NEW YORK (Reuters Health) - Many tyrosine kinase inhibitors (TKIs) induce small increases in corrected QT-interval (QTc) duration, researchers from the Netherlands and Italy report.
Like many other drugs, TKIs have been reported to prolong the QT interval, but since these anticancer drugs usually gain approval without testing in healthy individuals, the prevalence and relevance of these prolongations remain unclear.
Dr. J. S. L. Kloth from Erasmus MC Cancer Institute in Rotterdam and colleagues from four centers in the Netherlands and Italy describe the incidence and relevance of QTc prolongations in a study of 363 patients who had ECGs before and during TKI treatment.
The median QTc interval at baseline was 401 ms, with 346 patients (95.3%) having a normal QTc interval and 17 patients having some degree of QTc prolongation. Thirty-four patients (9.4%) were taking other medications implicated in QTc prolongation.
Overall, TKI treatment was associated with a median increase in QTc of 11 ms (p<0 .00001="" 5="" according="" british="" cancer.="" in="" journal="" march="" of="" online="" p="" report="" the="" to="">
Sunitinib, vemurafenib, sorafenib, imatinib, and erlotinib were associated with significant increases in QTc interval, whereas lapatinib and pazopanib appeared not to induce QTc increases.
Thirty-three patients (9.1%) experienced increases in QTc prolongation grade with the initiation of TKI treatment, and nine patients (2.5%) had reduced QTc prolongation grade after the start of TKI treatment.
Only five patients (1.4%) developed QTc intervals of at least 500 ms after starting therapy, although 76 patients (20.9%) experienced a clinically relevant QTc increase after starting TKI treatment.
Patients treated with vemurafenib were the only group that had statistically significant increases in QTc prolongation grade, the probability of becoming high-risk patients, and the probability of clinically relevant QTc increase.
Other factors associated with QTc prolongation in these patients were higher age, hypokalemia, and treatment with QTc-prolonging comedication.
"Treating physicians should anticipate this possible increase in QTc intervals and perform ECGs during treatment with TKI, and be aware of symptoms, such as palpitation, seizures, and collapse, which may be the result of drug-induced long-QT syndrome," the researchers conclude.
"In those diseases where alternative treatment is available, such as in metastatic renal cell carcinoma where sunitinib and pazopanib have equivalent efficacy, consideration should be given to use a TKI with less QTc prolongation effects if the QTc is prolonged at baseline or develops during treatment."
Dr. Toni K. Choueiri from Dana-Farber Cancer Institute/Brigham and Women's Hospital and Harvard Medical School in Boston has found similar QTc prolongations in an earlier study of TKI agents.
"More prospective research should be done to investigate whether the increased QTc translates into clinically relevant cardiac adverse events, such as torsade de pointes and other arrhythmias," he told Reuters Health by email. "Patients at an already increased risk or previous history of cardiac events need to be monitored even more closely. Especially patients on vemurafenib."
Dr. Kloth did not respond to a request for comments.
SOURCE: http://bit.ly/19F7H8m
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