Serum cardiac troponin I levels and ECG/Echo monitoring in breast cancer patients undergoing high-dose (7 g/m2) cyclophosphamide

Abstract

Summary:High-dose cyclophosphamide (HD-CTX) is largely employed in high-dose chemotherapy (HD-CHT) protocols. HD-CTX dose-limiting toxicity expresses itself as cardiac toxicity which is fatal in a minority of patients. The pathophysiology of HD-CTX-associated cardiotoxicity is still poorly understood. Autopsy studies in patients who died from acute HD-CTX-induced cardiac toxicity revealed hemorrhagic myocardial cell death and interstitial edema. Recently troponins, in particular troponin I (cTnI), have been found to represent a uniquely sensitive and specific marker of myocyte membrane integrity and therefore to increase in response to minimal myocardial cell damage in different settings, including doxorubicin-induced cardiotoxicity. We performed a multiparametric cardiologic monitoring in 16 consecutive breast cancer patients undergoing HD-CTX by means of serial ECG registrations and cardiac enzymes (CPK, CPK-MB and cTnI) determinations plus echocardiography in order to clarify acute cardiac events following HD-CTX administration. Neither overt cardiac toxicity nor cardiac enzymes elevation were recorded. Serial ECGs revealed in six cases little and reversible reduction of QRS voltage and/or ST abnormalities. Echo monitoring showed in four cases mild and transient increase of LV diastolic/systolic diameter/volume without decrease of FS% or EF% below normal values: in two of them abnormalities of diastolic function (E/A mitral doppler ratio) were also recorded. We conclude that our protocol of HD-CTX administration does not cause myocardial cell damage as analyzed by serum cTnI levels, thus suggesting that myocyte membrane injury may not be the first direct mechanism of HD-CTX cardiotoxicity. ECG (ie QRS voltages ) and Echo (ie E/A ratio) monitoring leads us to hypothesize that slight interstitial edema with reduction of LV diastolic compliance may be initial signs of cardiac dysfunction in this clinical setting. Bone Marrow Transplantation (2001) 28, 277-282.

Cardiac toxicity of high-dose chemotherapy

“…HD thiotepa has been associated with a 5% cardiac toxicity in two studies, 54,55 while other series did not confirm these findings. 8,25 HD ifosfamide cardiotoxicity is reported in only two studies more than 20 years old. 56,57 Anecdotal evidence is reported for HD carmustine-associated cardiac toxicity.…”

“…8,10,17,18,26,[76][77][78][79] On the other hand, Steinherz et al 22 observed that HD cyclophosphamide-associated cardiac damage was most frequent in pediatric patients receiving cyclophosphamide X170 mg/kg or in those receiving X120 mg/kg who had received X100 mg/m 2 anthracyclines prior to transplant. Other authors found a trend towards significance also.…”

“…10 However, in recent years, the percentage of patients receiving singleagent HD cyclophosphamide up to 7 g/m 2 or 200 mg/kg experiencing cardiotoxicity has diminished to nearly zero with the adoption of multifractionated schedule of administration. 4,5,[7][8][9]25 Available evidence indicates that singleagent HD cyclophosphamide-associated cardiac toxicity is dose and schedule dependent, and it is not related to the cumulative drug dose. 13,16,21 No pharmacokinetic parameter has been consistently associated with cardiotoxicity, although a significant inverse association between a reduced HD cyclophosphamide area under the curve (AUC) (ie accelerated clearance due to an increased conversion to active metabolites) and cardiotoxicity was found in three independent studies, 17,26,27 but not confirmed in a larger one.…”

“…These alterations are expected to return toward baseline within a few days or weeks in most cases. 8,10,15,18,21,23 Therapy with diuretics should be started in the first instance. The addition of an angiotensin-converting enzyme inhibitor in case of ECG and/or two-dimensional echocardiogram (2D echo) evidence of impaired left ventricular contraction, the patient not being hypotensive, should be considered according to established guidelines.…”

Clinical Significance of Cyclophosphamide-induced Cardiotoxicity

“…CY-induced myocarditis increases blood levels of cardiac enzymes (e.g. CK, CK-MB, and troponin-I), however, these parameters can not predict the early phase of cardiotoxicity (8). Recently, the noninvasive method of cardiac magnet resonance imaging (MRI) has proved useful for evaluating LV function and contrast enhancement of cardiac MRI may detect myocardial interstitial edema (9).…”