Abstract
BackgroundVandetanib is a multikinase inhibitor that is under assessment for the treatment of various cancers. QTc interval prolongation is one of the major adverse effects of this drug, but the reported incidence varies substantially among clinical trials. We performed a systematic review and meta-analysis to obtain a better understanding in the risk of QTc interval prolongation among cancer patients administered vandetanib.Methodology and Principal FindingsEligible studies were phase II and III prospective clinical trials that involved cancer patients who were prescribed vandetanib 300 mg/d and that included data on QTc interval prolongation. The overall incidence and risk of QTc interval prolongation were calculated using random-effects or fixed-effects models, depending on the heterogeneity of the included studies. Nine trials with 2,188 patients were included for the meta-analysis. The overall incidence of all-grade and high-grade QTc interval prolongation was 16.4% (95% CI, 8.1–30.4%) and 3.7% (8.1–30.4%), respectively, among non-thyroid cancer patients, and 18.0% (10.7–28.6%) and 12.0% (4.5–28.0%), respectively, among thyroid cancer patients. Patients with thyroid cancer who had longer treatment duration also had a higher incidence of high-grade events, with a relative risk of 3.24 (1.57–6.71), than patients who had non-thyroid cancer. Vandetanib was associated with a significantly increased risk of all-grade QTc interval prolongation with overall Peto odds ratios of 7.26 (4.36–12.09) and 5.70 (3.09–10.53) among patients with non-thyroid cancer and thyroid cancer, respectively, compared to the controls.Conclusions/SignificanceTreatment with vandetanib is associated with a significant increase in the overall incidence and risk of QTc interval prolongation. Different cancer types and treatment durations may affect the risk of developing high-grade QTc interval prolongation.
Highlights
Vandetanib is a multikinase inhibitor that is currently under assessment for the treatment of a number of solid tumours
To the best of our knowledge, this is the first meta-analysis to investigate the overall risk of QTc interval prolongation associated with vandetanib in cancer patients and to find the differences in the risk between patients with thyroid cancer and those with a non-thyroid malignancy
We noted that the overall incidence of all-grade and high-grade QTc interval prolongation with vandetanib (300 mg/day) was 16.4% and 3.7% (1.7%–7.8%), respectively, among patients with non-thyroid cancer, and 18.0% (10.7– 28.6%) and 12.0% (4.5–28.0%), respectively, among patients with thyroid cancer
Summary
Vandetanib is a multikinase inhibitor that is currently under assessment for the treatment of a number of solid tumours. Clinical benefits from the administration of vandetanib single agent were observed in a phase II clinical trial, and durable objective partial responses and disease control were observed among patients with advanced or metastatic hereditary medullary thyroid cancer (MTC) [3]. A phase III randomised controlled trial (ZETA) demonstrated a 54% reduction in the risk of disease progression among MTC patients treated with vandetanib compared to placebo [4]. An open-label phase II study (ZACTHYF) that assessed the benefit of vandetanib for patients with locally advanced or metastatic papillary or follicular thyroid cancer showed significantly improved PFS compared with placebo (11.0 months vs 5.8 months) [8]. We performed a systematic review and meta-analysis to obtain a better understanding in the risk of QTc interval prolongation among cancer patients administered vandetanib
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