Incidence and relevance of QTc-interval prolongation caused by tyrosine kinase inhibitors.
BACKGROUND
Tyrosine kinase inhibitors (TKIs) are associated with prolongation of the QTc interval on the electrocardiogram (ECG). The QTc-interval prolongation increases the risk of life-threatening arrhythmias. However, studies evaluating the effects of TKIs on QTc intervals are limited and only consist of small patient numbers.


METHODS
In this multicentre trial in four centres in the Netherlands and Italy we screened all patients who were treated with any TKI. To evaluate the effects of TKIs on the QTc interval, we investigated ECGs before and during treatment with erlotinib, gefitinib, imatinib, lapatinib, pazopanib, sorafenib, sunitinib, or vemurafenib.


RESULTS
A total of 363 patients were eligible for the analyses. At baseline measurement, QTc intervals were significantly longer in females than in males (QTcfemales=404 ms vs QTcmales=399 ms, P=0.027). A statistically significant increase was observed for the individual TKIs sunitinib, vemurafenib, sorafenib, imatinib, and erlotinib, after the start of treatment (median ΔQTc ranging from +7 to +24 ms, P<0.004). The CTCAE grade for QTc intervals significantly increased after start of treatment (P=0.0003). Especially patients who are treated with vemurafenib are at increased risk of developing a QTc of ⩾470 ms, a threshold associated with an increased risk for arrhythmias.


CONCLUSIONS
These observations show that most TKIs significantly increase the QTc interval. Particularly in vemurafenib-treated patients, the incidence of patients at risk for arrhythmias is increased. Therefore, especially in case of combined risk factors, ECG monitoring in patients treated with TKIs is strongly recommended.
Department of Medical Oncology, Erasmus MC Cancer Institute, PO Box 5201, 3075EA Rotterdam, The Netherlands.
J S L
JS
Kloth
Department of Medical Oncology, Fondazione S. Maugeri, Via Maugeri 10, 27100 Pavia, Italy.
A
A
Pagani
Department of Clinical Oncology, Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, The Netherlands.
M C
MC
Verboom
Laboratory of Informatics and Systems Engineering for Clinical Research, Salvatore Maugeri Research and Care Institute, Pavia, Italy.
A
A
Malovini
Department of Molecular Cardiology, IRCCS Fondazione S. Maugeri, Via Maugeri 10, 27100 Pavia, Italy.
C
C
Napolitano
Department of Medical Oncology, Erasmus MC Cancer Institute, PO Box 5201, 3075EA Rotterdam, The Netherlands.
W H J
WH
Kruit
1] Department of Medical Oncology, Erasmus MC Cancer Institute, PO Box 5201, 3075EA Rotterdam, The Netherlands [2] Cancer Genomics Netherlands, Amsterdam, The Netherlands.
S
S
Sleijfer
Department of Medical Oncology, Netherlands Cancer Institute, PO Box 90203, 1006 BE Amsterdam, The Netherlands.
N
N
Steeghs
Department of Medical Oncology, Ospedale Papa Giovanni XXIII, P.zza OMS n 1, 24127 Bergamo, Italy.
A
A
Zambelli
Department of Medical Oncology, Erasmus MC Cancer Institute, PO Box 5201, 3075EA Rotterdam, The Netherlands.
R H J
RH
Mathijssen
D000368:Aged; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000453:epidemiology; D004562:Electrocardiography / Q000379:methods; D005260:Female; D006801:Humans; D015994:Incidence; D007558:Italy / Q000453:epidemiology; D029593:Jervell-Lange Nielsen Syndrome / Q000139:chemically induced* / Q000201:enzymology / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009426:Netherlands / Q000453:epidemiology; D047428:Protein Kinase Inhibitors / Q000009:adverse effects*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D012189:Retrospective Studies; D012306:Risk
D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases