1Cardiology Unit, 2Pathology and Laboratory Medicine and 3Clinical Haemato-Oncology Divisions, Istituto Europeo di Oncologia, University of Milan, Milan, Italy
Received 14 September 2001; revised 28 November 2001; accepted 19 December 2001.
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Abstract |
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High-dose chemotherapy (HDC) has been widely utilized in high-risk breast cancer, but it may induce cardiac toxicity. Cardiac dysfunction may become evident weeks or months after HDC and, to date, no early markers of myocardial injury that are able to predict late ventricular impairment are available. We investigated the role of plasma troponin I (TnI) in this setting.
Patients and methods
We measured TnI plasma concentration after HDC in 211 high-risk breast cancer women (46 ± 11 years, mean ± SD). According to TnI value (<0.5 or 0.5 ng/ml), patients were allocated into a troponin positive (TnI+; n = 70) and a troponin negative (TnI; n = 141) group. All patients underwent left ventricular ejection fraction (LVEF, Echo) examination during the following 12 months.
Results
LVEF progressively decreased in the TnI+ group but not in the TnI group. In TnI+ patients a close relationship between the TnI increase, as well as the number of positive TnI assays, and the maximal LVEF decrement, was found (r = 0.92, P <0.0001 and r = 0.93, P <0.0001, respectively).
Conclusions
In our population, the elevation of TnI soon after HDC accurately predicts the development of future LVEF depression. In this setting, TnI can be considered a sensitive and reliable marker of myocardial damage with relevant clinical and prognostic implications.
Key words: breast cancer, cardiotoxicity, high-dose chemotherapy, troponin I
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Introduction |
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Hence, there is a rapidly growing expectation, in both oncologists and cardiologists, for new non-invasive and cost-effective opportunities for the early identification of patients most likely to develop late ventricular dysfunction. This would allow clinicians to closely monitor cardiovascular function, to prevent cardiac impairment and to support cardiac function with a specific heart failure treatment. In addition, it might be possible to adjust chemotherapeutic dosages or to shift patients with increased cardiac risk toward a less cardiotoxic schedule.
Acute myocardial injury can be sensitively and accurately identified by measurement of plasma concentration of troponin I (TnI), one of the contractile proteins of the myocardium [10]. A rise in the concentration of TnI in the circulation indicates various degrees of myocardial cell damage, and its determination provides the highest diagnostic accuracy for detecting myocardial cell necrosis [11]. The clinical and prognostic significance of TnI in acute coronary syndromes is well appreciated [1214], but the possible application of this peptide in the detection of HDC-induced cardiac damage, as well as in the short- and long-term cardiac risk assessment of breast cancer patients undergoing this kind of treatment, has never been investigated.
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Patients and methods |
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Informed consent was obtained from all patients before participation in the study, and the protocol was approved by the ethics committee of our institution.
Study protocol
Clinical examination, electrocardiogram and chest X-ray were part of the preliminary evaluation. All eligible patients received HDC after breast surgery in different drug combinations, according to our institutions oncological protocols. Patients previously treated with anthracyclines (n = 75) were assigned to ICE (ifosfamidecarboplatinetoposide; n = 43) or TICE (taxotereifosfamidecarboplatinetoposide; n = 32) regimens. The remaining patients were treated accordingly to EC (epirubicincyclophosphamide; n = 51) and TEC (taxotereepirubicincyclophosphamide; n = 85) schemes (Table 1). All drugs were administered intravenously, via a central venous catheter. Cycles were delivered at 28-day intervals three times, and each cycle was supported by autologous peripheral blood progenitors cells and filgrastim (granulocyte colony-stimulating factor, G-CSF) [15]. Peripheral blood progenitors cells were mobilized by filgrastim and collected before the beginning of chemotherapy. After completion of HDC, all patients received radiotherapy to the chest wall in the case of mastectomy (n = 78; 41 to the left side), or to the residual breast in the case of breast-conserving surgery (n = 133; 81 to the left side).
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Cardiac assessment was performed by echocardiography and electrocardiography. In all patients, LVEF (biplane method according to Simpsons rule) was evaluated before HDC and 1, 2, 3, 4, 7 and 12 months after the end of the treatment (i.e. starting 3 months after the baseline evaluation).
Electrocardiogram was performed before and after each HDC cycle and then at all follow-up checks. For all patients, the duration of the follow-up was 14 months from the baseline evaluation. During this period, none were treated with other chemotherapic drugs and all patients management decisions were made without the knowledge of their TnI result.
