Topical diclofenac 3% plus sodium hyaluronate for actinic keratosis

Actinic keratosis (AK), also referred to as solar keratosis or squamous cell carcinoma in situ (SCC), is a localised area of dysplasia with malignant potential. It is regarded as a strong predictor of a subsequent squamous cell carcinoma, a form of non-melanoma skin cancer. The risk of progression of AK to invasive SCC has been estimated to range from <1% to 16%. It is impossible to predict the point at which an individual AK lesion will evolve into invasive SCC, so the treatment of all AK lesions is advocated.

Current treatment involves surgical or non-surgical interventions, or a combination of both. Cryosurgery and curettage are used to treat small areas with few lesions. Fluorouracil is used when treating numerous lesions covering a large area. Other treatment options include chemical peels, dermabrasion, laser therapy, excision, photodynamic therapy, topical imiquimod, and topical diclofenac 3% with sodium hyaluronate (DHA).

There are few clinical trials, and until now no systematic reviews. One of DHA [1] provides at least provides a baseline from which to judge future reviews of therapy.

Only Medline was searched, up to mid-2005, with a simple search strategy. Inclusion criteria included only outcomes, either the complete resolution of all target lesions in the treatment area, or the complete resolution of all target and new lesions in the treatment area, with assessment 30 days after the end of treatment. There was no requirement for trials to be randomised.

Three trials with 364 patients were described as double blind and included. Each tested diclofenac with sodium hyaluronate against vehicle containing hyaluronate. In these trials the lesions were on face, scalp, arms, or hands. Treatment was with 0.25 g or 0.5 g DHA daily for 60-90 days.

The outcome of complete resolution of all target lesions in the treatment area 30 days after end of treatment was reported in two trials, in which 45/106 (42% of patients) had resolution with DHA and 17/108 (16%) with placebo. The relative benefit was 2.7 (95% CI 1.7 to 4.4), and the number needed to treat 3.7 (2.6 to 6.6).

The outcome of complete resolution of all target and new lesions in the treatment area 30 days after end of treatment was reported in all three trials, in which 70/179 (39% of patients) had resolution with DHA and 23/185 (12%) with placebo (Figure 1). The relative benefit was 3.1 (95% CI 2.1 to 4.8), and the number needed to treat 3.8 (2.8 to 5.5).

Adverse events were not commented upon in detail. Common adverse events were apparently pruritus, contact dermatitis, dry skin, rash, and scaling.

At one level this is not satisfactory. We cannot be certain from the review that the trials were randomised, though the fact that they were described as double blind makes it likely, and we could find out for ourselves by finding the three papers, which were relatively recent (2001-2003). It is also argued that follow up of several years should be a part of trials in actinic keratosis, as this is the timescale during which recurrence is likely. Searching was perfunctory, though major omissions are unlikely. Moreover, the small patient numbers result in wide confidence intervals, and a lack of robustness about the result.

On another level, it is at least one systematic review of some trials, in a subject not well endowed by clinical trials. Most therapies have few or no trials. The exception is imiquimod, with more and larger trials, but not yet available in many places. Bandolier will keep an eye peeled for other systematic reviews.

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