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© 2001 American Society for Clinical Oncology Prospective Evaluation of Early Cardiac Damage Induced by Epirubicin-Containing Adjuvant Chemotherapy and Locoregional Radiotherapy in Breast Cancer PatientsFrom the Departments of Medical Oncology, Cardiology, and Radiation Oncology, University Hospital, Groningen; and Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands. Address reprint requests to W.T.A. van der Graaf, MD, PhD, Department of Medical Oncology, University Hospital, PO Box 30.001, 9700 RB Groningen, the Netherlands; email: w.t.a. van.der.graaf{at}int.azg.nl
PURPOSE: To evaluate prospectively the cardiotoxic effects of epirubicin-containing adjuvant chemotherapy in breast cancer patients. PATIENTS AND METHODS: Patients (median age, 46 years; range, 28 to 55 years) were treated with five cycles of fluorouracil, epirubicin (90 mg/m2), and cyclophosphamide (FEC) (group I, n = 21) or with four cycles of FEC followed by high-dose chemotherapy consisting of cyclophosphamide, thiotepa, and carboplatin (group II, n = 19). Locoregional radiotherapy was applied subsequently. Cardiac evaluation was performed before chemotherapy (T0), 1 month after chemotherapy, 1 month after radiotherapy (T2), and 1 year after start of chemotherapy (T3). Left ventricular ejection fraction (LVEF) was determined by radionuclide ventriculography and diastolic function by echocardiography. Autonomic function was assessed by 24-hour ECG registration for heart rate variability (HRV) analysis. Time-corrected QT (QTc) was assessed and N-terminal atrial natriuretic peptide (NT-ANP) and brain natriuretic peptide (BNP) were measured as biochemical markers of cardiac dysfunction. RESULTS: No patient developed overt congestive heart failure (CHF) and the mean LVEF declined from 0.61 at T0 to 0.54 at T3 (P = .001), resulting in an LVEF below 0.50 (range, 0.42 to 0.49) in 17% of the patients, whereas 28% had a decline of more than 0.10. Plasma NT-ANP levels increased gradually from 237 pmol/L at T0 to 347 pmol/L at T3 (P < .01), whereas plasma BNP levels increased from 2.9 pmol/L to 5.1 pmol/L (P = .04). Mean QTc increased from 406 msec at T0 to 423 msec at T3 (P < .01). No persistent alterations were found in diastolic function and HRV. CONCLUSION: Relatively low doses of epirubicin in adjuvant chemotherapy for breast cancer results in mild subclinical myocardial damage demonstrated by a decline in LVEF, an increase in natriuretic peptide levels, and an increase in QTc, which may indicate a long-term risk of CHF.
ANTHRACYCLINES SUCH as doxorubicin and epirubicin, nowadays increasingly used in the adjuvant treatment of locally advanced breast cancer, have improved the prognosis of these patients.1,2 Awareness of the long-term side effects of such treatment is therefore becoming more important. The most serious side effect of anthracyclines is chronic cardiotoxicity, which can culminate in congestive heart failure (CHF).3 Although the majority of cases of CHF become clinically overt within the first year after discontinuation of chemotherapy,4 in some patients this may take many years.5,6 The risk of late-onset CHF in breast cancer patients treated with anthracyclines is uncertain because of the still limited follow-up of these patients. Prospective evaluation of cardiac function may help to identify at-risk patients at an early stage and provide information on the long-term risk of CHF. Anthracycline cardiotoxicity is most commonly assessed by determination of the left ventricular ejection fraction (LVEF) by radionuclide ventriculography, although its sensitivity and specificity for early detection of cardiotoxicity is limited.7 Since in the development to CHF several other physiologic changes occur that may precede or coincide with systolic dysfunction, assessment of these changes may be useful to detect cardiotoxicity at an earlier stage.8 The aim of the current study was to evaluate prospectively the cardiotoxic effects of epirubicin-containing adjuvant chemotherapy in breast cancer patients by means of various detection techniques. In addition to the assessment of LVEF, echocardiography was performed for the determination of various cardiac parameters, including diastolic function. This is of interest because diastolic dysfunction is thought to precede systolic dysfunction.9-11 Furthermore, heart rate variability (HRV) analysis was studied as a measure to assess autonomic activity. HRV is reduced in patients with heart failure from any cause, and this reduction of HRV also occurs in an early stage of CHF.12,13 Furthermore, the plasma levels of the natriuretic peptides N-terminal atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were determined. These biochemical markers of cardiac dysfunction are secreted by, respectively, the atria and the ventricles in response to increased wall pressure.14 An ECG was obtained to investigate the usefulness of the QT time corrected for heart rate (QTc), because prolongation of the QTc has been suggested as a measure of anthracycline-induced cardiotoxicity.15
Patients and Treatment Between September 1997 and June 1999, all consecutive patients who participated in a nationwide randomized trial evaluating two adjuvant chemotherapy regimens16 were also asked to participate in a prospective evaluation of cardiac function. Eligibility criteria for the randomized trial were breast cancer with four or more tumor-involved axillary lymph nodes (stages II and III), age 55 years or younger, and no metastases based on chest x-ray, liver ultrasound, and bone scan. Patients were eligible for the trial after modified radical mastectomy or after breast-conserving treatment. Patients were randomized between a control treatment arm consisting of five cycles of fluorouracil, epirubicin (90 mg/m2), and cyclophosphamide (FEC) (group I) and an arm containing four cycles of FEC, followed by high-dose combination chemotherapy with hematopoietic stem-cell rescue (group II).
