Association Between Topical Calcineurin Inhibitor Use and Risk of Cancer | Cancer Screening, Prevention, Control | JN Learning | AMA Ed Hub [Skip to Content]
[Skip to Content Landing]

Association Between Topical Calcineurin Inhibitor Use and Risk of Cancer, Including Lymphoma, Keratinocyte Carcinoma, and MelanomaA Systematic Review and Meta-analysis

Educational Objective
To evaluate the association between topical calcineurin inhibitors and risk of malignant neoplasms.
1 Credit CME
Key Points

Question  Is topical calcineurin inhibitor (TCI) use associated with an increased risk of cancer?

Findings  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.

Meaning  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.

Abstract

Importance  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.

Objective  To evaluate the association between TCI use and risk of malignant neoplasms compared with nonactive and active comparator groups.

Data Sources  Electronic searches were conducted in MEDLINE via Ovid, Embase via Ovid, and Web of Science from database inception to August 21, 2020.

Study Selection  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).

Results  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.

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 CME Credit™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

Article Information

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 (aaron.drucker@wchospital.ca).

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.

References
1.
Food and Drug Administration, Office of the Commissioner. Minutes of the Pediatric Advisory Committee meeting. February 14, 2005. Accessed August 24, 2020. https://wayback.archive-it.org/7993/20170404062542/https://www.fda.gov/ohrms/dockets/ac/05/minutes/2005-4089m1_Minutes.pdf
2.
Radovic  TC , Kostovic  K , Ceovic  R , Mokos  ZB .  Topical calcineurin inhibitors and malignancy risk.   Int J Cancer Manag. 2017;10(4):e6173. doi:10.5812/ijcm.6173 Google Scholar
3.
Hanna  S , Zip  C , Shear  NH .  What is the risk of harm associated with topical calcineurin nhibitors?   J Cutan Med Surg. 2019;23(4_suppl):19S-26S. doi:10.1177/1203475419857688PubMedGoogle ScholarCrossref
4.
Ormerod  AD .  Topical tacrolimus and pimecrolimus and the risk of cancer: how much cause for concern?   Br J Dermatol. 2005;153(4):701-705. doi:10.1111/j.1365-2133.2005.06899.x PubMedGoogle ScholarCrossref
5.
US Food and Drug Administration. Information for healthcare professionals: pimecrolimus (marketed as Elidel). Published 2006. Accessed August 24, 2020. https://wayback.archive-it.org/7993/20170112032734/http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm153525.htm
6.
US Food and Drug Administration. FDA approves updated labeling with boxed warning and medication guide for two eczema drugs, Elidel and Protopic. Published 2006. Accessed August 24, 2020. https://wayback.archive-it.org/7993/20171115034557/https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm153941.htm
7.
Drucker  AM , Tadrous  M .  Topical calcineurin inhibitors and skin cancer—another piece of the puzzle.   JAMA Dermatol. 2020;156(10):1053-1054. doi:10.1001/jamadermatol.2020.2239 PubMedGoogle ScholarCrossref
8.
Hui  RL , Lide  W , Chan  J , Schottinger  J , Yoshinaga  M , Millares  M .  Association between exposure to topical tacrolimus or pimecrolimus and cancers.   Ann Pharmacother. 2009;43(12):1956-1963. doi:10.1345/aph.1M278 PubMedGoogle ScholarCrossref
9.
Deleuran  M , Vestergaard  C , Vølund  A , Thestrup-Pedersen  K .  Topical calcineurin inhibitors, topical glucocorticoids and cancer in children: a nationwide study.   Acta Derm Venereol. 2016;96(6):834-835. doi:10.2340/00015555-2392PubMedGoogle Scholar
10.
National Institute for Health Research. The association between topical calcineurin inhibitor use and risk of cancer: a systematic review and meta-analysis. CRD42020190452. Accessed August 21, 2020. https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=190452
11.
