Annals of Oncology Advance Access originally published online on October 26, 2005
Annals of Oncology 2006 17(1):85-92; doi:10.1093/annonc/mdj034
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© 2005 European Society for Medical Oncology
Long-term cardiac toxicity after adjuvant epirubicin-based chemotherapy in early breast cancer: French Adjuvant Study Group Results
1 Centre Georges-François Leclerc, Dijon; 2 Institut Claudius Régaud, Toulouse; 3 Centre Eugène Marquis, Rennes; 4 Centre Oscar Lambret, Lille; 5 Centre Hospitalier Jules Courmont, Lyon; 6 Centre Antoine Lacassagne, Nice; 7 Centre Hospitalier André Boulloche, Montbéliard; 8 Clinique Saint-Vincent, Besançon; 9 Centre Hospitalier de Bretagne Sud, Lorient; 10 Centre Alexis Vautrin, Nancy, France
* Correspondence to: Prof. P. Fumoleau, Département d'Oncologie Médicale, Centre Georges François Leclerc, 1 rue du Professeur Marion, BP 77980, 21079 Dijon Cedex, France. Tel: +33-3-80-73-75-06; Fax: +33-3-80-73-77-12; E-mail: pfumoleau{at}dijon.fnclcc.fr
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Abstract |
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Background: The aim of the study was to evaluate and compare incidence and risk factors of left ventricular dysfunction (LVD) in early breast cancer patients receiving (E+) or not (E–) epirubicin-based adjuvant chemotherapy.
Patients and methods: Among eight FASG trials, 3577 assessable patients were analyzed retrospectively: 2553 received epirubicin, 662 received hormonotherapy alone and 362 had no systemic treatment. Chemotherapy was FEC regimen in 86% of cases (fluorouracil, epirubicin, cyclophosphamide). Epirubicin cumulative dose was <300 mg/m2 in 1040 patients, 300–600 in 1155, 
600 in 279, followed by radiotherapy in 96% of cases.
Results: Twenty delayed LVD occurred: two in E– patients and 18 in E+ patients. In E+ patients, 14 patients normalized their cardiac function or did not require further investigations, one patient was stabilized with specific treatment, two patients worsened their functions and one died of congestive heart failure. The 7-year risk of LVD was 1.36% (95% CI 0.85–1.87) in E+ patients and 0.21% (95%CI: 0.00–0.52) in E– patients (P = 0.004). Two significant risk factors were identified: age 65 years and body mass index >27 kg/m2.
Conclusion: After a long-term follow-up, epirubicin-related LVD risk was acceptable (1.36%) with one toxic death (0.04%). In 78% of cases, LVD were transient or well controlled.
Key words: adjuvant chemotherapy, breast cancer, epirubicin, cardiotoxicity
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introduction |
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TopAbstractintroductionpatient and methodsresultsdiscussionReferences |
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Anthracyclines are among the most active agents for the treatment of women with breast cancer and their use in combination regimens as adjuvant therapy is the standard of care for most women with early-stage disease [1
]. This widespread use of anthracyclines has raised concerns about the risk of cardiotoxicity. Two major types of cardiotoxicity have been identified: an acute cardiotoxicity, independent of the anthracycline dose, generally slight and reversible, going from asymptomatic changes in electrocardiogram (ECG) until rare cases of severe acute myocarditis; and a delayed cardiotoxicity, dose-dependent, leading to irreversible, chronic and life-threatening congestive heart failure (CHF), which is the main limiting factor in the use of anthracyclines. Two types of delayed cardiotoxicity, according to the onset period, are distinguished: an early subacute cardiotoxicity occurring less than 1 year after chemotherapy completion; and a cardiotoxicity occurring with a latency period greater than 1 year, generally observed in long survivors [2]. In adult patients who do not develop cardiotoxicity within the first year, CHF is rarely diagnosed later [2]. In the vast majority of patients receiving anthracyclines for the adjuvant treatment of breast cancer, there are no clinical symptoms. However, the risks associated with subclinical decrease in left ventricular ejection fraction (LVEF) require further investigation.
The risk of developing cardiotoxicity, particularly CHF, is strongly correlated to the cumulative anthracycline drug dose [3–5]. In breast cancer treatment, two anthracyclines are at our disposal: doxorubicin and epirubicin. The probability of developing CHF with doxorubicin increases substantially at cumulative doses of 450–550 mg/m2 and higher, and with epirubicin at cumulative doses of 900–1000 mg/m2 and higher [3, 5]. The following doxorubicin-to-epirubicin dose ratios producing similar degrees of cardiac toxicity have been defined: 1:1.8 for clinical cardiac events and 1:2.2 when considering injury on endomyocardial biopsy [6, 7]. Other risk factors have been identified as increasing the occurrence of cardiomyopathy. The risk is increased in women compared with men, and in elderly patients [8]. Pre-existing cardiovascular diseases such as angina, myocardial and valvular injuries, and hypertension favor subsequent cardiac failures, as well as an elevated body mass index (BMI) [9]. Irradiation of the heart and mediastinum has been reported to be an independent risk factor for the occurrence of early subacute cardiotoxicity in adults [10, 11].
