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Is topical calcineurin inhibitor (TCI) use associated with an increased risk of cancer?
This systematic review and meta-analysis of 11 studies revealed no association between TCI use and risk of cancer overall or skin cancer. Lymphoma risk was elevated with TCI use.
Although this study found a positive association between TCI use and lymphoma, the low absolute risk of lymphoma makes the potential increased risk attributable to TCI use for any individual patient very small.
Topical calcineurin inhibitors (TCIs) are commonly used as second-line treatment for atopic dermatitis. In 2006, the US Food and Drug Administration issued a black box warning against TCI use, citing data from case reports and animal studies indicating a potential risk of cancer.
To evaluate the association between TCI use and risk of malignant neoplasms compared with nonactive and active comparator groups.
Electronic searches were conducted in MEDLINE via Ovid, Embase via Ovid, and Web of Science from database inception to August 21, 2020.
Observational studies investigating the association between treatment with TCIs (ie, tacrolimus and pimecrolimus) and the development of cancer with nonactive or active comparators were included. The population of interest was not limited to any specific disease state, age, or sex. All articles were assessed independently and in duplicate by 2 reviewers. Risk of bias was assessed using the Newcastle-Ottawa scale. Of 2464 nonduplicate records retrieved from the search, 11 studies met the inclusion criteria.
Data Extraction and Synthesis
Data extraction was conducted independently by 2 reviewers according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Random-effects meta-analyses were used to derive pooled relative risk (RR) estimates. Data were analyzed from July 25 to October 25, 2020.
Main Outcomes and Measures
Risk of cancer overall and risk of specific cancer types (lymphoma, melanoma, and keratinocyte carcinoma).
Eight unique cohort studies (408 366 treated participants [55.1% female], 1 764 313 nonactive comparator controls, and 1 067 280 controls using topical corticosteroids) and 3 unique case-control studies (3898 cases [55.0% male] and 14 026 cancer-free controls [52.4% male]) were included. There was no association between TCI use and cancer overall compared with nonactive comparators (RR, 1.03; 95% CI, 0.92-1.16). Lymphoma risk was elevated with TCI use with both nonactive (RR, 1.86; 95% CI, 1.39-2.49) and topical corticosteroid comparators (RR, 1.35; 95% CI, 1.13-1.61). No significant association was found between TCI use and increased skin cancer (melanoma and keratinocyte carcinoma).
Conclusions and Relevance
The findings of this systematic review and meta-analysis suggest an association between TCI use and risk of lymphoma but not other cancers. Combined with the low absolute risk of lymphoma, the potential increased risk attributable to TCI use for any individual patient is likely very small.
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Accepted for Publication: February 2, 2021.
Published Online: March 31, 2021. doi:10.1001/jamadermatol.2021.0345
Corresponding Author: Aaron M. Drucker, MD, ScM, Division of Dermatology, University of Toronto, 76 Grenville St, Toronto, ON M5S 1B2, Canada (firstname.lastname@example.org).
Author Contributions: Ms Lam had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Lam, Tadrous, Drucker.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Lam, Tadrous.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Lam.
Supervision: Tadrous, Drucker.
Conflict of Interest Disclosures: Dr Tadrous reported consulting for the Canadian Agency for Drugs and Technologies in Health (CADTH). Dr Drucker reported receiving compensation from the British Journal of Dermatology (as a reviewer and section editor), the American Academy of Dermatology (as a guidelines writer), and the National Eczema Association (as a grant reviewer); consulting for CADTH; and receiving honoraria from CME Outfitters. No other disclosures were reported.
Additional Contributions: Stephanie Sanger, MLIS, and the research consultation team at McMaster University, Health Sciences Library, Hamilton, Ontario, Canada, assisted with the development of the search strategy, for which they were not compensated.
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