Moher  D , Liberati  A , Tetzlaff  J , Altman  DG ; PRISMA Group.  Preferred Reporting Items for Systematic Reviews and Meta-analyses: the PRISMA statement.   PLoS Med. 2009;6(7):e1000097. doi:10.1371/journal.pmed.1000097 PubMedGoogle Scholar
12.
Stroup  DF , Berlin  JA , Morton  SC ,  et al.  Meta-analysis of observational studies in epidemiology: a proposal for reporting: Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group.   JAMA. 2000;283(15):2008-2012. doi:10.1001/jama.283.15.2008 PubMedGoogle ScholarCrossref
13.
Wells  GS. , O’Connell  D , Peterson J, Welch V, Losos L, Tugwell P. The Newcastle-Ottawa scale (NOS) for assessing the quality of nonrandomized studies in meta-analyses. Ottawa Health Research Institute. Published 2019. Accessed August 1, 2020. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp
14.
Eyawo  O , Brockman  G , Goldsmith  CH ,  et al.  Risk of myocardial infarction among people living with HIV: an updated systematic review and meta-analysis.   BMJ Open. 2019;9(9):e025874. doi:10.1136/bmjopen-2018-025874 PubMedGoogle Scholar
15.
Fernández  MDM , Saulyte  J , Inskip  HM , Takkouche  B .  Premenstrual syndrome and alcohol consumption: a systematic review and meta-analysis.   BMJ Open. 2018;8(3):e019490. doi:10.1136/bmjopen-2017-019490 PubMedGoogle Scholar
16.
Byrne  AL , Marais  BJ , Mitnick  CD , Lecca  L , Marks  GB .  Tuberculosis and chronic respiratory disease: a systematic review.   Int J Infect Dis. 2015;32:138-146. doi:10.1016/j.ijid.2014.12.016 PubMedGoogle ScholarCrossref
17.
Bateson  D , Butcher  BE , Donovan  C ,  et al.  Risk of venous thromboembolism in women taking the combined oral contraceptive: a systematic review and meta-analysis.   Aust Fam Physician. 2016;45(1):59-64.PubMedGoogle Scholar
18.
Beckett  MW , Ardern  CI , Rotondi  MA .  A meta-analysis of prospective studies on the role of physical activity and the prevention of Alzheimer’s disease in older adults.   BMC Geriatr. 2015;15(1):9. doi:10.1186/s12877-015-0007-2 PubMedGoogle ScholarCrossref
19.
Review Manager (RevMan) [computer program]. Version 5.3. Nordic Cochrane Centre, Cochrane Collaboration; 2014.
20.
Cai  SCS , Li  W , Tian  EAL , Allen  JC , Tey  HL .  Topical calcineurin inhibitors in eczema and cancer association: a cohort study.   J Dermatolog Treat. 2016;27(6):531-537. doi:10.3109/09546634.2016.1163317 PubMedGoogle ScholarCrossref
21.
Castellsague  J , Kuiper  JG , Pottegård  A ,  et al.  A cohort study on the risk of lymphoma and skin cancer in users of topical tacrolimus, pimecrolimus, and corticosteroids (Joint European Longitudinal Lymphoma and Skin Cancer Evaluation - JOELLE study).   Clin Epidemiol. 2018;10:299-310. doi:10.2147/CLEP.S146442PubMedGoogle ScholarCrossref
22.
Margolis  DJ , Abuabara  K , Hoffstad  OJ , Wan  J , Raimondo  D , Bilker  WB .  Association between malignancy and topical use of pimecrolimus.   JAMA Dermatol. 2015;151(6):594-599. doi:10.1001/jamadermatol.2014.4305 PubMedGoogle ScholarCrossref
23.
Schneeweiss  S , Doherty  M , Zhu  S ,  et al.  Topical treatments with pimecrolimus, tacrolimus and medium- to high-potency corticosteroids, and risk of lymphoma.   Dermatology. 2009;219(1):7-21. doi:10.1159/000209289 PubMedGoogle ScholarCrossref
24.
Asgari  MM , Tsai  AL , Avalos  L , Sokil  M , Quesenberry  CP  Jr .  Association between topical calcineurin inhibitor use and keratinocyte carcinoma risk among adults with atopic dermatitis.   JAMA Dermatol. 2020;156(10):1-8. doi:10.1001/jamadermatol.2020.2240PubMedGoogle Scholar
25.
Paller  AS , Fölster-Holst  R , Chen  SC ,  et al.  No evidence of increased cancer incidence in children using topical tacrolimus for atopic dermatitis.   J Am Acad Dermatol. 2020;83(2):375-381. doi:10.1016/j.jaad.2020.03.075 PubMedGoogle ScholarCrossref
26.
Arellano  FM , Arana  A , Wentworth  CE , Fernández-Vidaurre  C , Schlienger  RG , Conde  E .  Lymphoma among patients with atopic dermatitis and/or treated with topical immunosuppressants in the United Kingdom.   J Allergy Clin Immunol. 2009;123(5):1111-1116.e13. doi:10.1016/j.jaci.2009.02.028 PubMedGoogle ScholarCrossref
27.
