A systematic review and meta-analysis of the risk of diarrhea associated with vandetanib treatment in carcinoma patients

Figures & data

Table 1 US National Cancer Institute grading for diarrhea

Grade 1	Increase of fewer than four stools per day over baseline
Grade 2	Increase of four to six stools per day over baseline, intravenous fluids <24 hours
Grade 3	Increase of seven or more stools per day over baseline Incontinence Intravenous fluids ≥24 hours Hospitalization indicated Limits self-care activities of daily living
Grade 4	Life-threatening consequences Urgent intervention indicated
Grade 5	Death

Figure 1 Identification of included studies in this systematic review and meta-analysis.

Table 2 Characteristics of studies included in the meta-analysis

First author	Year	Trial design	Vandetanib arm	Control arm	Population of vandetanib arm	Population of control arm	Underlying cancer
Ahn et al^Citation12	2013	Randomized Phase II study	Vandetanib 300 mg	Placebo	75	42	Advanced or metastatic NSCLC
Wells et al^Citation13	2012	Randomized Phase III study	Vandetanib 300 mg	Placebo	231	100	Medullary thyroid cancer
Kreisl et al^Citation14	2012	Single arm Phase II study	Vandetanib 300 mg		64		Recurrent malignant glioma
Leboulleux et al^Citation15	2012	Randomized Phase II study	Vandetanib 300 mg	Placebo	72	73	Differentiated thyroid cancer
Lee et al^Citation16	2012	Randomized Phase III study	Vandetanib 300 mg	Placebo	617	307	Advanced NSCLC
Hsu et al^Citation17	2012	Randomized Phase II study	Vandetanib 300 mg	Placebo	19	23	Inoperable HCC
Natale et al^Citation18	2011	Randomized Phase III study	Vandetanib 300 mg	Erlotinib 150 mg	623	617	Advanced NSCLC
Wells et al^Citation19	2010	Single arm Phase II study	Vandetanib 300 mg		30		Medullary thyroid cancer
Natale et al^Citation20	2009	Randomized Phase II study	Vandetanib 300 mg	Gefitinib 250 mg	83	85	Advanced NSCLC
Heymach et al^Citation22	2008	Randomized Phase II study	Vandetanib 300 mg		56		NSCLC
Kiura et al^Citation21	2008	Randomized Phase II study	Vandetanib 300 mg		18		NSCLC
Arnold et al^Citation23	2007	Randomized, Phase II study	Vandetanib 300 mg	Placebo	52	53	SCLC
Miller et al^Citation24	2005	Nonrandomized Phase II study	Vandetanib 300 mg		24		Metastatic breast cancer

Abbreviations: HCC, hepatocellular carcinoma; NSCLC, non-small-cell lung carcinoma; SCLC, small-cell lung carcinoma.

Figure 2 Forest plot of the total incidence of all-grade diarrhea of patients with carcinomas receiving vandetanib.

Notes: The size of the gray square corresponded to the weight of the study in the meta-analysis. The horizontal line represented the 95% confidence interval (CI), and the vertical dotted line showed the total incidence of all-grade diarrhea. Since heterogeneity test indicated no heterogeneity, the total incidence of all-grade diarrhea was calculated using the fixed-effects model.
Abbreviation: ES, effect size.

Figure 3 Forest plot of the total incidence of high-grade diarrhea of patients with carcinomas receiving vandetanib.

Notes: The size of the gray square corresponded to the weight of the study in the meta-analysis. The horizontal line represented the 95% confidence interval (CI) and the vertical dotted line showed the total incidence of high-grade diarrhea. Since heterogeneity test indicated no heterogeneity, the total incidence of high-grade diarrhea was calculated using the fixed-effects model.
Abbreviation: ES, effect size.

Figure 4 Forest plot of the relative risk (RR) of all-grade diarrhea events.

Notes: The size of the gray square corresponded to the weight of the study in the meta-analysis. The horizontal line represented the 95% confidence interval (CI) and the vertical dotted line showed the total RR of all-grade diarrhea.

Figure 5 Forest plot of the relative risk (RR) of high-grade diarrhea events.

Notes: The size of the gray square corresponded to the weight of the study in the meta-analysis. The horizontal line represented the 95% confidence interval (CI) and the vertical dotted line showed the total RR of high-grade diarrhea.

Figure S1 Forest plot of the total incidence of all-grade diarrhea of patients with non-small-cell lung cancer receiving vandetanib.

Notes: The size of the gray square corresponded to the weight of the study in the meta-analysis. The horizontal line represented the 95% confidence interval (CI) and the vertical dotted line showed the total incidence of all-grade diarrhea. Since heterogeneity test indicated no heterogeneity, the total incidence of all-grade diarrhea was calculated using the fixed-effects model.

