Interventions for actinic keratoses
Actinic keratoses are a skin disease caused by long‐term sun exposure, and their lesions have the potential to develop into squamous cell carcinoma. Treatments for actinic keratoses are sought for cosmetic reasons, for the relief of associated symptoms, or for the prevention of skin cancer development. Detectable lesions are often associated with alteration of the surrounding skin (field) where subclinical lesions might be present. The interventions available for the treatment of actinic keratoses include individual lesion‐based (e.g. cryotherapy) or field‐directed (e.g. topical) treatments. These might vary in terms of efficacy, safety, and cosmetic outcomes.
To assess the effects of topical, oral, mechanical, and chemical interventions for actinic keratosis.
We searched the following databases up to March 2011: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library, MEDLINE (from 2005), EMBASE (from 2010), and LILACS (from 1982). We also searched trials registers, conference proceedings, and grey literature sources.
Randomised controlled trials (RCTs) comparing the treatment of actinic keratoses with either placebo, vehicle, or another active therapy.
Data collection and analysis
At least two authors independently abstracted data, which included adverse events, and assessed the quality of evidence. We performed meta‐analysis to calculate a weighted treatment effect across trials, and we expressed the results as risk ratios (RR) and 95% confidence intervals (CI) for dichotomous outcomes (e.g. participant complete clearance rates), and mean difference (MD) and 95% CI for continuous outcomes (e.g. mean reduction in lesion counts).
We included 83 RCTs in this review, with a total of 10,036 participants. The RCTs covered 18 topical treatments, 1 oral treatment, 2 mechanical interventions, and 3 chemical interventions, including photodynamic therapy (PDT). Most of the studies lacked descriptions of some methodological details, such as the generation of the randomisation sequence or allocation concealment, and half of the studies had a high risk of reporting bias. Study comparison was difficult because of the multiple parameters used to report efficacy and safety outcomes, as well as statistical limitations. We found no data on the possible reduction of squamous cell carcinoma.
The primary outcome 'participant complete clearance' significantly favoured four field‐directed treatments compared to vehicle or placebo: 3% diclofenac in 2.5% hyaluronic acid (RR 2.46, 95% CI 1.66 to 3.66; 3 studies with 420 participants), 0.5% 5‐fluorouracil (RR 8.86, 95% CI: 3.67 to 21.44; 3 studies with 522 participants), 5% imiquimod (RR 7.70, 95% CI 4.63 to 12.79; 9 studies with1871 participants), and 0.025% to 0.05% ingenol mebutate (RR 4.50, 95% CI 2.61 to 7.74; 2 studies with 456 participants).
It also significantly favoured the treatment of individual lesions with photodynamic therapy (PDT) compared to placebo‐PDT with the following photosensitisers: aminolevulinic acid (ALA) (blue light: RR 6.22, 95% CI 2.88 to 13.43; 1 study with 243 participants, aminolevulinic acid (ALA) (red light: RR 5.94, 95% CI 3.35 to 10.54; 3 studies with 422 participants), and methyl aminolevulinate (MAL) (red light: RR 4.46, 95% CI 3.17 to 6.28; 5 studies with 482 participants). ALA‐PDT was also significantly favoured compared to cryotherapy (RR 1.31, 95% CI 1.05 to 1.64).
The corresponding comparative risks in terms of number of participants completely cleared per 1000 were as follows: 313 with 3% diclofenac compared to 127 with 2.5% hyaluronic acid; 136 with 0.5% 5‐fluorouracil compared to 15 with placebo; 371 with 5% imiquimod compared to 48 with placebo; 331 with ingenol mebutate compared to 73 with vehicle; 527 to 656 with ALA/MAL‐PDT treatment compared to 89 to 147 for placebo‐PDT; and 580 with ALA‐PDT compared to 443 with cryotherapy.
5% 5‐fluorouracil efficacy was not compared to placebo, but it was comparable to 5% imiquimod (RR 1.85, 95% Cl 0.41 to 8.33).
A significant number of participants withdrew because of adverse events with 144 participants affected out of 1000 taking 3% diclofenac in 2.5% hyaluronic acid, compared to 40 participants affected out of 1000 taking 2.5% hyaluronic acid alone, and 56 participants affected out of 1000 taking 5% imiquimod compared to 21 participants affected out of 1000 taking placebo.