Chemotherapy
Radiotherapy
Cardiac Evaluation
Radionuclide Ventriculography
Echocardiography
HRV Analysis
ECG
Natriuretic Peptides
Statistics
In total, 50 consecutive patients were asked and 40 agreed to participate in the cardiac evaluation. Of the total of 40 patients who participated in this study, 21 were treated with five courses FEC (group I) and 19 with four courses of FEC followed by high-dose chemotherapy (group II). The cumulative dose of epirubicin was 450 mg/m2 in group I and 360 mg/m2 in group II. The dose-intensity of chemotherapy in all patients was 100%. The median age of all patients at the time of treatment was 46 years (range, 28 to 55 years). No difference in age was found between groups I and II (group I: median 48 years, range, 28 to 55 years v group II: median 46 years, range, 35 to 53 years; P = not significant [NS]). In group I, 15 (71%) of the 21 patients were treated with mastectomy and six (29%) with breast-conserving surgery, whereas in group II, 18 (94%) of the 19 patients were treated with mastectomy and one patient (6%) was treated with breast-conserving surgery. In group I, 13 (62%) of the 21 patients were irradiated to the left side of the chest and eight (38%) to the right side. In group II, 12 (63%) of the 19 patients were irradiated to the left side of the chest and seven (37%) to the right side. None of the patients was known to have cardiac disease at the start of chemotherapy. Two patients had long-standing hypertension for which they were treated with an angiotensin-converting enzyme inhibitor and a calcium-blocker. Two patients did not complete the cardiac evaluation because of tumor recurrence. Of these, one patient participated only at T0 and T1; the other participated at T0, T1, and T2. Furthermore, some data are missing due to logistic or technical reasons.
Cardiac Evaluation
Radionuclide Ventriculography LVEF was determined at T0 in 39 patients and at T3 in 35 patients. The mean LVEF for the total group at T3 was lower compared with T0 (T0: 0.61 ± 0.08 v T3: 0.54 ± 0.06; P = .001). Between groups I and II, no difference was found in LVEF mean decline. At T3, six patients (17%) had an LVEF less than 0.50 (range, 0.42 to 0.49), although all had a normal LVEF at T0. Two of these six patients were in group I and four were in group II. Ten patients (28%) had a decline of more than 0.10 (range, 0.10 to 0.22); however, six patients still had an LVEF at T3 that was above 0.50. Of these 10 patients, five were in group I and five were in group II.
Echocardiography
HRV Analysis
ECG In total, 37 ECGs were performed at T0, 35 at T1, 35 at T2, and 35 at T3. At T3, the mean QTc time of the total group was significantly prolonged compared with T0 (T0, 406 ± 11 msec v T3, 423 ± 16 msec; P < .001). Between groups I and II, no difference was found in the mean increase in QTc time from T0 to T3. At T1, the mean QTc time of the total group (420 ± 11 msec) was already increased compared with T0 (P = .006) and was 426 ± 18 msec at T2. From T1 to T3, no significant change was observed. Between groups I and II, no differences in the mean QTc time were found at the different time points. The QTc time was increased (> 440 msec) in none of the patients at T0 and in four patients (11%) at T1, five patients (17%) at T2, and six patients (17%) at T3.
Natriuretic Peptides
At T3, the mean BNP plasma level of the total group was significantly higher compared with that at T0 (T0: 2.9 ± 2.8 pmol/L v T3: 5.1 ± 4.3 pmol/L; P = .04). Between groups I and II, no difference was found in the increase in BNP. At T1, the mean BNP plasma level of the total group was 4.2 ± 3.5 pmol/L, which was higher compared with that at T0 (P = .048). At T2, mean BNP level was 3.0 ± 3.0 pmol/L, which was not different from that at T1. From T2 to T3, the BNP level increased (P = .002). Between group I and group II, no difference was observed in mean BNP level at different points in time.
