ED Drugs Linked to Melanoma? No Hard Evidence

Neil Osterweil

June 23, 2015

Take your pick: either drugs for erectile dysfunction (ED) slightly increase the risk for malignant melanoma, or men who take drugs for ED play too much tennis without a hat or sunscreen.

Results of a large cohort study suggest that lifestyle factors might explain why men who take popular phosphodiesterase type 5 (PDE5) inhibitors for ED ― sildenafil (Viagra, Pfizer Inc), vardenafil (Levitra, Bayer HealthCare Pharmaceuticals), and tadalafil (Cialis, Eli Lilly and Company) -― are at a slightly but significantly increased risk of developing malignant melanoma, according to Stacy Loeb, MD, from the NYU Langone Medical Center, in New York City, and colleagues.

Among more than 4000 Swedish men diagnosed with malignant melanoma, use of a PDE5A inhibitor was associated with a 20% increase in the relative risk for melanoma.

But the data contained a curiosity.

The risk was highest among men who filled only a single prescription for a PDE5 inhibitor. Thus, the risk was not highest among men who filled multiple prescriptions, suggesting that the risk might be associated with lifestyle or demographic factors, the authors reported online June 23 in JAMA.

"A previous study suggested that there is an association, but we were just dubious whether it's really a causal relationship," Dr Loeb said in an interview with Medscape Medical News.

 
We were just dubious. Dr Stacy Loeb
 

The previous study she referred to, published in JAMA Internal Medicine in 2014, found that in a cohort of 25,848 participants in the Health Professionals Follow-up Study, recent use of sildenafil at baseline was associated with a significantly increased risk for melanoma (hazard ratio [HR], 1.84; 95% confidence interval [CI], 1.04 - 3.22), as was ever-use of the PDE5 inhibitor (HR, 1.92; 95% CI, 1.14 - 3.22).

The rationale for the earlier study was that in melanoma, the RAS/RAF/mitogen-activated protein kinase and the extracellular signal–regulated kinase (MEK/ERK) signaling pathway is involved in malignant cell proliferation and survival. PDE5A inhibitors work within this pathway, raising concerns that the drugs might promote the growth of malignant melanoma.

In the Halls of the Data King

To see whether there could be a causal relationship, as suggested by the earlier study, Dr Loeb and colleagues took advantage of the treasure trove of data provided by Swedish healthcare data registries; in this case, it was the comparison cohort from the Prostate Cancer Data Base Sweden.

Using the unique identifier for every Swedish citizen, they linked the data to the Swedish Cancer Registry and identified men diagnosed with incident melanoma from 2006 through 2012. They then matched each melanoma case with five randomly selected control individuals, stratified by birth year, who were cancer free at the time of diagnosis of the index melanoma case.

The investigators also mined data from other registries on the extent and severity of melanoma, prescriptions for PDE5 inhibitors, and potential demographic and socioeconomic factors.

They found that of the 4065 men with melanoma, 435 (11%) had filled at least one prescription for a PDE5 inhibitor, compared with 1713 (8%) of the 20,325 control individuals.

In a multivariable model controlling for comorbidities, marital status, educational level, and disposable income, they found that among all men, PDE5-inhibitor use was associated with an OR of 1.21 (95% CI, 1.08 - 1.36) for the risk for melanoma.

As noted, the strongest association with ED drug use and risk was among men who filled only one prescription (OR, 1.32; 95% CI, 1.10 - 1.59). Among men who filled 2-5 or 6 or more scripts, however, the association was not significant (OR, 1.14; 95% CI, 0.95 - 1.37; and OR, 1.17; 95% CI, 0.95 - 1.44, respectively).

"If it was a causal relationship, indeed, we would have expected that the men who filled the most prescriptions would have the highest risk, and that was not the case at all," Dr Loeb told Medscape Medical News.

Married men and those with higher educational levels and incomes were also at significantly increased risk for melanoma. In contrast, men with a score of 2 or more on the Charlson Comorbidity Index were significantly less likely to receive a melanoma diagnosis.

The investigators also found a significant association between use of PDE5 inhibitors and increased risk for basal cell carcinoma (adjusted OR, 1.19; 95% CI, 1.14 - 1.25), and the effect remained significant for each of the three drugs available.

This latter finding shows that the association between ED drugs and melanoma fails another test for causality: specificity.

"If it was really due to some kind of causal relationship because of the melanoma pathway, then we wouldn't have expected that it would have any kind or relationship with basal cell skin cancer, and it did," Dr Loeb noted.

The association between ED drugs and basal cell carcinoma strongly supports the lifestyle theory, says an oncologist who was not involved in the study.

"The thing that I think is critical is the fact that they had data about basal cell carcinoma, which is not thought to be at all related to this pathway," said Ryan J. Sullivan, MD, from the Massachusetts General Hospital Cancer Center, in Boston.

"Basal cell carcinoma is entirely related to sun exposure, so the fact that they saw a similar increase in basal cell carcinoma as in melanoma is corroborative of there being a higher socioeconomic status and that [the men with melanoma] are probably getting more sun exposure," he said in an interview with Medscape Medical News.

Casting further doubt on causality is the lack of a dose response, Dr Sullivan noted. The investigators found that there were no significant differences in effect between sildenafil, the shortest-acting agent, and tadalafil, the PDE5 with the longest serum half life.

Finally, there was no association between the use of the drugs and advanced melanoma, suggesting that the association between the drugs and melanoma was due to other causes, Dr Loeb said.

"We see an association, but we think it's more likely that it's not a causal relationship, it's just that the same men who are risk for melanoma are the same types of men who take erectile dysfunction drugs," she said.

The study was supported by the Swedish Research Council, the Swedish Cancer Foundation (11 0471), the Västerbotten County Council, the Lion's Cancer Research Foundation at Umeå University, and grants to Dr Loeb from the Louis Feil Charitable Lead Trust and the Laura and Isaac Perlmutter NYU Cancer Institute. Dr Loeb has received personal fees from Bayer and sanofi-aventis. Dr Sullivan has disclosed no relevant financial relationships.

JAMA. Published online June 23, 2015. Abstract

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