Highlights from Literature

What is the most effective treatment for actinic keratosis? A head-to-head comparison of 4 field treatments

by Emily Newsom, MD

Jansen, Kessels, Nelemans, et al. Randomized Trial of Four Treatment Approaches for Actinic Keratosis. N Engl J Med 2019; 380:935-946. DOI: 10.1056/NEJMoa1811850

Actinic keratosis (AK) is an extremely common pre-cancerous skin lesion caused by ultraviolet radiation exposure. Cryosurgery is typically used for focal lesions, while field therapy is used for more extensive ill-defined actinic keratoses in a continuous area. There is no consensus on which field therapy is preferred.

A group out of the Netherlands has published a multi-center, single-blind, randomized controlled trial to compare treatment success at 12 months of 4 treatment modalities: fluorouracil 5% cream, imiquimod 5% cream, ingenol mebutate 0.015% gel, and methyl aminolevulinate PDT (MAL-PDT) in 624 patients with actinic keratoses. No commercial support was provided for the trial.  

The treatment protocols are as follows:  fluorouracil was applied twice daily for 4 weeks; imiquimod was applied once daily 3 times a week for 4 weeks. For ingenol, one 0.47 g tube was applied once a day for 3 days to an area of 25 cm2. For MAL-PDT, a thin layer of MAL cream was applied, covered with aluminum foil for 3 hours, and illuminated with LED light at a wavelength of 635 nm for 7.23 minutes. Some patients received a 2nd treatment in case of insufficient treatment response. Treatment success was defined as a 75% or more reduction of AKs. The number and extent of AKs was measured at baseline, 3 months and 12 months after treatment by a blinded investigator.

The results are illustrated in Table 2. The “modified intention-to-treat” group included 602 patients who started treatment and were evaluated at 3 and 12 months post-treatment. In this group, the cumulative probability of treatment success at 12 months for fluorouracil was 74.7%, for imiquimod 53.9%, MAL-PDT 37.7%, and ingenol mebutate 28.9%, according to the modified intention-to-treat analysis.

Overall, fluorouracil was found to be the most effective at treating actinic keratoses. Adherence was higher in the ingenol group (98.7%) and MAL-PDT (96.8%) compared to the fluorouracil group (88.7%) and imiquimod group (88.2%). Patient satisfaction with treatment overall was highest in fluorouracil group.  Cosmetic outcome was best in the MAL-PDT group.  

The significant superiority in efficacy of fluorouracil 5% was interesting. Of note, aminolevulanic acid photodynamic therapy (ALA-PDT), which is available in the US, was not studied. Also notable is the use of alternative protocols, for example use of imiquimod more than 3 times a week, could result in different efficacy. Combination of multiple treatment modalities was also not studied.

Patient preference and lifestyle should be considered.  The authors note that about half of patients assessed for eligibility declined participation due to the patient’s specific preference for one of the four modalities. Although MAL-PDT and ingenol had lower efficacy, their higher adherence and shorter, more convenient protocol may make these methods a good choice for certain patients. From a cost perspective, fluorouracil is an attractive option.