Increased cutaneous squamous cell carcinoma risk with hydrochlorothiazide use: is there a safe alternative?
Authors: L.M. Hollestein, S. Arnspang Pedersen
Journal: British Journal of Dermatology (2021)

Linked Article: Schneider et al. Br J Dermatol 2021; 185:343–352. Multiple studies have shown that hydrochlorothiazide, a photosensitizing drug, increases the risk of skin cancer.1-6 In this issue of the BJD, Schneider et al. confirm the strongly increased risk of cutaneous squamous cell carcinoma (cSCC) in a cohort study using a UK primary care database.7 Although, weak associations with melanoma and basal cell carcinoma (BCC) have been observed in some studies, these were not observed in the cohort study of Schneider et al.7 The first studies on hydrochlorothiazide compared users with nonusers of antihypertensive drugs.5, 6 In order to address the clinically important question of how skin cancer risk compares with alternative first-line antihypertensives, Schneider et al.7 compared the skin cancer incidence of users of hydrochlorothiazide, bendroflumethiazide (another thiazide) and indapamide (a thiazide-like diuretic) with users of calcium channel blockers (another type of first-line antihypertensive drug). Recently, Rouette et al.8 compared hydrochlorothiazide with all other thiazides. They obtained comparable results to Schneider et al.: an increased risk of cSCC was observed, but no associations for BCC and melanoma were observed.8 While most studies report relative risk (e.g. odds ratios or hazard ratios), Schneider et al.7 calculated absolute risk increases, which is of importance for health policymakers to determine the absolute amount of extra skin cancers that can be expected among hydrochlorothiazide users. Despite the fact that these estimates were not yet available back in 2018, the European Medicines Agency, had already evaluated the two Danish studies carefully in 2018, and concluded that the association found between hydrochlorothiazide and risk of SCC was strong enough to incorporate an alert to the summary of product characteristics, recommending to reconsider the use of hydrochlorothiazide carefully, in patients with a history of skin cancer.9 In the two Danish case–control studies performed,1, 2 other drugs with comparable indications to hydrochlorothiazide, including bendroflumethiazide, had no association to skin cancer. The findings of Schneider et al. confirmed that bendroflumethiazide may be a safe alternative to hydrochlorothiazide, as there was no association with SCC and BCC. However, short-term use was associated with a 36% increase in melanoma incidence rate. Due to the absence of a clear dose–response relationship (i.e. long-term use was not associated with melanoma risk) causality seems unlikely and this may have been a chance finding. On the other hand, most melanomas occurred 3.6 years after initiation of bendroflumethiazide therapy, which may be a sufficiently long duration for a carcinogenic effect. The association between BCC and hydrochlorothiazide showed the same pattern: short-term use seemed to increase the risk of BCC, but there was no association with long-term use. Therefore, external validation of their results is of vital importance. While the association with hydrochlorothiazide and cSCC is now externally validated in multiple studies,7, 8 Schneider et al. confirmed that bendroflumethiazide is an example of a safe alternative for prescribing physicians, in terms of choice of thiazide for patients at increased risk of nonmelanoma skin cancer. Loes Maria Hollestein: Writing-original draft (lead); Writing-review & editing (equal). Sidsel Arnspang Pedersen: Writing-original draft (supporting); Writing-review & editing (supporting).