Comparison of Detection Techniques A subanalysis was performed between the patients who had developed a decline in LVEF of more than 0.10 or an LVEF of less than 0.50 at T3 (group A) versus the patients with a decline of less than 0.10 and an LVEF of more than 0.50 at T3 (group B). This analysis did not show differences in the diastolic function parameters E/A ratio and IVRT, but the DT increased more in group A patients. Whereas at T0 the DT was not different between these groups (group A, 169 ± 37 msec v group B, 189 ± 38 msec; P = NS), at T3 patients in group A had a higher DT compared with patients in group B (209 ± 42 msec v 176 ± 30 msec; P = .012). The mean HR between groups A and B was not different at T0 (group A, 77 ± 8 bpm v 80 ± 6 bpm), but at T1 the mean HR was higher in group A (group A, 89 ± 6 bpm v group B, 81 ± 10 bpm; P = .024). The hemoglobin level was not different (group A, 6.8 ± 0.8 mmol/L v group B, 6.6 ± 0.7 mmol/L; P = NS). This difference was no longer observed at T2 (group A, 83 ± 9 bpm v group B, 80 ± 8 bpm; P = NS) nor at T3 (group A, 80 ± 5 bpm v group B, 79 ± 8 bpm; P = NS). Between groups A and B, no difference was found in the HRV, QTc time, and natriuretic peptides at the various points of time.
Left-Sided Versus Right-Sided Radiotherapy
Anthracyclines are increasingly used as part of adjuvant chemotherapy regimens for locally advanced breast cancer.1,2 However, concern exists that in the long-term the survival benefit is counterbalanced by chronic cardiotoxicity. The risk of anthracycline-induced CHF depends on the cumulative dose; for epirubicin, the estimated risk has been reported to be less than 1% at doses below 550 mg/m2, but it increases to 4% at 900 mg/m2 and to 15% at 1,000 mg/m2.19 However, the prevalence of subclinical cardiotoxicity is probably much higher. In the current prospective study, we found during the first year after chemotherapy a mild but significant impairment of the cardiac function in breast cancer patients treated with relatively low cumulative doses of epirubicin. In the high-dose chemotherapy treatment arm (group II), this cumulative dosage of epirubicin was lower (360 mg/m2) than in the standard-dose adjuvant treatment arm (group I, 450 mg/m2), but this did not result in a significant difference in cardiac function parameters. The impairment of cardiac function was most clearly indicated by a decline in the mean LVEF from 0.61 to 0.54, which resulted in 17% of the patients having an ultimate LVEF below 0.50. In addition, plasma NT-ANP and BNP levels increased over the course of time and a prolongation of the QTc time was observed. We found no indications for an increase in cardiotoxicity by irradiation nor by high-dose cyclophosphamide, both factors having been suggested to increase the risk of cardiotoxicity. Parameters, such as QTc and natriuretic peptides, that were changed 1 year after the start of chemotherapy (T3) and that could also be measured sequentially during the first year, were already changed significantly at T1, ie, after chemotherapy only. The observed drop in LVEF is a clear indication that even at low dosages epirubicin-containing adjuvant chemotherapy causes impairment of the systolic function as a result of myocardial damage. The magnitude of the mean decline in LVEF found in our study is somewhat greater than that observed by Cottin et al,20 who found in 61 breast cancer patients treated with a cumulative epirubicin dose of 438 ± 96 mg/m2 a decrease in the mean LVEF from 0.58 to 0.55 12 months after chemotherapy. Although the mean LVEF in the present study remained within the normal range, 17% of the patients had an ultimate LVEF below 0.50 (range, 0.42 to 0.49) and 28% of the patients had a decline in the LVEF of more than 0.10. In particular, patients with an LVEF below 0.50 might be at an increased risk for the development of CHF in the long-term. On the other hand, an absolute decrease in LVEF of more than 0.10, even if LVEF remains within the limits of normal, may also be a risk factor. Whether the observed deterioration in cardiac function is a stable process or slowly progressive remains to be determined by further follow-up. Although LVEF determination is most commonly used by oncologists, its sensitivity and specificity for early detection of cardiotoxicity has been demonstrated to be limited.7 We therefore evaluated the usefulness of several other detection techniques that may be more indicative for subclinical cardiotoxicity. Natriuretic peptides have been demonstrated to be useful markers of left ventricular dysfunction in both symptomatic and asymptomatic patients.21 Previous studies evaluating their value in the detection of anthracycline cardiotoxicity suggested that the levels of natriuretic peptides become elevated before the development of CHF and even before a decline in LVEF occurs.22,23 The increase in NT-ANP, which was already present 1 month after completion of chemotherapy, developed progressively over the study time, suggesting that