Evaluation of biomarkers for cardiotoxicity of anthracyclin-based chemotherapy
F. J. F. Broeyer
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S. Osanto
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H. J. Ritsema van Eck
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A. Q. M. J. van Steijn
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B. E. P. B. Ballieux
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R. C. Schoemaker
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A. F. Cohen
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J. Burggraaf
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H. J. Ritsema van Eck Advanced Medical Systems
, Maasdam,
The Netherlands
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S. Osanto A. Q. M. J. van Steijn B. E. P. B. Ballieux Leiden University Medical Center
,
Leiden, The Netherlands
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F. J. F. Broeyer (&) R. C. Schoemaker A. F. Cohen J. Burggraaf Centre for Human Drug Research
, Zernikedreef 10, 2333 CL Leiden,
The Netherlands
Introduction The clinical assessment of the myocardial damage caused by anthracyclin (ANT)-therapy is diYcult. Therefore a study was performed to evaluate non-invasive markers of anthracyclin-induced cardiac eVects, with emphasis on course-to-course variation. Methods Eligible for study participation were patients, without known cardiologic abnormalities who did not use cardiotoxic medication (except for ANT-therapy), who had previously completed at least three cycles of anthracyclincontaining chemotherapy (n = 14) and patients who were ANT-nave and who were scheduled to receive doxorubicin-containing chemotherapy (n = 12). Seven patients in this last group also completed at least three cycles and were available for follow-up assessments; thus a total population of 21 patients (12F/9M) completed at least three courses ANT-chemotherapy. In these patients blood samples and ECG-recordings were taken within 6 months after completion of ANT-therapy. In 12 patients (10F/2M) assessments were also done before, immediately afterwards and at 24 h after each course of ANT. Results and Conclusions In the patients who completed chemotherapy, NT-proBNP was 277% (n = 21; 95% CI: 86-661%, P < 0.001) higher compared to healthy volunteers. During the Wrst course NT-proBNP rose 269% (n = 12; 167-409%, P < 0.0001) at 24 h post-administration. The linear corrected QT (QTcL) directly after the Wrst administration of ANT increased by 9.56 ms (n = 12; 3.8515.27, P < 0.001) and this prolongation was still present at 24 h, 11.48 ms (n = 12; 5.61-17.34, P < 0.0001). Both NTproBNP and QTcL returned to baseline before the start of the next course and a similar pattern was observed during each course. NT-proBNP and QTcL may be useful markers for course-to-course evaluation of anthracyclin-induced cardiotoxicity.
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Anthracyclines, such as doxorubicin (DXR), cause serious
cardiac side-eVects (Singal et al. 1997). Acute
tachyarrhythmias and acute heart failure may occur after high
doses, but these reactions are now rare due to changed
dosage-schemes (e.g. slower infusion) with the aim to prevent
this. However, the sub-acute or chronic cardiac eVects of
anthracyclines remain a clinical problem. Clinically,
anthracyclin-induced cardiotoxicity manifests itself as left
ventricular failure which develops insidiously over months to
years after completion of the anthracyclin-based
chemotherapy and may result in congestive heart failure (CHF)
(Shan et al. 1996; Minotti et al. 2004).
Recent studies suggest an incidence of this type of
cardiotoxicity of 5% in doses up to 400 mg/m2 increasing to
48% in subjects receiving 700 mg/m2 (Swain et al. 2003).
But even at doses up to 150 mg/m2 CHF was occasionally
reported (Swain et al. 2003). In addition to the cumulative
dose, age, gender and dosing schedule have been reported
as independent risk factors (Von HoV et al. 1979).
The mechanism of anthracyclin-induced cardiotoxicity
is not totally unravelled. It is likely that the decline in
myocardial function is related to apoptosis of cardiac myocytes
that occurs apparently at random in the myocardium
(Thorburn and Frankel 2006). Anthracyclin-induced formation of
reactive oxygen species (ROS) in the presence of
intracellular iron, impaired homeostasis of intracellular iron and
calcium (that may facilitate the apoptosis induced by the
ROS) have been put forward as mechanisms. However,
other possible mechanisms have been suggested and it is
likely that anthracyclin-induced cardiotoxicity develops as
a result of a large number of diVerent insults (Minotti et al.
2004).
It is generally acknowledged that anthracyclin-induced
cardiotoxicity becomes evident after completion of the
chemotherapy. The gold standards to detect
anthracyclininduced cardiotoxicity are cardiac imaging techniques or
myocardial biopsy. However, these methods have either the
disadvantage that cardiotoxicity is detected late, namely
when decline in left ventricular ejection fraction (LVEF)
already has occurred (imaging techniques) or that it is
highly invasive and based on the assumption that the
damage is equally distributed over the myocardium (biopsy).
Animal studies have shown that anthracyclin-induced
apoptosis can occur already after a single dose (Bennink
et al. 2004; Kumar et al. 2001; Arola et al. 2000). This is
line with the Wnding in humans that even at low cumulative
doses cardiotoxicity have been reported (Swain et al. 2003).
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