Photodynamic therapy with aminolevulinate (ALA-PDT); imiquimod, 5%; photodynamic therapy with methyl aminolevulinate (MAL-PDT); and cryosurgery are associated with significant long-term benefits in treatment of patients with actinic keratosis, according to study data published in JAMA Dermatology.

Investigators sought to assess the long-term efficacy (≥12 months) of interventions for actinic keratosis from parallel-arm randomized clinical trials. They searched MEDLINE, Embase, and the Cochrane library CENTRAL until April 6, 2020, for studies that included adults (aged ≥18 years) with a clinical or histopathologic diagnosis of actinic keratosis.

A total of 17 published records that referred to data from 15 independent randomized controlled trials with 4252 patients met the eligibility criteria and were included. Of this group, 10 studies with 16 direct comparisons of 10 distinct interventions were included in a network meta-analysis (NMA) for the participant complete clearance outcome.

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The analysis showed that ALA-PDT (risk ratio [RR], 8.06; 95% CI, 2.07-31.37; GRADE, moderate); imiquimod, 5% (RR, 5.98; 95% CI, 2.26-15.84; GRADE, very low); MAL-PDT (RR, 5.95; 95% CI, 1.21-29.41; GRADE, low); and cryosurgery (RR, 4.76; 95% CI, 1.36-16.66; GRADE, very low) were significantly superior to placebo in the NMA.

A total of 8 studies with 12 direct comparisons of 9 distinct interventions were included in the analysis for lesion-specific clearance. ALA-PDT (RR, 3.16; 95% CI, 1.30-7.71; GRADE, moderate) and cryosurgery (RR, 2.52; 95% CI, 1.03- 6.16; GRADE, moderate) were significantly superior to placebo.

In the NMA with placebo as reference intervention (I2 = 92.1%), ALA-PDT (RR 5.08; 95% CI, 2.49-10.33; GRADE, moderate), MAL-PDT (RR, 4.24; 95% CI, 1.91-9.41; GRADE, moderate), cryosurgery (RR, 3.60; 95% CI, 1.77-7.33; GRADE, moderate), and imiquimod, 5% (RR, 2.83; 95% CI, 1.00-8.02; GRADE, low) were significantly superior to placebo.

The study has several limitations, noted the investigators. The NMAs were poorly connected and the comparisons were based on few trials. Also, there was unexplained heterogeneity and inconsistency, particulary regarding the comparison of fluorouracil and cryosurgery for the outcome of participant complete clearance. In addition, field-directed treatments, such as imiquimod, PDT, and fluorouracil, were compared with lesion-directed approaches, such as cryosurgery, which may limit the generalizability of the findings.

“The performance of NMA appeared to enable the comparison of multiple interventions that were not investigated in head-to-head trials,” stated the researchers. “This study provides data that might contribute to an evidence-based framework to guide the selection of interventions for actinic keratosis with proven long-term efficacy and sustained actinic keratosis clearance.”

Disclosure: Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


Steeb T, Wessely A, Petzold A, et al. Evaluation of long-term clearance rates of interventions for actinic keratosis a systematic review and network meta-analysis. JAMA Dermatol. Published online August 4, 2021. doi:10.1001/jamadermatol.2021.2779