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Cited by 1,115Cancer Immunotherapy and BiomarkersAdrenal Hormones and DisordersPharmacovigilance and Adverse Drug Reactions

The DOI matches its Crossref record; 66 of the 67 references it cites were found in a registry or an index.

Incidence of Endocrine Dysfunction Following the Use of Different Immune Checkpoint Inhibitor Regimens: A Systematic Review and Meta-analysis

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Barroso-Sousa, Romualdo, Barry, William T., Garrido-Castro, Ana C., Hodi, F. Stephen, Min, Le, Krop, Ian E., Tolaney, Sara M.·2018·JAMA Oncology
DOI 10.1001/jamaoncol.2017.3064PMC PMC5838579
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Abstract

IMPORTANCE: If not promptly recognized, endocrine dysfunction can be life threatening. The incidence and risk of developing such adverse events (AEs) following the use of immune checkpoint inhibitor (ICI) regimens are unknown. OBJECTIVE: To compare the incidence and risk of endocrine AEs following treatment with US Food and Drug Administration-approved ICI regimens. DATA SOURCES: A PubMed search through July 18, 2016, using the following keywords was performed: "ipilimumab," "MDX-010," "nivolumab," "BMS-963558," "pembrolizumab," "MK-3475," "atezolizumab," "MPDL3280A," and "phase." STUDY SELECTION: Thirty-eight randomized clinical trials evaluating the usage of these ICIs for treatment of advanced solid tumors were identified, resulting in a total of 7551 patients who were eligible for a meta-analysis. Regimens were categorized by class into monotherapy with a PD-1 (programmed cell death protein 1) inhibitor, a CTLA-4 (cytotoxic T-lymphocyte-associated protein-4) inhibitor, or a PD-L1 (programmed cell death 1 ligand 1) inhibitor, and combination therapy with PD-1 plus CTLA-4 inhibitors. DATA EXTRACTION AND SYNTHESIS: The data were extracted by 1 primary reviewer (R.B.-S.) and then independently reviewed by 2 secondary reviewers (W.T.B. and A.C.G.-C.) following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Inferences on the incidence of AEs were made using log-odds random effects models. MAIN OUTCOMES AND MEASURES: Incidence of all-grade hypothyroidism, hyperthyroidism, hypophysitis, primary adrenal insufficiency, and insulin-deficient diabetes. RESULTS: Overall, 38 randomized clinical trials comprising 7551 patients were included in this systematic review and meta-analysis. The incidence of both hypothyroidism and hyperthyroidism was highest in patients receiving combination therapy. Patients on the combination regimen were significantly more likely to experience hypothyroidism (odds ratio [OR], 3.81; 95% CI, 2.10-6.91, P < .001) and hyperthyroidism (OR, 4.27; 95% CI, 2.05-8.90; P = .001) than patients on ipilimumab. Compared with patients on ipilimumab, those on PD-1 inhibitors had a higher risk of developing hypothyroidism (OR, 1.89; 95% CI, 1.17-3.05; P = .03). The risk of hyperthyroidism, but not hypothyroidism, was significantly greater with PD-1 than with PD-L1 inhibitors (OR, 5.36; 95% CI, 2.04-14.08; P = .002). While patients who received PD-1 inhibitors were significantly less likely to experience hypophysitis than those receiving ipilimumab (OR, 0.29; 95% CI, 0.18-0.49; P < .001), those who received combination therapy were significantly more likely to develop it (OR, 2.2; 95% CI, 1.39-3.60; P = .001). For primary adrenal insufficiency and insulin-deficient diabetes no statistical inferences were made due to the smaller number of events. CONCLUSIONS AND RELEVANCE: Our study provides more precise data on the incidence of endocrine dysfunctions among patients receiving ICI regimens. Patients on combination therapy are at increased risk of thyroid dysfunction and hypophysitis.

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  1. Yang JC, Hughes M, Kammula U, et al. Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis. J Immunother. 2007;30(8):825-830.

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Metadata

Authors
Barroso-Sousa, R., Barry, W. T., Garrido-Castro, A. C., Hodi, F. S., Min, L., Krop, I. E., & Tolaney, S. M.
Affiliations
  • Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
  • Dana-Farber Cancer Institute (US)
  • Brigham and Women's Hospital (US)
Corresponding author
Tolaney, Sara M.
ORCID
Venue
JAMA Oncology
Publisher
American Medical Association (AMA)
Published
2018-02-01
Volume
4
Issue
2
Pages
173
ISSN
2374-2437 (ISSN-L)
DOI
10.1001/jamaoncol.2017.3064
PMC
PMC5838579
OpenAlex
W2760410509
Cited by
1,115
References
67
Citations by year
2026: 113 · 2025: 134 · 2024: 116 · 2023: 138 · 2022: 173 · 2021: 150 · 2020: 150 · 2019: 93 · 2018: 46
FWCI
8.35
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • JAMA Oncology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pharmacovigilance and Adverse Drug Reactions
Keywords
endocrine adverse events, immune checkpoint inhibitors, hypothyroidism, hyperthyroidism, hypophysitis, adrenal insufficiency, insulin-deficient diabetes, PD-1 inhibitors, CTLA-4 inhibitors, PD-L1 inhibitors, combination immunotherapy, ipilimumab, nivolumab, pembrolizumab, atezolizumab, advanced solid tumors, adverse event incidence, randomized controlled trials
MeSH terms
Antineoplastic Agents, Immunological, Antibodies, Monoclonal, Endocrine System Diseases, Endocrine Glands, Humans, Immunotherapy, Neoplasms, Incidence, Randomized Controlled Trials as Topic, Protein Kinase Inhibitors, Cell Cycle Checkpoints

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