Abbreviation: ES, effect size.

Figure S2 Forest plot of the total incidence of high-grade diarrhea of patients with non-small-cell lung cancer receiving vandetanib.

Notes: The size of the gray square corresponded to the weight of the study in the meta-analysis. The horizontal line represented the 95% confidence interval (CI) and the vertical dotted line showed the total incidence of high-grade diarrhea. Since heterogeneity test indicated no heterogeneity, the total incidence of high-grade diarrhea was calculated using the fixed-effects model.

Abbreviation: ES, effect size.

Figure S3 Forest plot of the total incidence of all-grade diarrhea of patients with thyroid cancer receiving vandetanib.

Notes: The size of the gray square corresponded to the weight of the study in the meta-analysis. The horizontal line represented the 95% confidence interval (CI) and the vertical dotted line showed the total incidence of all-grade diarrhea. Since heterogeneity test indicated no heterogeneity, the total incidence of all-grade diarrhea was calculated using the fixed-effects model.

Abbreviation: ES, effect size.

Figure S4 Forest plot of the total incidence of high-grade diarrhea of patients with thyroid cancer receiving vandetanib.

Notes: The size of the gray square corresponded to the weight of the study in the meta-analysis. The horizontal line represented the 95% confidence interval (CI) and the vertical dotted line showed the total incidence of high-grade diarrhea. Since heterogeneity test indicated no heterogeneity, the total incidence of high-grade diarrhea was calculated using the fixed-effects model.

Abbreviation: ES, effect size.

AhnJSLeeKHSunJMA randomized, phase II study of vandetanib maintenance for advanced or metastatic non-small-cell lung cancer following first-line platinum-doublet chemotherapyLung Cancer20138245546024075125

 PubMed Web of Science ®Google Scholar

WellsSAJrRobinsonBGGagelRFVandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trialJ Clin Oncol20123013414122025146

 PubMed Web of Science ®Google Scholar

KreislTNMcNeillKASulJIwamotoFMShihJFineHAA phase I/II trial of vandetanib for patients with recurrent malignant gliomaNeuro Oncol2012141519152623099652

 PubMed Web of Science ®Google Scholar

LeboulleuxSBastholtLKrauseTVandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trialLancet Oncol20121389790522898678

 PubMed Web of Science ®Google Scholar

LeeJSHirshVParkKVandetanib Versus placebo in patients with advanced non-small-cell lung cancer after prior therapy with an epidermal growth factor receptor tyrosine kinase inhibitor: a randomized, double-blind phase III trial (ZEPHYR)J Clin Oncol2012301114112122370318

 PubMed Web of Science ®Google Scholar

HsuCYangTSHuoTIVandetanib in patients with inoperable hepatocellular carcinoma: a phase II, randomized, double-blind, placebo-controlled studyJ Hepatol2012561097110322245891

 PubMed Web of Science ®Google Scholar

NataleRBThongprasertSGrecoFAPhase III trial of vandetanib compared with erlotinib in patients with previously treated advanced non-small-cell lung cancerJ Clin Oncol2011291059106621282542

 PubMed Web of Science ®Google Scholar

WellsSAJrGosnellJEGagelRFVandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancerJ Clin Oncol20102876777220065189

 PubMed Web of Science ®Google Scholar

NataleRBBodkinDGovindanRVandetanib versus gefitinib in patients with advanced non-small-cell lung cancer: results from a two-part, double-blind, randomized phase ii studyJ Clin Oncol2009272523252919332730

 PubMed Web of Science ®Google Scholar

HeymachJVPaz-AresLDe BraudFRandomized phase II study of vandetanib alone or with paclitaxel and carboplatin as first-line treatment for advanced non-small-cell lung cancerJ Clin Oncol2008265407541518936474

 PubMed Web of Science ®Google Scholar

KiuraKNakagawaKShinkaiTA randomized, double-blind, phase II a dose-finding study of Vandetanib (ZD6474) in Japanese patients with non-small cell lung cancerJ Thorac Oncol2008338639318379357

 PubMed Web of Science ®Google Scholar

ArnoldAMSeymourLSmylieMNational Cancer Institute of Canada Clinical Trials Group Study BR.20Phase II study of vandetanib or placebo in small-cell lung cancer patients after complete or partial response to induction chemotherapy with or without radiation therapy: National Cancer Institute of Canada Clinical Trials Group Study BR.20J Clin Oncol2007254278428417878480

 PubMed Web of Science ®Google Scholar

MillerKDTrigoJMWheelerCA multicenter phase II trial of ZD6474, a vascular endothelial growth factor receptor-2 and epidermal growth factor receptor tyrosine kinase inhibitor, in patients with previously treated metastatic breast cancerClin Cancer Res2005113369337615867237

 PubMed Web of Science ®Google Scholar