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Am Fam Physician. 2020;101(4):249-250

Clinical Question

Do topical interventions improve outcomes in addition to cryosurgery for actinic keratoses compared with cryosurgery alone?

Bottom Line

Based on a review of low-quality evidence, adding a topical intervention after cryosurgery for actinic keratosis improves the likelihood of complete clearance from 46% to 79% (number needed to treat [NNT] = 3). In the absence of better evidence, fluorouracil and diclofenac may be preferable to ingenol (Picato) based on cost. (Level of Evidence = 1a–)


The authors of this well-conducted meta-analysis screened 1,758 studies and ultimately included only nine of them. Limitations include poor descriptions of the studies, with unclear accounts of randomization or allocation concealment, and failure to mask the participants in five trials and the outcome assessors in two trials. The topical interventions applied after cryosurgery for actinic keratosis included imiquimod (Aldara) in four studies, ingenol in two studies, diclofenac 3% in 2.5% hyaluronic acid in one study, fluorouracil 0.5% cream in one study, and photodynamic therapy with aminolevulinic acid in one study. The overall likelihood of complete lesion clearance when combining all nine studies was greater with the addition of topical therapy (relative risk [RR] = 1.74; 95% CI, 1.25 to 2.43). Applied to a base rate of complete lesion clearance of 46% with cryosurgery alone, the addition of a topical intervention would increase the rate to 79%. A similar pattern was seen for partial clearance in three studies with 421 patients (RR = 1.64; 95% CI, 0.88 to 3.03). There was no difference in withdrawals, indicating good tolerability. There was substantial heterogeneity between studies (I2 = 73%). Individual studies of diclofenac, fluorouracil, and ingenol showed significant benefit consistent with the overall effect, whereas imiquimod and photodynamic therapy with aminolevulinic acid did not, but sample sizes for most studies were small.

Study design: Meta-analysis (randomized controlled trials)

Funding source: Foundation

Setting: Various (meta-analysis)

Reference: Heppt MV, Steeb T, Ruzicka T, et al. Cryosurgery combined with topical interventions for actinic keratosis: a systematic review and meta-analysis. Br J Dermatol. 2019;180(4):740–748.

Editor's Note: Dr. Ebell is deputy editor for evidence-based medicine for AFP and cofounder and editor-in-chief of Essential Evidence Plus, published by Wiley-Blackwell.

POEMs (patient-oriented evidence that matters) are provided by Essential Evidence Plus, a point-of-care clinical decision support system published by Wiley-Blackwell. For more information, see Copyright Wiley-Blackwell. Used with permission.

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