For more than 20 years, the French Adjuvant Study Group (FASG) chose epirubicin as the standard anthracycline in adjuvant therapy of breast cancer. We conducted eight adjuvant trials between 1986 and 2001 involving 3778 patients of whom 3577 were assessable for follow-up. We evaluated retrospectively reported cardiac events in those patients in order to estimate the cardiac risk related to the use of epirubicin at different doses and schedules, associated cardiac risk factors and the outcome of cardiac events.
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patient and methods |
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study population
Between 1986 and 2001, 3778 women with operable breast cancer, recruited from 32 institutions in France, were randomized in eight adjuvant trials. Follow-up data were available in 3577 patients (Table 1). The women had all undergone modified radical mastectomy or lumpectomy plus axillary dissection. The main eligibility criteria were World Health Organization (WHO) performance status
2, normal hematologic (granulocyte count 2000/mm3, platelet count 100 000/mm3), hepatic (bilirubin 35 µmol/l) and renal (serum creatinine level 130 µmol/l) functions, and no cardiac dysfunction (LVEF 50%). LVEF was measured at rest by radioisotopic or ultrasonographic methods. Patients were excluded from the study if they had evidence of metastases, a documented history of cardiac disease or previous cancer (except treated basal cell and squamous cell carcinoma of the skin or cancer of the uterine cervix), a serious underlying medical illness or psychiatric disorder, inflammatory or locally advanced breast cancer before surgery, previous radiation therapy, or hormonotherapy or chemotherapy for breast cancer, or if treatment start exceeded 42 days from initial surgery for breast cancer. Potentially eligible patients also underwent bone scan, chest radiograph, abdominal ultrasound or computed tomographic scan, and contralateral mammography. Written informed consent was obtained from each patient in a standard procedure at each participating institution according to the French law.
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treatment regimens
Patients had received either epirubicin-based chemotherapy combined or not with tamoxifen, either hormonotherapy alone, or no systemic treatment (Table 1). The allocated treatment was started within 42 days after initial surgery. Tamoxifen was given at the dose of 30 mg/day for 3 years, and started at the first chemotherapy cycle if both treatments were combined.
Locoregional radiotherapy was delivered within 6 weeks after initial surgery in the hormonotherapy or no systemic treatment groups. In the chemotherapy group, radiotherapy was delivered within 30 days after the third chemotherapy cycle in FASG 01 and 02 trials, and within 30 days after the last chemotherapy cycle in the other trials. After mastectomy, radiation to the chest wall, supraclavicular area, internal mammary chain, and, in case of pN1 tumor, to the axillary area was delivered and consisted of 50 Gy in 25 fractions for each target. Patients who underwent lumpectomy received local radiation to the breast that consisted of 55 Gy in 27 fractions plus a complementary breast irradiation of 10–15 Gy, and local radiation to the supraclavicular area, internal mammary chain and axillary area (in case of pN1 tumor) consisting of 50 Gy in 25 fractions for each target.
For chemotherapy, preventive use of granulocyte-colony stimulating factor (G-CSF), and antibiotics were prohibited. An absolute granulocyte count of less than 2000/mm3 or a platelet count of less than 100 000/mm3 on day 21 led to a treatment interruption of at least 1 week. Treatment was stopped if hematologic recovery took more than 3 weeks. The epirubicin dose was reduced by 50% if serum bilirubin levels were 35–50 µmol/l and treatment was stopped if bilirubin levels exceeded 50 µmol/l. The tolerability of chemotherapy was evaluated before each cycle: an ECG and a complete blood count were performed on day 21, and non-hematologic toxicity was evaluated during the period between each cycle, according to WHO criteria. Subjects underwent clinical and biochemical assessments every 6 months during the 5-year follow-up period, and yearly thereafter. A radiological assessment was performed every year during the 5-year follow-up period and every 2 years thereafter. It was recommended to assess the LVEF at the end of chemotherapy, using the same method as for pretherapeutic measurement. No specific recommendations were given during the follow-up period.
data management and data analysis
Patients enrolled in the FASG trials were followed from the time of randomization until death. Cases of cardiac events were reported by the investigators to Pfizer France, and then transmitted to Pfizer Oncology Pharmacovigilance, Milan. At the same time, reports of severe adverse cardiac events were declared to the French Health Authorities.
