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

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.

Conflict of interest statement

CONFLICTS OF INTEREST

The authors have no conflicts of interest to report.

Figures

Fig. 1. Flow Diagram of Included Studies

Flow diagram demonstrating the selection of trials in this review of the literature and meta-analysis.

Fig. 2. Hand-Foot Skin Reaction

Note desquamative hyperkeratosis and erythema over pressure-bearing areas of the foot in a patient during treatment with sorafenib.

Fig. 3. Meta-analysis of Adverse Events

Forest Plot of all randomized trials demonstrating odds ratio of all grade rash, hand-foot skin reaction (HFSR), pruritus and diarrhea by drug versus placebo.

Fig. 4. A–D. Box Plots of Adverse Events

Box plots demonstrating percent of patients who experienced rash (A), HFSR (B), pruritus (C), and diarrhea (D), with data derived from both randomized and nonrandomized clinical trials (n= 78).

Fig. 5. Scatter Plots of Adverse Events By Time Interval

Time interval scatter plots demonstrating percent of patients reporting all grade HFSR (top) and diarrhea (bottom) by drug class, sunitinib and sorafenib.

Fig. 6. A–D. Subgroup Analysis of Monotherapy v. Combination Therapy

Forest Plot subgroup analysis of randomized trials demonstrating odds ratio of all grade rash (A), HFSR (B), pruritus (C) and diarrhea (D) by drug versus placebo, according to whether drug was given as monotherapy or in combination with conventional cytotoxic chemotherapy.