Viagra and Melanoma: Search for Link Inconclusive

A potential link between erectile dysfunction drugs and melanoma may exist, but inconsistencies in the data make a cause-and-effect relationship questionable, an analysis of a large melanoma database suggests.

Men who had a history of using phosphodiesterase type 5 (PDE5) inhibitors had a 20% greater risk of melanoma as compared with men who never used the drugs. However, the strongest association involved men who filled a single prescription for a PDE5 inhibitor. Total number of prescriptions filled did not significantly affect melanoma risk.

Moreover, the PDE5 inhibitor-melanoma association pertained only to early-stage disease (stage 0-I), did not differ by type of PDE5 inhibitor, and was not limited to melanoma, as an increased risk of basal cell carcinoma was seen among users of PDE5 inhibitors, Stacy Loeb, MD, of NYU Langone Medical Center in New York City, and colleagues reported online in JAMA.

"It doesn't seem like it's a very specific relationship," Loeb told MedPage Today. "Rather, men who are at risk for melanoma are the same types of men who are taking erectile dysfunction drugs."

The findings are consistent with those of a similar study reported a year ago. However, the previous study was based on data that showed only whether a man had ever used a PDE5 inhibitor. Extracted from the Health Professionals Follow-up Study, the data were limited to the original PDE5 inhibitor, sildenafil (Viagra), and lacked details about use of the drug, such as the number of prescriptions filled.

"Our study cannot prove cause and effect," authors of the 2014 study concluded. "A longer follow-up and more detailed assessment of the dose and frequency of sildenafil use at multiple times in the [study cohort] would be necessary for future studies."

Nonetheless, Jiali Han, PhD, of the Fairbanks School of Public Health at Indiana University-Purdue University in Indianapolis, and colleagues said their data warranted further investigation.

Background

In theory, a causal association between PDE5 inhibitor use and melanoma has biologic plausibility. Several studies have provided evidence of interaction between PDE5 and signaling pathways involved in melanoma evolution and progression, including BRAF and NRAS.

In an effort to address some of the unanswered questions from the previous study, Loeb and colleagues turned to several comprehensive databases in Sweden: the Swedish Melanoma Register, Swedish Cancer Registry, and the Swedish Prescribed Drug Register.

From the melanoma register, they identified all newly diagnosed melanoma cases in Sweden from 2006 through 2012. They used the cancer registry to examine the association between PDE5 inhibitor use and the risk of basal-cell carcinoma, the most common form of skin cancer. The prescription drug register provided data on all prescribed medications in Sweden since 2006.

If PDE5 inhibitors promote melanoma, the authors hypothesized, then:

• Men who filled the most prescriptions would have the highest risk
• PDE5 inhibitors with the longest half-life would confer the greatest risk
• Users of PDE5 inhibitors would have an increased risk of late-stage melanoma
• Use of PDE5 inhibitors would have no association with basal cell carcinoma, which involves a different signaling pathway

The authors performed a nested case-control study. They identified a total of 4,065 men with newly diagnosed melanoma during the study period, including 435 who had a history of PDE5 inhibitor use. Each man who developed melanoma was matched by age with five men who did not develop melanoma. The analysis involved a total of 24,390 men.

Of the 435 men who used PDE5 inhibitors and developed melanoma, 275 had filled one or more prescriptions for sildenafil and 224 had filled at least one prescription for vardenafil (Levitra) or tadalafil (Cialis).

Key Results

Overall, men who used PDE5 inhibitors had an odds ratio for melanoma of 1.21 versus nonusers (95% CI 1.08-1.36). The odds ratio did not differ significantly across the three types of PDE5 inhibitors.

Men who filled a single prescription for a PDE5 inhibitor had a melanoma OR of 1.32 versus the control group (95% CI 1.10-1.59, 4% for cases versus 3% for control group). The OR was 1.14 among men who had filled two to five prescriptions and 1.17 in men who filled six or more prescriptions, neither of which achieved statistical significance.

With respect to melanoma stage at diagnosis, the incidence of stage 0 disease was 13% among PDE5 inhibitor users and 8% among nonusers, a statistically significant 49% higher risk (OR 1.49, 95% CI 1.22-1.83). A smaller but statistically significant association was seen for stage I and PDE5 inhibitor use (OR 1.21, 1.02-1.43). Men who used PDE5 inhibitors did not have an increased risk of stage II-IV melanoma.

Analysis of melanoma stage at diagnosis by number of prescriptions filled showed a significant association only for stage 0 and a single prescription (OR 1.86, 95% CI 1.36-2.53). The type of PDE5 inhibitor had no influence on stage at diagnosis, regardless of the number of prescriptions filled.

The data also failed to support the authors' hypothesis that PDE5 inhibitors would have no association with basal cell skin cancer. The analysis showed that use of PDE5 inhibitors increased the risk to a similar extent as with melanoma (OR 1.19, 95% CI 1.14-1.25).

The study by Han's group showed a statistical association between PDE5 inhibitor use and melanoma and potential biological explanation, tempered by several caveats, said Alexander Pastuszak, MD, a urologist at Baylor College of Medicine in Houston, who was not involved in either study. The study by Loeb's group took the investigation to a different level by linking information from several different databases.

Still, key questions remain unanswered.

"What is the relationship between mutations in RAS-RAF-MEK-ERK signaling pathway that's important in melanoma and PDE5 inhibitor use?" Pastuszak told MedPage Today. "Can you link to PDE5 inhibitor use? One of the limitations of the [Loeb] study is you still don't know whether the patients are actually taking the drugs. The other big question that hasn't been answered is what is the effect of PDE5 inhibitor use on melanoma severity."

Until the questions are answered, "I wouldn't change my practice," he added.

The study was supported by the Swedish Research Council, Swedish Cancer Foundation, Vasterbotten County Council, Lion's Cancer Research Foundation at Umea University, Louis Feil Charitable Lead Trust, and the Perlmutter NYU Cancer Institute.

Loeb disclosed relevant relationships with Bayer and sanofi-aventis.

• Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

Primary Source

Journal of the American Medical Association

Source Reference: Loeb S, et al "Use of phosphodiesterase type 5 inhibitors for erectile dysfunction and risk of malignant melanoma" JAMA 2015; DOI: 10.1001/jama.2015.6604

This article was first published on MedPage Today and reprinted with permission. Free registration is required.