Evaluation of biomarkers for cardiotoxicity of anthracyclin-based chemotherapy

Journal of Cancer Research and Clinical Oncology, Sep 2008

Introduction The clinical assessment of the myocardial damage caused by anthracyclin (ANT)-therapy is difficult. Therefore a study was performed to evaluate non-invasive markers of anthracyclin-induced cardiac effects, 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 anthracyclin-containing chemotherapy (n = 14) and patients who were ANT-naïve 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 first 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 first administration of ANT increased by 9.56 ms (n = 12; 3.85–15.27, 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 NT-proBNP 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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Evaluation of biomarkers for cardiotoxicity of anthracyclin-based chemotherapy

F. J. F. Broeyer 0 1 2 S. Osanto 0 1 2 H. J. Ritsema van Eck 0 1 2 A. Q. M. J. van Steijn 0 1 2 B. E. P. B. Ballieux 0 1 2 R. C. Schoemaker 0 1 2 A. F. Cohen 0 1 2 J. Burggraaf 0 1 2 0 H. J. Ritsema van Eck Advanced Medical Systems , Maasdam, The Netherlands 1 S. Osanto A. Q. M. J. van Steijn B. E. P. B. Ballieux Leiden University Medical Center , Leiden, The Netherlands 2 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. - 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). If this could be measured and c (...truncated)


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F. J. F. Broeyer, S. Osanto, H. J. Ritsema van Eck, A. Q. M. J. van Steijn, B. E. P. B. Ballieux, R. C. Schoemaker, A. F. Cohen, J. Burggraaf. Evaluation of biomarkers for cardiotoxicity of anthracyclin-based chemotherapy, Journal of Cancer Research and Clinical Oncology, 2008, pp. 961-968, Volume 134, Issue 9, DOI: 10.1007/s00432-008-0372-8