Based on investigator and participant evaluation, imiquimod treatment and photodynamic therapy resulted in better cosmetic outcomes than cryotherapy and 5‐fluorouracil.
For individual lesions, photodynamic therapy appears more effective and has a better cosmetic outcome than cryotherapy. For field‐directed treatments, diclofenac, 5‐fluorouracil, imiquimod, and ingenol mebutate had similar efficacy, but their associated adverse events and cosmetic outcomes are different. More direct comparisons between these treatments are needed to determine the best therapeutic approach.
Aditya K Gupta, Maryse Paquet, Elmer Villanueva, William Brintnell
Plain language summary
Interventions for actinic keratoses
Actinic keratoses are a skin disease caused by long‐term sun exposure. Damaged skin shows small, red, rough, scaly, flat spots called actinic keratoses or lesions, which feel like patches of dry skin. Symptoms such as bleeding and pain can be associated with actinic keratoses. Moreover, actinic keratoses have the potential to develop into skin cancer if left untreated. The reasons for treatment may include cosmetic appearance, relief of symptoms, or prevention of skin cancer. Treatment can be directed either at individual lesions or to larger areas of the skin where several visible and less visible lesions occur (field‐directed treatment).
This systematic review included results from 83 randomised controlled clinical trials evaluating 24 treatments, with a total of 10,036 participants diagnosed with actinic keratosis. We included 18 topical creams or gels applied to a skin area by the participants: adapalene gel, aretinoid methyl sulfone (Ro 14‐9706), betulin‐based oleogel, calcipotriol (vitamin D), colchicine, diclofenac, 2‐(difluoromethyl)‐dl‐ornithine (DFMO), 5‐fluorouracil, β‐1,3‐D‐glucan, imiquimod, ingenol mebutate (PEP005), isotretinoin, masoprocol, nicotinamide, resiquimod, sunscreen, DL‐α‐tocopherol (vitamin E), and tretinoin. One treatment, etretinate, was taken orally. Clinical staff administered two mechanical treatments (carbon dioxide and Er:YAG laser resurfacing) on a skin area, and they administered three chemical treatments: cryotherapy on individual lesions, photodynamic therapy on individual lesions or a skin area, and trichloroacetic acid peel on a skin area.
The clinical effects resulting from the treatment of actinic keratoses were reported differently from one study to another. In spite of this inconsistency, it can be concluded that several good treatment options exist for the treatment of actinic keratoses. Actinic keratoses were successfully treated with cryotherapy, diclofenac, 5‐fluorouracil, imiquimod, ingenol mebutate, photodynamic therapy, resurfacing, and trichloroacetic acid peel. These different treatments were generally comparably effective. Skin irritation was associated with some of these treatments, such as diclofenac and 5‐fluorouracil, but other side‐effects were uncommon. The final cosmetic appearance varies from one treatment to another. Imiquimod treatment and photodynamic therapy resulted in better cosmetic appearance than treatment with cryotherapy and 5‐fluorouracil.
Treatment with photodynamic therapy gives better therapeutic and cosmetic results than cryotherapy for individual lesions. For field‐directed treatments, diclofenac, 5‐fluorouracil, imiquimod, and ingenol mebutate are good options associated with different side‐effects and cosmetic results. Thus, the choice of treatment option for actinic keratosis depends on the number of lesions, the individual's desired results, and tolerance to the treatments.
Aditya K Gupta, Maryse Paquet, Elmer Villanueva, William Brintnell
Implications for practice
The treatment of actinic keratoses is generally recommended to limit the morbidity and mortality of squamous cell carcinoma. Surprisingly, there was no evidence in the included studies that treating actinic keratoses prevented squamous cell carcinoma. Only a few studies reported the observation of squamous cell carcinoma, basal cell carcinoma, or both. In these studies, it was not specified if the cell carcinoma was observed in the treated area. Thus, it was impossible to correlate treatment of actinic keratoses with prevention of cell carcinoma. Of course, this lack of information on prevention of squamous cell carcinoma could have been a consequence of our criteria, which included interventions to treat actinic keratoses but not prophylaxis of cancers. As mentioned previously, this review did not cover long‐term follow‐up studies that could give useful information on recurrence of actinic keratoses as well as prevention of squamous cell carcinoma. We did include the recurrence rates, appearance of new actinic keratoses or incidence of cancer if they were provided in the tables of 'Characteristics of included studies'. Because of the importance of this issue, a systematic review with these long‐term outcomes must be performed, and we suggest that randomised clinical trials on interventions for actinic keratoses include observation of squamous cell carcinoma for a follow‐up period of at least one year as an efficacy outcome.