Laboratory methods
The laboratory method employed for TnI determination was an immunoenzymatic fluorescent assay (Stratus II; Dade, International Inc., Miami, FL, USA). This method utilizes two TnI-specific monoclonal antibodies for independent epitopes [16] and has no detectable cross reactivity with skeletal muscle TnI. The lower limit of detection was 0.35 ng/ml; since at levels between 0.4 and 1.5 ng/ml, the coefficient of variation is 914%, we set the cut-off level at 0.5 ng/ml. After centrifuging, plasma was stored immediately at 30°C. All samples were analyzed in duplicate, with an interassay variability 0.1 ng/ml and all positive samples were immediately re-tested to confirm the result.
Statistical analysis
The LVEF values were analyzed using a repeated measures model taking into account the correlation among the time periods with an unstructured covariance matrix. Time was treated as a factor and the interaction between time, and TnI value was included in the model. All interactions were tested using F tests based on type 3 sums on squares. Least squares means and corresponding confidence intervals of time x TnI value interactions were calculated. All calculations were performed using PROC MIXED in SAS. Differences in LVEF values at baseline between the two groups were analyzed using a generalized linear model. Significance was taken at the 5% level. Results are presented as mean ± SD. Differences in TnI positivity percentage among the different schedules utilized were analyzed according to logistic regression and contrasts method.
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Results |
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At the baseline evaluation, as well as before each cycle of HDC, the TnI value was within the normal range in all cases. A rise in the concentration of circulating TnI was detected in 70 of the 211 patients treated (33%) and, when the total number of HDC cycles was considered, in 120 of 633 (19%) cycles. Figure 1 shows the percentage distribution of TnI positive (TnI+) assays at the various time points considered and of TnI+ patients after each cycle. Fifty-two per cent of TnI+ patients had only one positive sample, 11% had two, 8% had three, 7% had four, 8% had five, 7% had six and 4% had seven.
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No electrocardiographic changes were observed in any of the patients, both after HDC and at the follow-up checks.
Patients were grouped according to the maximal TnI value detected after HDC into a negative troponin group (TnI; n = 141) and a positive troponin group (n = 70). The TnI group was defined by a value <0.5 ng/ml in every determination, and the TnI+ group was defined by a value 0.5 ng/ml at least at one of the points of measurement considered (mean value 0.9 ± 0.5 ng/ml; range 0.52.3). The two populations were similar with regard to age and other clinical characteristics (incidence of hypertension, smoking habits, kind of surgical intervention, stage of neoplasm).
At the baseline evaluation, LVEF was similar in the two groups, and, in all cases, was within the normal range (63 ± 4% and 62 ± 5% in TnI+ and TnI, respectively; P = 0.23, not significant). After HDC, there was a different behavior of LVEF in the TnI+ group compared with the TnI group (Figure 2). In the TnI+ group, a significant reduction in LVEF was observed after the first month of follow-up. Thereafter, LVEF further worsened during the follow-up period. The TnI group did not show any significant decrease in LVEF during the entire period of observation.
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Figure 4 shows the different LVEF pattern in TnI+ versus TnI patients, according to the four different chemotherapy regimens. A similar LVEF course was observed, independently from the HDC schedule.
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Discussion |
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While its major acute toxic effects can be largely overcome with hematological growth factors, stem-cell infusion and appropriate supportive care, cardiotoxicity remains an un-resolved problem. Typically, cardiac involvement becomes manifest late in the course of the natural history of the cardiac disease; it is generally considered to be irreversible and can lead to overt heart failure. Cardiotoxicity is an emerging problem commensurate with the growing number of long-term breast cancer survivors and the increasing number of patients treated with adjuvant chemotherapy.
To detect HDC-induced cardiac damage, regular monitoring of cardiac function is recommended at present [7, 20]. It could be performed during chemotherapy to allow administration of the highest dose without inducing severe cardiac damage. After completion of chemotherapy, monitoring must be carried out again to identify cardiac damage at an early pre-clinical stage, in order to prevent further heart function deterioration by timely medical intervention. The limit of such an approach is that it is too late. In fact, cardiac damage is usually detected when functional impairment has already occurred [17, 19]. Furthermore, the evidence of an unaffected heart function does not exclude the possibility of a future cardiac deterioration [19, 21, 22]. Accordingly, several methods of identifying cardiotoxicity, before it causes irreversible cardiac function depression, have been proposed. Among these are the following: radionuclide imaging tests utilizing monoclonal antimyosin antibodies or metaiodobenzylguanidine [23, 24], study of cardiac autonomic function [25] and endomyocardial biopsy [26]. Although some of these techniques are very sensitive in the detection of heart damage, they have specific limitations and poor positive predictive value.
