Topical Calcineurin Inhibitors Pose Very Little Cancer Risk

The topical calcineurin inhibitors (TCIs) tacrolimus and pimecrolimus, widely used to treat atopic dermatitis, do not have any association with common cancer types, according to a new systematic review and meta-analysis.

"Overall, our findings ought to be reassuring to patients and physicians," Dr. Aaron M. Drucker told Reuters Health by email. "Most of our analyses found that using topical calcineurin inhibitors was not associated with increased cancer risk."

"When we compared calcineurin inhibitors with topical steroids," he added, "we did find that calcineurin inhibitors were associated with a 35% increased risk of lymphoma, but lymphoma is rare overall, so the absolute risk is low."

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In an online paper in JAMA Dermatology, Dr. Drucker and colleagues at the University of Toronto, Canada, note that the tacrolimus ointment and pimecrolimus cream are used as second-line treatment of atopic dermatitis when first-line topical corticosteroids are ineffective or contraindicated.

But in 2006, the U.S. Food and Drug Administration (FDA) issued a black box warning on TCIs and possibly elevated cancer risk. Of more than 6.7 million patients receiving TCI treatment the warning was based on about 25 case reports. Moreover, there was no systematic analysis supporting the link.

Nevertheless, say the researchers, "Given the long potential latency for cancer development, postmarketing studies with long follow-up are necessary to determine whether there is an association between TCIs and cancer."

To investigate further, they examined data from eight cohort studies with more than 408,000 treated participants. Also included were 1.76 million nonactive comparator controls and more than a million controls using topical corticosteroids. Further analysis was of three case-control studies involving almost 4,000 cases and more than 14,000 cancer-free controls.

The team found no significant association between TCI use and cancer overall compared with nonactive comparators (relative risk, 1.03). This was particularly the case for melanoma and keratinocyte carcinoma.

Lymphoma risk was significantly elevated with TCI use, however. This was true of both nonactive comparators (RR, 1.86) and topical corticosteroid comparators (RR, 1.35). But lymphoma is rare, the team notes, with an annual worldwide incidence of 1.35 per 100,000 in children and 9.88 per 100,000 in adults.

Thus, concluded Dr. Drucker, "A physician would need to treat over 200,000 children or almost 30,000 adults with topical calcineurin inhibitors in order to see one excess case of lymphoma."

Commenting on the findings by email, Dr. Steven T. Chen of Massachusetts General Hospital Cancer Center, in Boston, noted, "While the risk of lymphoma has been reported before, this is the first article to perform high-level statistics to look at the question. Importantly, the number needed to harm is very high. That means that while there is a signal there, the risk is still very low."

Dr. Chen, who is co-director of the Comprehensive Cutaneous Lymphoma Program, added, "In the real world, I would have the conversation with my patients about this risk but realize that the risk still remains low. Just like any other medication or treatment, we have to weigh the risks and benefits, and for many of our patients with inflammatory skin conditions, I expect the benefit will still outweigh the risks. We and our patients just have to know the data to make an informed decision."

The researchers report no funding or conflicts of interest.

—David Douglas

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