Based on the evidence presented in this review, there are many effective options available for the treatment of actinic keratoses. The most effective treatment options were diclofenac, 5‐fluorouracil, imiquimod, ingenol mebutate, laser resurfacing, trichloracetic acid peel, ALA‐PDT, and MAL‐PDT. Other treatment options should not be ruled out as they are still effective, and many have reduced side‐effects, which may be preferable or better suited to certain patients.
Ultimately, the decision about which treatment option to use should be agreed upon by both the physician and the patient, based on which intervention suits the participant's specific situation. Certain treatments are better for treating diffuse actinic damage, while others are better for individual lesions. Moreover, the appropriate treatments would depend on the patient's wishes, whether it is cosmetic, symptom relief, or prevention of squamous cell carcinoma. If the risk associated with treatment is greater than the potential benefit, observation without treatment may also be an option.
Implications for research
Our review did not directly compare the methodology used by the studies to evaluate the efficacy outcomes of the interventions for actinic keratoses. Some studies did not give any details on their methodology, whereas others described in detail how individual lesions were mapped, photographed, and followed throughout the study. Mapping of the lesions allowed the investigators to make a distinction between baseline lesions and new or subclinical lesions. For several studies, it was not clear if the efficacy assessment included only target (baseline) lesions or all lesions, which could greatly influence the final outcome. Thus, we recommend that the authors of studies describe in details the methodology used to evaluate the efficacy of the interventions investigated and specify which lesions (baseline/target, subclinical/new, or all lesions) are included in these evaluations.
A clear definition of the lesions being treated is particularly important when comparing individual lesion‐based and field‐directed treatments, as well as to show that new lesions appeared in response to some treatments. An increase in the number of lesions during treatment was observed for imiquimod (see the 'Notes' section of the 'Characteristics of included studies' tables for Chen 2003;Korman 2005;Lebwohl 2004; and Tan 2007), 5‐fluorouracil (Jorizzo 2006; Tanghetti 2007), and tretinoin (Misiewicz 1991). This unmasking of lesions during treatment might have important implications for treatment of actinic keratoses and its associated recurrence. Long‐term randomised clinical trials comparing lesion‐based and field‐directed treatments are needed to address this issue.
Diclofenac in 2.5% hyaluronic acid has been compared directly to 5% 5‐fluorouracil (1 excluded study: Smith 2006) and 5% imiquimod for the treatment for actinic keratosis. Diclofenac and 5% imiquimod are both associated with significant adverse events based on the related withdrawals, and 5‐fluorouracil treatment is associated with significant skin irritation based on our analyses. It would be advantageous to perform randomised clinical trials comparing diclofenac with other interventions in order to clearly assess its safety outcomes. Similarly, the new treatment ingenol mebutate (PEP005) has only been compared to placebo, and comparison with other interventions for actinic keratosis is needed to evaluate its efficacy and safety compared to established therapy. As mentioned in the summary of main results, additional data are also needed to support or confirm the conclusion of some included studies.
Photodynamic therapy is a newer form of treatment that presents good results in clinical trials. Several studies tried to determine the optimal treatment regimen, output, and photosensitising agents, but most studies did not observe significant changes in efficacy in the variations studied. A few studies investigated the use of daylight for photodynamic therapy using the photosensitiser MAL, and one study showed an efficacy equivalent to MAL‐red light PDT. This source of light could be more convenient, more cost effective and easily applicable as field‐directed treatment. This is a good prospective area for further research. One ongoing study (NCT01475071) is comparing daylight PDT with conventional PDT.