The early detection of myocardial damage is one of the major challenges to contemporary cardiology. Many recent studies have elucidated the value of both TnT and TnI in the diagnosis and in the risk assessment of acute coronary syndromes [1014]. Our study addresses the question of whether TnI measurement gives significant information in a population of patients with aggressive breast cancer undergoing HDC, in relation to its possible direct cardiotoxic effect.
Our data demonstrate that TnI is a risk marker for future development of significant LVEF reduction. This information cannot be usually obtained by conventional criteria, such as symptoms, and electrocardiographic and echocardiographic changes. The innovative aspect of this new marker of myocardial damage is that it gives us this information at a very early phase (immediately after the HDC administration), long before a functional impairment can be detected with the other available techniques. The possibility of identifying patients who will develop late myocardial function depression is a golden opportunity for both oncologists and cardiologists. This information can permit oncologists to modify, or to discontinue, the oncologic regimen, or to shift patients toward a less cardiotoxic schedule. In addition, it could allow cardiologists to support cardiac function or to prevent heart dysfunction with cardioprotective agents or with cardiovascular therapy [27, 28]. This issue is particularly important in patients with cancer disease in which onset of cardiac dysfunction, even asymptomatic, importantly limits the therapeutic opportunities and negatively influences the prognosis. On the other hand, the presence of cardiac dysfunction, either symptomatic or not, could be widely counterbalanced by improvement in survival due to enhanced control of the cancer. In contrast, the development of overt heart failure might negatively affect the overall long-term survival, independently from the cancer stage. Compared with other methods of cardiac damage detection, TnI appears to be a more sensitive and specific, and less costly method for the early identification of cardiotoxicity.
The observation that pathological TnI release and significant LVEF reduction can also occur after schedules that are classically considered to have low (TICE) or no (ICE) cardiotoxic properties suggests that their toxic effects probably derive from the combined interaction of different drugs. Indeed, in a previous report, congestive heart failure has been described as occurring when intermediate cumulative doses with multi-agent chemotherapy were utilized [29]. Furthermore, it can be speculated that, in our patients, the previous treatment with anthracyclines might have played either a synergic or a cumulative role.
Evidence of TnT and TnI release after chemotherapy was previously shown in animal studies [30] and in children undergoing anthracycline chemotherapy [31]. In these studies, the elevated troponin levels were correlated with acute clinical toxicity. In addition, Missov et al. [32] described TnI increase during the course of anthracycline chemotherapy in patients with hematological malignancies. However, this is the first study that correlates the presence of TnI increase with the long-term development of cardiac dysfunction, even asymptomatic.
Although the small amount of TnI increase, at least in comparison with that observed in acute coronary syndromes, indicates that only a minimal acute necrosis occurs during HDC, the clinical interest of this increment is quite relevant, as the minor myocardial damage seems to precede left ventricular systolic impairment. Both the underlying mechanism(s) and the time course of the cardiac damage are unclear, and further studies are needed to elucidate whether patients with TnI acute increment and with following LVEF reduction will develop an irreversible dilated cardiomyopathy at a longer observation period. On the other hand, normal TnI values clearly identify patients at lower risk, in which no cardiac damage, at least in the first year after HDC, occurs. In brief, at the present time, TnI result allows separation of patients in which a close monitoring of cardiac function is mandatory from those in which it is not required.
In addition to these prognostic data, TnI also provides us with quantitative information. Indeed, we observed a close relationship between the TnI maximal value after HDC, as well as the number of positive samples after each HDC cycle, and the degree of LVEF reduction (Figure 3). These findings suggest that the HDC-induced myocardial injury, although limited, is an ongoing phenomenon that, once elicited by these drugs, could last for several days or months and results in a cumulative effect reflected by a global left ventricular dysfunction. A more prolonged TnI follow-up could permit us to better understand the time course of the myocardial damage, as well as to better assess the long-term outcome of high-risk patients (TnI+). In this regard, the lack of information about TnI behavior after the first 72 h does not allow for obtaining more accurate indications concerning a possible different evolution of cardiac dysfunction among TnI+ patients.
Despite this limitation, however, the amplitude of TnI elevation and its release pattern in the days following the oncologic treatment allows us to anticipate, for each patient, the cardiac functional status that will characterize the first year after HDC.
Conclusion
In patients undergoing HDC for aggressive breast cancer, TnI is a sensitive, specific and low cost way to predict the development of ventricular systolic dysfunction in the months to follow, as well as the degree of cardiac impairment. The possibility of carrying out a risk stratification in such a patient population, in a very early phase, has relevant clinical and prognostic implications.
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Footnotes |
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