A left ventricular dysfunction (LVD) was defined as the occurrence of cardiac symptoms, a LVEF below normal value of the center, and/or a LVEF decrease 20% of baseline value. The LVEF normal range was validated by measurements performed by each participating center in a normal population. In patients in whom there was no baseline LVEF determination, only the LVEF at the time of cardiac assessment could be considered. If there was a discrepancy between methods of measuring LVEF (radioisotopic or echocardiographic), the poorer of the two results was considered. The reproductibility of cardiac assessment remains an issue. An early assessment (within 1 year after baseline LVEF) could be considered as reproducible as it had been performed in the same center with the same materials. On the other hand, the LVEF variations between baseline and long-term value must be interpreted carefully because materials and operators were different. Acute toxicity was defined as the occurrence of a cardiac event during chemotherapy and within the last month after the last chemotherapy cycle. Delayed toxicity was defined as the occurrence of a cardiac event at least 1 month after chemotherapy completion and during the follow-up period or before diagnosis of breast cancer relapse. We compared the occurrence of LVD between patients who received (E+) or no (E–) adjuvant epirubicin therapy. The risk of developing a LVD was compared between both groups using a log-rank test. The patients were considered at risk from the date of randomization until relapse or last follow-up.
We determined the role of different risk factors using a log-rank test. In patients who received chemotherapy, we compared the risk according to cumulative dose and dose intensity of epirubicin. In the whole population, we determined the risk according to age, BMI and side of radiotherapy.
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results |
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patient and treatment characteristics
Among patients randomized in the FASG trials, an overall number of 3577 were assessable for follow-up. Actually, 2553 received an epirubicin-based adjuvant chemotherapy and 1024 received either hormonotherapy alone (n = 662) or no systemic treatment (n = 362). The main patient and tumor characteristics were significantly different between both groups: patients treated with chemotherapy presented with worse prognostic factors (Table 2). The difference in BMI was related to the great number of unknown data in the E– group. If we considered only the available data, the rate of patients with BMI
27 kg/m2 was similar to 25% of cases in both groups (P = 0.93).
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Treatment characteristics are described in Table 3. Patients who did not receive chemotherapy were less likely to receive radiotherapy. In case of radiotherapy delivery, patients in the E– group were less irradiated on breast/chest wall, axillary area and supraclavicular area, whereas the rate of patients irradiated on internal mammary chain and those who received a boost were similar between both groups. More patients were irradiated on the left side in the E+ group (P = 0.05). Patients who received FEC 100 represented 19% of the population and 58% of them received an epirubicin cumulative dose of at least 600 mg/m2 (maximum 628 mg/m2).
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baseline cardiac function
Baseline ECG was not performed in 10% of E+ patients and in 22% of E– patients. An abnormal ECG was diagnosed in 2.5% and 3.6%, respectively (P = 0.09). Baseline LVEF was not performed in 24% of E+ patients and in 58% of E– patients. Before treatment initiation, LVEF was below the normal range in 46 patients (2.4%) randomized to receive epirubicin-based chemotherapy and in 13 patients (3%) randomized in hormonotherapy or control groups (P = 0.43).
description of acute and delayed cardiac events
In E– patients during the follow-up period, two cases of delayed, asymptomatic and transient LVD occurred (0.2%). Cardiac events in E+ patients are described in Tables 4–6. During epirubicin-based adjuvant chemotherapy, 15 patients (0.6%) were diagnosed with LVD: asymptomatic LVEF decrease in 11 cases, asymptomatic LVEF decrease associated with left ventricular hypertrophia (LVH) in three (of whom one patient presented with a pre-existing LVH) and transient NYHA 2 exercise dyspnea in one. No case of CHF occurred during chemotherapy. Among the 11 asymptomatic cases, three patients normalized their LVEF, one patient kept a LVEF value at 49% without developing further cardiac clinical signs, and no subsequent cardiac investigation was required in the seven remaining patients. The outcome of LVH showed a stabilization of cardiac function in one, and was not reported in the two other cases, which were free of cardiac clinical signs at last follow-up.
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After epirubicin-based adjuvant chemotherapy, 18 patients (0.7%) were diagnosed with LVD. Five patients (0.2%) developed a CHF: one was normalized with specific treatment, one was stabilized, two worsened their cardiac function of whom one was treated with FEC 100 in spite of a baseline LVEF of 44% (low normal value = 50%), and one died of her CHF (0.04%). The 13 remaining cases were asymptomatic LVEF decrease normalized in four cases, or not requiring further investigations in the others. Three patients died of cardiac complications not related to chemotherapy: rhythm disturbances related to hypokaliemia in one, myocardial infarct in one and mitral insufficiency in one.
incidence rate and risk factors of left ventricular dysfunction
After 7 years of median follow-up (range 1 month to 15 years), the risk of developing a LVD after epirubicin-based adjuvant chemotherapy was of 1.36% (95% confidence interval (CI) 0.85–1.87) and 0.21% (95% CI 0.00–0.52) in non epirubicin-exposed patients (P = 0.004). In E+ patients, LVD occurred mainly within 2 years after chemotherapy completion and decreased thereafter, closer to E– patients. No case was reported after the 9th year of follow-up (Figure 1). The analysis of LVD risk factors showed that age >65 years and BMI 27 kg/m2 were significantly associated with LVD occurrence (Table 7). The epirubicin cumulative dose, which did not exceed 628 mg/m2, was not significantly involved in the risk of developing a LVD.
