Vascular regression after diclofenac 3% gel (Solaraze™) treatment for actinic keratoses: Clinical evidence of a promising target for skin cancer therapy

Background: Diclofenac is the anti-neoplastic compound in diclofenac 3% gel (Solaraze TM), used for topical treatment of actinic keratoses (AKs). The precise mechanism of action of this non-steroidal anti-inflammatory drug in cutaneous cells is still unclear, but induction of apoptosis seems to play a key role. Diclofenac exerts antineoplastic actions by inhibition of the inducible cyclo-oxygenase 2 (COX-2) enzyme and reduction of the levels of prostaglandins; it is also able to reduce the synthesis of pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factors. In several tumour models, a correlation between COX-2 activity and tumour vascularization, increased microvessel density and VEGF production has been demonstrated. The COX-2 inhibitors, including diclofenac, have been shown to reduce PGE2 synthesis and VEGF expression in squamous cell carcinoma of the skin. Aim: To investigate the effects of diclofenac 3% gel on the clearance rates of extensive AKs, with particular regard to vascular regression. Methods: An open label, uncontrolled, non-randomised study was conducted in 6 patients treated with diclofenac 3% gel, twice daily for 12-16 weeks. Results: All the patients showed a marked improvement in their overall AKs lesion count and a significant reduction of vascular density. Local adverse events at the site of application were very mild (i.e. erythema, marginal erosion, post-inflammatory hypopigmentation) and no systemic side effects were reported. Clinically and dermoscopically, no apparent signs of persisting AKs could be detected and no recurrences were reported over 6 months of follow-up. Conclusions: This study confirms the therapeutic effectiveness of diclofenac 3% gel in the treatment of multiple and extensive AKs; the striking reduction in vascularity observed in our patients suggests that diclofenac-induced inhibition of angiogenesis may play a role in determining tumour regression.