OBJECTIVES : Assess the feasibility of comparing interventions in Actinic Keratosis (AK) and perform Network Meta-Analyses (NMA) to document their relative effect with a focus on 5-fluorouracil 4% (5-FU 4%) cream.

METHODS : A Systematic Literature Review (SLR) was conducted prior to the methodological assessment (MA). The SLR aimed at identifying and retrieving Randomised Controlled Trials assessing field- and lesion-directed interventions (5-fluorouracil, imiquimod [various concentrations], diclofenac, ingenol mebutate, methyl/aminolevulinic acid photodynamic therapy [PDT], cryotherapy, LASER) on lesions located in head region among immunocompetent AK population. The MA included an evaluation of the clinical and methodological comparability or potential sources of heterogeneity across the studies for key efficacy (complete and partial clearance) and tolerability (proxy: withdrawal due to adverse events) binary outcomes. Homogeneous studies were connected in evidence networks and NMA were performed in base case and sensitivity analyses according to a Statistical Analysis Plan. A generalized linear regression model with binomial likelihood and logit link was considered. Both fixed and random effects were used. Heterogeneity and potential impact on results were explored. Results were expressed through different measures including the surface under the cumulative ranking (SUCRA) probabilities.

RESULTS : Of the 75 studies identified from the SLR, 32 studies meeting the summary of product characteristics or clinicians’ recommendation were selected. The majority of interventions were superior to placebo in terms of efficacy, except diclofenac 3%, imiquimod 2.5% and 3.75%, 5-FU 0.5% (solution), and placebo + PDT. 5-FU 0.5% (cream), diclofenac 3%, and imiquimod 5% had greater risk for withdrawals in comparison to placebo. 5-FU 4% had a good efficacy and tolerability profile versus other interventions (with the highest SUCRA on partial clearance).

CONCLUSIONS : The comparison of AK interventions informed about their relative profile including for 5-FU 4%. These findings are important for guiding treatment choices in addition to economic analyses.