PDE-5 inhibitors and melanoma: No causal link found

Findings from a meta-analysis show that, while phosphodiesterase type 5 (PDE-5) inhibitor use is associated with a statistically significant increased risk of melanoma, they do not support a causal relationship, said lead author Stacy Loeb, MD, MSc, of NYU School of Medicine, New York.

The research, published online in the Journal of the National Cancer Institute (May 19, 2017), represents the first meta-analysis of published studies investigating PDE-5 inhibitors and melanoma, and its objective was to determine whether there was an association that meets Hill’s criteria for causality. It included three case-control and two cohort studies with 866,049 men, of whom 41,874 had a diagnosis of melanoma.

Using random effects models to calculate summary statistics, the overall analysis found an increased risk of melanoma in men using a PDE-5 inhibitor (relative risk [RR]=1.11, 95% confidence interval [CI]=1.02-1.22). Results of other analyses showed that the association between PDE-5 inhibitor use and melanoma, however, did not meet five of nine Hill’s causal criteria.

“We believe that physicians and patients should not be concerned about using PDE-5 inhibitors on account of worry about melanoma,” said Dr. Loeb. “Nevertheless, men should continue to be careful about the risk of any kind of skin cancer from excessive sun exposure and use sun protection.”

The investigation of causality between PDE-5 inhibitor use and melanoma included analyses looking for dose-response, biologic gradient, and specificity.

Analyses with men categorized based on extent of PDE-5 inhibitor exposure showed a statistically significant increased risk of melanoma only among men who took lower amounts of the medication (RR=1.15, 95% CI=1.01-1.31), but not in those with high exposure (RR=1.09, 95% CI=0.97-1.23).

Analyses using information from two studies reporting data on melanoma stage did not find any evidence of biologic gradient. High PDE-5 inhibitor exposure was associated with an increased risk of stage 0 melanoma (RR=1.45, 95% CI=1.09-1.92), but the risk of stage II to IV melanoma was actually decreased in men with high PDE-5 inhibitor exposure (RR=0.67, 95% CI=0.46-0.97).

Lack of specificity was demonstrated by an analysis that showed risk of basal cell carcinoma was also increased among PDE-5 inhibitor users and by a magnitude similar to that observed for melanoma (RR=1.16, 95% CI=1.13-1.20).

Next: Association may be due to confounding factors, lifestyle behaviors associated with sun exposure

Dr. Loeb and colleagues suggested that the overall association of PDE-5 inhibitor use with melanoma and other skin cancers may be due to confounding factors and particularly lifestyle behaviors associated with sun exposure considering that socioeconomic status is strongly associated with both PDE-5 inhibitor use and skin cancer. They also noted that the associations between high PDE-5 inhibitor exposure and increased risk of stage 0 melanoma and decreased risk of more advanced disease suggest a role for detection bias.

Concern that use of a PDE-5 inhibitor may promote the development of melanoma relates to the fact that PDE-5 is downregulated in BRAF mutations that are commonly seen in melanoma. A prospective cohort study published in 2014 reported an 84% increase in melanoma risk with sildenafil citrate (Viagra) use (JAMA Intern Med 2014; 174:964-70). In a study using Swedish registry data, Dr. Loeb and colleagues also found a statistically significant increased risk of melanoma among PDE-5 inhibitor users (JAMA 2015; 313:2449-55). Because it was not present among men who had filled more than one prescription, however, they questioned whether the medication had a causal effect. Subsequently, two other large studies based on European populations either found no association between PDE-5 inhibitor use and melanoma or did not support causality.

In 2016, however, the FDA placed PDE-5 inhibitors on its Adverse Event Reporting System watch list, indicating the agency determined a need to evaluate the association with cutaneous melanoma.

Dr. Loeb receives honoraria for lectures from Astellas, GenomeDx Biosciences, MDx Health, and Boehringer Ingelheim, consulting fees from Lilly, and reimbursed travel to conferences from Minomic and Astellas.

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