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Tyrosine kinase inhibitors directed against the vascular endothelial growth factor receptor (VEGFR) have distinct cutaneous toxicity profiles: a meta-analysis and review of the literature

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Abstract

Purpose

Inhibition of the vascular endothelial growth factor receptor (VEGFR) with tyrosine kinase inhibitors (TKIs) is associated with cutaneous adverse effects that increase patient morbidity. Our objective was to examine the skin toxicity profile of anti-VEGFR TKIs and determine the changing incidence in clinical trials.

Methods

PubMed was queried for phase II or III trials of anti-VEGFR TKIs between 2000 and 2013 involving ≥50 patients. Adverse events were abstracted, with results presented in both fixed and random effects models. Odds ratios (OR) and 95 % confidence intervals (CIs) were estimated for studies with at least two arms.

Results

Across 82 included studies, all grades rash (OR, 2.68; 95 % CI, 2.45–2.94), hand-foot skin reaction (HFSR) (OR, 2.70; 95 % CI, 2.43–3.00), and pruritus (OR, 1.25; 95 % CI, 1.12–1.39) were associated with anti-VEGFR TKIs. Vandetanib had the highest incidence of rash (41 %), while sorafenib was most commonly associated with HFSR (37 %) and pruritus (14 %). The incidence of HFSR from 2000 to 2013 showed an upward trend (r 2 = 0.042, p = 0.10) and in sunitinib therapy increased significantly (r 2 = 0.237, p = 0.04).

Conclusion

The incidence of HFSR, rash, and pruritus varies considerably by drug. Our data suggest a continued need to address skin toxicities and improve reporting strategies.

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Acknowledgments

We would like to thank Drs. Mark Udey and Heidi Kong of the NCI for assistance in editing this manuscript and Dr. Tito Fojo for his general advice regarding this project.

Author attribution

All authors had full access to all of the data in the study and take responsibility for the integrity of the data. Study concept and design: Massey, Cowen. Acquisition of data: Massey, Okman. Analysis and interpretation of data: all authors. Drafting of the manuscript: Massey, Okman, Cowen. Critical revision of the manuscript for important intellectual content: all authors. Statistical analysis: Wilkerson. Obtained funding: N/A. Administrative, technical, or material support: N/A. Study supervision: Cowen.

Funding/support/role of the sponsors

This research was made possible in part by the Intramural Research Program of the NIH, National Cancer Institute.

Financial disclosure

None reported.

Conflict of interest

The authors have no conflicts of interest to report.

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Authors and Affiliations

  1. Dell Medical School, The University of Texas at Austin, 601 E. 15th Street, CEC 2.470, Austin, TX, 78701, USA

    Paul R. Massey

  2. Department of Internal Medicine, Lankenau Medical Center, Philadelphia, PA, USA

    Jonathan S. Okman

  3. Medical Oncology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Julia Wilkerson

  4. Dermatology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Edward W. Cowen

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  1. Paul R. Massey
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Correspondence to Paul R. Massey.

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Massey, P.R., Okman, J.S., Wilkerson, J. et al. Tyrosine kinase inhibitors directed against the vascular endothelial growth factor receptor (VEGFR) have distinct cutaneous toxicity profiles: a meta-analysis and review of the literature. Support Care Cancer 23, 1827–1835 (2015). https://doi.org/10.1007/s00520-014-2520-9

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