Cryosurgery Combined With Topical Interventions for Actinic Keratosis

A Systematic Review and Meta-analysis

M.V. Heppt; T. Steeb; T. Ruzicka; C. Berking


The British Journal of Dermatology. 2019;180(4):740-748. 

In This Article

Abstract and Introduction


Background: Actinic keratoses (AKs) are early in situ carcinomas of the skin caused by cumulative sun exposure. Cryosurgery is an easy and practicable lesion-directed approach for treatment of isolated lesions.

Objectives: To investigate whether an upfront combination of cryosurgery with a topical intervention is superior to cryosurgery alone for treatment of AK.

Methods: We performed a systematic literature search in MEDLINE, Embase and CENTRAL and hand searched pertinent trial registers for eligible randomized controlled trials until 17 July 2018. Results from individual studies were pooled using a random effects model. The risk of bias was estimated with the Cochrane Risk of Bias Tool and the quality of evidence of the outcomes with the GRADE approach.

Results: Out of 1758 records initially identified, nine studies with a total sample size of 1644 patients were included. Cryosurgery in combination with a topical approach showed significantly higher participant complete clearance rates than monotherapy [risk ratio (RR) 1·74, 95% confidence interval (CI) 1·25–2·43, I 2 = 73%, eight studies]. The participant partial clearance rate was not statistically different (RR 1·64, 95% CI 0·88–3·03, I 2 = 77%, three studies). The number of patients who completed the study protocol and did not withdraw due to adverse events was equal in both groups (RR 0·98, 95% CI 0·95–1·01, I 2 = 75%, seven studies). The studies were estimated to have high risk for selective reporting bias.

Conclusions: Our results suggest the superiority of a combination regimen for AK clearance, with equal tolerability. This study highlights the importance of a field-directed approach in patients with multiple AKs or field cancerization.


Actinic keratoses (AKs) are common lesions of the skin caused by long-term exposure to ultraviolet radiation.[1,2] They can progress to cutaneous squamous cell carcinoma, although the risk is presumably low for single lesions.[3] However, if multiple AKs are present and if they are accompanied by signs of chronic actinic damage, the risk of malignant progression increases rapidly.[4,5] Visible AK lesions may be surrounded by tissue that clinically appears unaltered but bears significant ultraviolet-induced histological and genetic abnormalities. This concept has generally been accepted as field cancerization, although an exact clinical definition has not yet been coined.[6]

As it is difficult to predict whether a lesion will become invasive cutaneous squamous cell carcinoma, international guidelines recommend early treatment of AK.[7,8] Cryosurgery is a fast and easy approach to target single lesions in an office-based setting. The procedure usually involves liquid nitrogen and is applied in one to three freeze–thaw cycles. The advantage of this treatment is its ease of application and efficacy in hyperkeratotic lesions.[9] In patients with multiple lesions or field cancerization, topical interventions offer advantages as they are primarily field directed. A variety of agents for the treatment of AKs are available, with distinct mechanisms of action ranging from cytostatic effects to immune activation. The downsides are a longer duration of application and questionable efficacy in patients with thicker lesions, who are commonly excluded from larger trials.

In this context, we were interested to determine whether an upfront combination of cryosurgery followed by a topical intervention is more efficient than cryosurgery alone. We hypothesized that such a combination can combine the benefits of both a field- and lesion-directed approach. To address this question, we performed a systematic review with meta-analysis to summarize the current knowledge on the efficacy and safety of the combination of cryosurgery and topical intervention in comparison with cryosurgery monotherapy in patients with AKs.