Meta-analysis of randomized controlled trials for the incidence and risk of treatment-related mortality in patients with cancer treated with vascular endothelial growth factor tyrosine kinase inhibitors.
OBJECTIVE
Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) have become the cornerstone in the treatment of several malignancies. These drugs have also been associated with an increase in the risk of potentially life-threatening adverse events, such as arterial thrombotic events, bleeding, congestive heart failure, and others. We performed an up-to-date meta-analysis to determine the risk of fatal adverse events (FAEs) in patients with cancer treated with VEGFR TKIs.


METHODS
MEDLINE and PubMed databases were searched for articles published from January 1966 to February 2011. Eligible studies were limited to trials of US Food and Drug Administration-approved VEGFR TKIs (pazopanib, sunitinib, and sorafenib) that reported on patients with cancer with any primary tumor type, randomized design, and adequate safety profile. Statistical analyses were conducted to calculate the summary incidence, relative risk (RR), and 95% CIs by using random-effects or fixed-effects models on the basis of the heterogeneity of included studies.


RESULTS
In all, 4,679 patients from 10 randomized controlled trials (RCTs) were included, with 2,856 from sorafenib, 1,388 from sunitinib, and 435 from pazopanib trials. The incidence of FAEs related to VEGFR TKIs was 1.5% (95% CI, 0.8% to 2.4%) with an RR of 2.23 (95% CI, 1.12 to 4.44; P = .023) compared with control patients. On subgroup analysis, no difference in the rate of FAEs was found between different VEGFR TKIs or tumor types. No evidence of publication bias was observed.


CONCLUSIONS
In a meta-analysis of RCTs, the use of VEGFR TKIs was associated with an increased risk of FAEs compared with control patients.
Dana-Farber Cancer Institute, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02215-5415, USA.
Fabio A B
FA
Schutz
Youjin
Y
Je
Christopher J
CJ
Richards
Toni K
TK
Choueiri
D000970:Antineoplastic Agents / Q000009:adverse effects; D001557:Benzenesulfonates / Q000009:adverse effects; D006801:Humans; D007191:Indazoles; D007211:Indoles / Q000009:adverse effects; D009369:Neoplasms / Q000188:drug therapy* / Q000401:mortality*; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000009:adverse effects*; D011725:Pyridines / Q000009:adverse effects; D011743:Pyrimidines / Q000009:adverse effects; D011758:Pyrroles / Q000009:adverse effects; D016032:Randomized Controlled Trials as Topic; D040262:Receptors, Vascular Endothelial Growth Factor / Q000009:adverse effects*; D000077157:Sorafenib; D013449:Sulfonamides / Q000009:adverse effects; D000077210:Sunitinib
D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D007191:Indazoles; D007211:Indoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D011758:Pyrroles; D013449:Sulfonamides; D009536:Niacinamide; C516667:pazopanib; D000077157:Sorafenib; D040262:Receptors, Vascular Endothelial Growth Factor; D000077210:Sunitinib