A Systematic Review and Meta-analysis of the Risk of Diarrhea Associated With Vandetanib Treatment in Carcinoma Patients

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Treatment with the tyrosine kinase inhibitor (TKI) vandetanib is associated with a significantly increased risk of diarrhea, which varies depending on the type of cancer for which the patient is being treated, a study published in the journal OncoTargets and Therapy has shown.

Vandetanib has exhibited activity of the EGFR and VEGFR families, RET, BRK, TIE2, and members of the EPH receptor and Src kinase families, which are involved in oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment. In the United States, vandetanib is indicated for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease; however, the kinase inhibitor has been studied in a variety of cancer types, including non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), breast cancer, malignant glioma, and hepatocellular carcinoma (HCC).

In all studies, diarrhea is a frequently reported treatment-related adverse event, but the incidence varies extensively according to study population. Therefore, researchers conducted a systematic review and meta-analysis to determine the risk of vandetanib-associated diarrhea with respect to cancer type. Results showed that patients with SCLC reported the highest incidence of all-grade diarrhea (79%), while patients with HCC had the lowest incidence (42%). For patients with thyroid carcinoma, the incidences of all-grade and high-grade diarrhea were 61% and 10.5%, respectively.

The findings suggest that clinicians should counsel patients on the early recognition of diarrhea associated with vandetanib and emphasize side effect management in order to minimize dose reductions and treatment interruption or discontinuation.

OncoTargets and Therapy
OncoTargets and Therapy

Background and purpose: Vandetanib is a promising anticancer targeted agent for treating advanced carcinomas, such as non-small-cell lung cancer, small-cell lung cancer, breast cancer, malignant glioma, hepatocellular cancer, and unresectable, locally advanced, or metastatic medullary thyroid cancer. However, diarrhea is a frequently reported adverse event. The incidence of vandetanib-associated diarrhea varies extensively in different study populations and has not been carefully estimated. This systematic review and meta-analysis of clinical trials aims to figure out the overall risks of all-grade and high-grade diarrhea during vandetanib treatment and get a better understanding of its prediction and management.

Materials and methods: A comprehensive search was performed in EMBASE, PubMed, and Cochrane Library for clinical trials studying vandetanib and diarrhea prior to April 2015. Eligible articles were selected according to the inclusion criteria. Data were extracted to calculate the summary incidence of all-grade and high-grade diarrhea caused by vandetanib treatment.

Results: Thirteen clinical trials that involved 3,264 patients were included in this meta-analysis. The overall incidences of all-grade and high-grade diarrhea caused by vandetanib treatment were 52.1% (95% confidence interval [CI], 48.3%–55.8%) and 5.6% (95% CI, 4.4%–76.7%), respectively. The risk ratios of the all-grade and high-grade diarrhea for vandetanib arm versus control arm were 1.932 (95% CI, 1.746–2.138; P<0.001) and 3.190 (95% CI, 2.061–4.938; P<0.001), respectively. Studies with small-cell lung cancer demonstrated the highest incidence of all-grade diarrhea (78.85%) and high-grade diarrhea (17.31%), whereas the lowest incidences of all-grade (42.11%) and high-grade (2.67%) diarrhea are seen in patients with hepatocellular carcinoma and non-small-cell lung cancer, respectively.

Conclusion: Our findings demonstrate that the administration of vandetanib leads to a significantly increased risk of diarrhea, which varies in different carcinoma patients. Early recognition and timely management may be key factors to avoid dose reduction, drug interruption, and drug discontinuation, which is significant to maximize the treatment benefits.

Keywords: vandetanib treatment, diarrhea, carcinoma 


Malignant tumor is the leading cause of death worldwide. Most cancer patients who are diagnosed at advanced stage are not candidates for surgical curative resection and are only amenable to palliative treatment. Traditional chemotherapy is a main treatment. However, the tumor response to traditional chemotherapy is not usually satisfactory. Nowadays, a large number of clinical studies have demonstrated that a newly developing therapy, molecular-targeted therapy, exerts a positive influence on advanced tumors, which shows considerable promise.

Vandetanib (ZD6474, Caprelsa; AstraZeneca plc, London, UK) is a once-daily oral anticancer agent that selectively targets the vascular endothelial growth factor receptor (VEGFR)-2 and -3, epidermal growth factor receptor (EGFR), and rearranged during transfection.1,2 The activity of competing the ATP binding sites of these receptors makes vandetanib a good agent inhibiting tumor cell proliferation, tumor progression, and angiogenesis.3

The mechanism and effect of vanditanib have been searched out by many prior studies. To our knowledge, VEGFR and EGFR are well-known pivotal drivers in tumor carcinogenesis, which actively contribute to the pathogenesis and progression of many different kinds of cancers. Furthermore, the VEGFR and EGFR pathways are shown to be relevant. Since EGFR regulates the production of VEGF, resistance of EGFR inhibitors, such as erlotinib and gefitinib, is thought to be associated with the increase of VEGF, which means targeting both VEGFR and EGFR simultaneously may be more effective than using the inhibitors of either pathway.4 EGFR and VEGFR are clinical validated targets in non-small-cell lung cancer (NSCLC), small-cell lung cancer (SCLC), thyroid cancer, breast cancer, malignant glioma, and hepatocellular cancer, which are common worldwide malignant tumors threatening people's health. As an inhibitor of both VEGFR and EGFR, vandetanib has been shown to have clinically meaningful benefits in these cancers in previous clinical trials. 

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