Should an elderly woman with hypertension, multiple non-melanoma skin cancers, and four melanomas be informed of the potential risks of thiazides, such as bendrofluazide, and considered for alternative antihypertensive medications?

Should Bendrofluazide Be Continued in a Patient with Multiple Melanomas and Non-Melanoma Skin Cancers?

Bendrofluazide should be discontinued and replaced with an alternative antihypertensive agent in this patient with a history of four melanomas and multiple non-melanoma skin cancers, as thiazide diuretics are associated with increased risk of all skin cancer types, particularly squamous cell carcinoma and melanoma.

Evidence Linking Thiazides to Skin Cancer Risk

Melanoma Risk

• Thiazide diuretics are associated with increased melanoma risk (pooled adjusted OR 1.10; 95% CI 1.04-1.15), though the effect size is very small 1
• Higher cumulative thiazide exposure specifically increases melanoma rates (adjusted HR 1.34; 95% CI 1.01-1.78 per Defined Annual Dose unit) in older adults 2

Non-Melanoma Skin Cancer Risk

• Thiazides demonstrate the strongest association with squamous cell carcinoma (pooled adjusted OR 1.35; 95% CI 1.22-1.48), representing a very small but consistent harmful effect 1
• Hydrochlorothiazide specifically shows a robust association with squamous cell carcinoma (adjusted OR 2.04; 95% CI 1.79-2.33) without significant heterogeneity between studies 3
• Basal cell carcinoma risk is also elevated with thiazide use (pooled adjusted OR 1.05; 95% CI 1.02-1.09), though the effect is smaller 1
• Increasing thiazide exposure correlates with higher rates of incident keratinocyte carcinoma (adjusted HR 1.08 per Defined Annual Dose; 95% CI 1.03-1.14) 2

Mechanism and Photosensitivity

• Thiazide diuretics possess photosensitizing properties that may explain their association with skin malignancies 3, 4
• The photosensitizing effect is a recognized property of this drug class, though the exact mechanism linking chronic use to malignancy remains under investigation 4

Recommended Alternative Antihypertensive Agents

First-Line Alternatives

• ACE inhibitors or ARBs show no consistent association with skin cancer risk and represent appropriate first-line alternatives 2, 4
• Calcium channel blockers are suitable alternatives, though one meta-analysis found a small increased overall skin cancer risk (SRR 1.14; 95% CI 1.07-1.21), this was not specific to melanoma or high-risk patients 4
• For most patients, thiazide diuretics are recommended as initial therapy alongside calcium channel blockers, ACE inhibitors, or ARBs, but this recommendation does not apply to patients with established high skin cancer risk 5

Treatment Algorithm for This Patient

1. Discontinue bendrofluazide immediately given the patient's history of four melanomas and multiple non-melanoma skin cancers 2, 1
2. Initiate an ACE inhibitor or ARB as the replacement antihypertensive, as these classes show no association with skin cancer risk 2, 4
3. Add a calcium channel blocker if blood pressure remains uncontrolled on monotherapy, creating a thiazide-free dual therapy regimen 5, 6
4. Consider a non-thiazide diuretic (such as a loop diuretic) only if volume-dependent hypertension persists and other combinations fail, though evidence for skin cancer risk with non-thiazide diuretics is limited 2

Critical Communication Points for the Healthcare Team

Provider and Cardiologist Notification

• The primary care provider and cardiologist must be immediately informed of the cumulative evidence linking thiazides to increased skin cancer risk in this high-risk patient 2, 1
• Regulatory safety warnings have been issued regarding thiazides and skin cancer risk, making this a recognized drug safety concern 2
• The patient's history of four melanomas places her in an exceptionally high-risk category where even small increases in relative risk translate to clinically significant absolute risk 1

Patient Counseling

• Inform the patient that thiazide diuretics may increase her already elevated risk of developing additional skin cancers 2, 1
• Explain that alternative antihypertensive medications without this association are available and equally effective for blood pressure control 5, 2
• Emphasize the importance of continued dermatologic surveillance regardless of medication changes, given her extensive skin cancer history 4

Important Caveats

Strength of Evidence Limitations

• The evidence linking thiazides to skin cancer comes entirely from observational studies (case-control and cohort designs), with no randomized controlled trials available 1
• The overall strength of evidence is rated as "very low" due to the observational nature of the data and potential for confounding 1
• However, the consistency of findings across multiple studies and the dose-response relationship strengthen the causal inference 2, 1

Population-Specific Considerations

• Most evidence derives from Caucasian populations, where skin cancer risk is inherently higher 7
• One study in an Asian population found no significant skin cancer risk with hydrochlorothiazide, suggesting ethnic differences in susceptibility 7
• The patient's ethnicity should be considered, though the precautionary principle favors medication change given her documented history of multiple skin cancers 7

Avoiding Common Pitfalls

• Do not continue thiazides simply because the absolute risk increase is small—in a patient with four prior melanomas, even small relative risks are clinically meaningful 1
• Do not switch to another thiazide diuretic (such as hydrochlorothiazide or chlorthalidone), as the skin cancer risk appears to be a class effect 3, 1
• Do not delay medication change while awaiting further evidence, as the patient's existing skin cancer burden warrants immediate risk reduction 2