transplantation, and are often associated with the use of prednisone and mycophenolate mofetil.35

The conversion from azathioprine to mycophenolate mofetil should be considered whenever possible.1 Substituting calcineurin inhibitors with mTOR inhibitors and reducing immunosuppression are also valid strategies to minimize the incidence rate of AK and SCC. It is recommended to make these immunosuppression changes in SOTR with > 10 SCCs/year, or in those with high-risk SCC. The immunosuppression regimen should always be discussed with the transplant team.1,28

Despite the decreased incidence of AK and SCC, mTOR inhibitors have side effects that can limit their use and lead to drug discontinuation. Common adverse events include mouth ulcers, edema, acneiform reactions, hyperlipidemia, thrombocytopenia, leukopenia, delayed wound healing, and postoperative complications.35

Currently, topical sirolimus has various indications without the severe adverse events associated with this drug. Recently, its potential efficacy profile to reduce keratinocytic lesions has been reported, with a 3-fold reduction in in situ SCCs at 24 weeks vs placebo, with no differences being reported in the overall number of SCCs.36

Retinoids are the most effective strategy to prevent AK and SCC in high-risk populations.37 Acitretin can prevent both premalignant and malignant skin lesions at skin level.38 A difference in the number of premalignant keratotic lesions of up to 43% has been reported in 6-month comparisons of SOTR on acitretin vs placebo.39 Additionally, low-dose acitretin (10mg to 30mg) for a longer period of time has been shown to reduce the occurrence of skin cancer by up to 50% in SOTR with tolerable adverse events.40 Other retinoids such as isotretinoin could be used in patients who remain intolerant to acitretin, or have near-term pregnancy plans requiring higher doses to reach the desired effects with a poorly established efficacy.37

Systemic treatment should be maintained because rebound effects have been reported shortly after drug discontinuation.38,39,41

Topical retinoids might be a future option, but their efficacy has not been sufficiently demonstrated to date.37

Capecitabine is a prodrug of 5-FU. Its potential preventive therapeutic effect to reduce AK and, consequently, SCC in SOTR has been reported anecdotally.42,43 In a case series, the impact of low-dose capecitabine (1g/m2/day, with a 1-week break every 14 days) in the management of AK in 15 SOTR was examined. More than half of the patients reduced their incidence of AK, while 20% remained stable.44

Adverse events associated with this treatment include fatigue, nausea, hand-foot syndrome, gout, or an impaired kidney function. Sometimes, these adverse events can lead to down-titration, or drug discontinuation, so the risk-benefit ratio should always be taken into consideration prior to using this therapy.42–44

Nicotinamide is a form of vitamin B3 that could reduce UV radiation-induced immunosuppression and enhance DNA repair, thereby reducing both the field cancerization and the number of skin cancers.45

Unlike in immunocompetent patients, in whom there seems to be fewer skin neoplasms (but not AK).45,46, recent reports have shown no significant differences in transplant recipients after comparing nicotinamide (500mg/12hours) to placebo, both in skin neoplasms and AK.47

According to the consensus of expert dermatologists, acitretin therapy and changing the immunosuppressive regimen should be spared for patients with multiple, or high-risk skin cancer.28