Arellano  FM , Wentworth  CE , Arana  A , Fernández  C , Paul  CF .  Risk of lymphoma following exposure to calcineurin inhibitors and topical steroids in patients with atopic dermatitis.   J Invest Dermatol. 2007;127(4):808-816. doi:10.1038/sj.jid.5700622 PubMedGoogle ScholarCrossref
28.
Margolis  DJ , Hoffstad  O , Bilker  W .  Lack of association between exposure to topical calcineurin inhibitors and skin cancer in adults.   Dermatology. 2007;214(4):289-295. doi:10.1159/000100879 PubMedGoogle ScholarCrossref
29.
Lau  J , Ioannidis  JPA , Terrin  N , Schmid  CH , Olkin  I .  The case of the misleading funnel plot.   BMJ. 2006;333(7568):597-600. doi:10.1136/bmj.333.7568.597 PubMedGoogle ScholarCrossref
30.
Yarosh  DB , Pena  AV , Nay  SL , Canning  MT , Brown  DA .  Calcineurin inhibitors decrease DNA repair and apoptosis in human keratinocytes following ultraviolet B irradiation.   J Invest Dermatol. 2005;125(5):1020-1025. doi:10.1111/j.0022-202X.2005.23858.x PubMedGoogle ScholarCrossref
31.
Datta  D , Contreras  AG , Basu  A ,  et al.  Calcineurin inhibitors activate the proto-oncogene Ras and promote protumorigenic signals in renal cancer cells.   Cancer Res. 2009;69(23):8902-8909. doi:10.1158/0008-5472.CAN-09-1404 PubMedGoogle ScholarCrossref
32.
Ume  AC , Pugh  JM , Kemp  MG , Williams  CR .  Calcineurin inhibitor (CNI)–associated skin cancers: new insights on exploring mechanisms by which CNIs downregulate DNA repair machinery.   Photodermatol Photoimmunol Photomed. 2020;36(6):433-440. doi:10.1111/phpp.12600 PubMedGoogle ScholarCrossref
33.
Thaçi  D , Salgo  R .  Malignancy concerns of topical calcineurin inhibitors for atopic dermatitis: facts and controversies.   Clin Dermatol. 2010;28(1):52-56. doi:10.1016/j.clindermatol.2009.04.001 PubMedGoogle ScholarCrossref
34.
Söderberg  KC , Hagmar  L , Schwartzbaum  J , Feychting  M .  Allergic conditions and risk of hematological malignancies in adults: a cohort study.   BMC Public Health. 2004;4:51. doi:10.1186/1471-2458-4-51 PubMedGoogle ScholarCrossref
35.
Zhang  Y , Holford  TR , Leaderer  B ,  et al.  Prior medical conditions and medication use and risk of non–Hodgkin lymphoma in Connecticut United States women.   Cancer Causes Control. 2004;15(4):419-428. doi:10.1023/B:CACO.0000027506.55846.5dPubMedGoogle Scholar
36.
Berger  TG , Duvic  M , Van Voorhees  AS , VanBeek  MJ , Frieden  IJ ; American Academy of Dermatology Association Task Force.  The use of topical calcineurin inhibitors in dermatology: safety concerns: report of the American Academy of Dermatology Association Task Force.   J Am Acad Dermatol. 2006;54(5):818-823. doi:10.1016/j.jaad.2006.01.054 PubMedGoogle ScholarCrossref
37.
Legendre  L , Barnetche  T , Mazereeuw-Hautier  J , Meyer  N , Murrell  D , Paul  C .  Risk of lymphoma in patients with atopic dermatitis and the role of topical treatment: a systematic review and meta-analysis.   J Am Acad Dermatol. 2015;72(6):992-1002. doi:10.1016/j.jaad.2015.02.1116 PubMedGoogle ScholarCrossref
38.
Institute for Health Metrics and Evaluation. Global Health Data Exchange. Accessed January 14, 2021. http://ghdx.healthdata.org/
39.
Tennis  P , Gelfand  JM , Rothman  KJ .  Evaluation of cancer risk related to atopic dermatitis and use of topical calcineurin inhibitors.   Br J Dermatol. 2011;165(3):465-473. doi:10.1111/j.1365-2133.2011.10363.x PubMedGoogle ScholarCrossref
40.
Wang  L , Bierbrier  R , Drucker  AM , Chan  AW .  Noncutaneous and cutaneous cancer risk in patients with atopic dermatitis: a systematic review and meta-analysis.   JAMA Dermatol. 2020;156(2):158-171. doi:10.1001/jamadermatol.2019.3786 PubMedGoogle ScholarCrossref
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_Multimedia_LoginSubscribe_Purchase
Close
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_Multimedia_LoginSubscribe_Purchase
Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close

Name Your Search

Save Search
Close
With a personal account, you can:
  • Track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
jn-learning_Modal_SaveSearch_NoAccess_Purchase
Close

Lookup An Activity

or

Close

My Saved Searches

You currently have no searches saved.

Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close