the atrial pressure increases. However, the mean NT-ANP levels remained within the normal range, whereas only two patients had an NT-ANP level above the normal values after 1 year. BNP levels also increased, reflecting an increase in ventricular pressure. In the current study, the increased level of natriuretic peptides was not associated with a decrease in LVEF. Since none of our patients developed CHF, the predictive value of the elevations of NT-ANP and BNP levels remains uncertain. Several studies have demonstrated that besides systolic dysfunction, anthracyclines also induce diastolic dysfunction at an early stage.9-11 We found no evident signs of diastolic dysfunction as measured by echocardiography. However, in a subgroup of patients with a decline in LVEF of more than 0.10 and/or an LVEF of less than 0.50, we found a higher increase in the deceleration time than in the other patients, indicating an impaired relaxation of the left ventricle. Because we were not able to find changes in the other diastolic function parameters, the significance of this finding is uncertain. Previously, we and others observed a reduction of HRV after anthracycline chemotherapy.24,25 In the current study, no persistent reduction of HRV was demonstrated. However, particularly the measuring of HRV shortly before start of chemotherapy may have resulted in a decreased HRV due to mental stress.26 This initial decrease may have masked a reduction of HRV due to epirubicin cardiotoxicity. The QTc time was also determined because it has been suggested to be a sign of cardiotoxicity.15,27 We observed a persistent increase in the mean QTc that was already present after completion of chemotherapy and that resulted in a significantly prolonged QTc (> 440 msec) in 17% of the patients after 1 year. Although prolongation of the QTc may be multifactorial, it could indicate a disturbance in the repolarization of the myocardium as a result of myocardial damage. The clinical significance of this finding is uncertain, but a prolonged QTc may predispose patients to the development of arrhythmias.28 Ferrari et al29 showed that prolongation of the QTc was more often found in patients treated with higher doses of anthracyclines, but they found no correlation between prolonged QTc and functional echocardiographic alterations. We also observed no correlation between the increase in QTc time and the decline in LVEF. No indications were found for an enhancement of cardiotoxicity by the use of left-sided irradiation of the chest compared with right-sided irradiation, although this study was not designed to address them. Cardiac irradiation as applied in the treatment of breast cancer has been suggested to be an additional risk factor for the development of anthracycline-induced cardiotoxicity.4,30,31 However, with the development of the currently used modern irradiation techniques, which make use of small daily fractions and sophisticated planning techniques resulting in low cardiac dose volumes, this risk has been reduced considerably. No significant increase in cardiotoxicity was found as a consequence of the high-dose cyclophosphamide–containing chemotherapy, although cyclophosphamide has been suggested as an additional risk factor of anthracycline cardiotoxicity.32 Erselcan et al33 also could not demonstrate an enhancement of subclinical cardiotoxicity as a consequence of high-dose cyclophosphamide after epirubicin-containing adjuvant chemotherapy. In summary, we observed several indications of (mild) cardiotoxicity in breast cancer patients after adjuvant chemotherapy that contained relatively low cumulative doses of epirubicin. This was demonstrated by a decrease in LVEF, an increase of the plasma levels of the natriuretic peptides, and an increase in the QTc time. Because these changes are already observed after low doses of anthracyclines and shortly after chemotherapy, they suggest that the extent of subclinical cardiotoxicity after treatment with anthracyclines is probably higher than previously described. The observed degree of subclinical cardiotoxicity may be no serious threat in the short term. However, in the long term, some of these patients may be at increased risk of developing late-onset cardiac dysfunction, which is especially relevant in patients with a favorable prognosis.
Supported in part by a grant from the University Hospital, Groningen, the Netherlands.
1. Misset JL, di Palma M, Delgado M, et al: Adjuvant treatment of node-positive breast cancer with cyclophosphamide, doxorubicin, fluorouracil, and vincristine versus cyclophosphamide, methotrexate, and fluorouracil: Final report after a 16-year median follow-up duration. J Clin Oncol 14: 1136-1145, 1996 2. Levine MN, Bramwell VH, Pritchard KI, et al: Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer: National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 16: 2651-2658, 1998[Abstract]
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
RR). A QTc time of more than 440 msec was considered prolonged. 