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discussion |
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We reported here the long-term risk of treatment-related LVD in 3577 patients in the eight trials conducted by the FASG from 1986 to 2001. Among the 2553 patients who received epirubicin, 15 (0.6%) developed non-complicated LVD during chemotherapy and 18 (0.7%) developed a delayed LVD, of whom five (0.2%) presented with CHF and one (0.04%) died as a result of CHF. As foreseen, the 7-year risk to develop a LVD was significantly higher in patients who received epirubicin compared with those who did not (1.36% versus 0.21%, P = 0.004). Our study has the limitations of a retrospective review, even if all patients were randomly assigned in prospective trials. It is a descriptive analysis that is not designed to be compared directly with doxorubicin data; patients who received epirubicin were different to those who did not receive epirubicin in terms of prognostic factors, as patients randomized in chemotherapy trials presented with higher risk of relapse. Baseline LVEF was not assessed in 24% of patients who received epirubicin, in particular for the older women randomized in the FASG 08 trial, which could explain in part the higher rate of LVD in this population.
Our knowledge about the cardiac safety of anthracyclines was initially based on comparisons between doxorubicin and epirubicin in experimental studies and in metastatic breast cancer clinical trials. In vivo, it has been shown that myocardial injuries were higher with doxorubicin compared with epirubicin [12]. In 1986, Torti et al. [13] evaluated cardiac toxicity of both anthracyclines using endomyocardial biopsies in 98 doxorubicin-treated patients and in 29 epirubicin-treated patients, showing significantly lower rate cardiac damages with epirubicin (P = 0.0013). Clinically, the direct comparisons between doxorubicin and epirubicin at equimolar doses of 50 mg/m2 among three metastatic breast cancer trials demonstrated a decrease in the incidence of CHF with epirubicin: 10 CHF (2.6%) occurred after doxorubicin versus one case (0.3%) after epirubicin [14–16]. This confirmed the results obtained in the present analysis in which after a long-term follow-up in adjuvant setting, the CHF rate was 0.2%.
Direct comparisons between doxorubicin and epirubicin in adjuvant breast cancer treatment have never been performed. With doxorubicin, few data have been published to date. In a study by Valagussa et al. [10], 0.8% of patients treated with doxorubicin (75 mg/m2, four cycles) developed a cardiotoxicity. This rate increased to 2.6% in those receiving doxorubicin and irradiation of the breast on the left side. After 6 years of follow-up, Shapiro et al. [17] observed 4.3% of CHF after five cycles of AC (doxorubicin, cyclophosphamide) and 11.8% after 10 cycles of AC. A recent report shows that the risk of doxorubicin-related CHF occurs with greater frequency and at a lower cumulative dose than previously reported [3]: the analysis indicated that an estimated cumulative 26% of patients would experience doxorubicin-related CHF at a cumulative dose of 550 mg/m2 [18]. In France, the widespread use of epirubicin led investigators to monitor carefully the cardiac side-effects, especially because the standard of care had increased to six cycles of FEC 100 [19, 20]. The results of early subacute and delayed cardiac toxicity are summarized in Table 8. With epirubicin, the CHF rate did not exceed 2.3% and one death related to CHF occurred among the three trials.
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In our study using epirubicin at a maximal cumulative dose of 600 mg/m2, we did not find that the epirubicin dose was correlated with an increased risk in LVD. This confirmed that below the higher recommended dose of 900–1000 mg/m2, the risk of developing a cardiotoxicity remains mild [5
]. Among the other recognized risk factors of cardiac impairment, we found that age 65 years and a BMI above the normal value, as defined by WHO scale, were significantly correlated with the occurrence of a LVD. The increased risk in older patients has been previously described [8]. In our patients 65 years treated with a particular regimen of weekly epirubicin single-agent at a fixed dose of 30 mg/week, they experienced a non-complicated decrease in LVEF with no case of CHF [21]. Moreover, those patients had a significant benefit in terms of disease-free survival with this schedule combined to tamoxifen compared with tamoxifen alone. As regards patients with an increased BMI, they probably have associated risk factors such as hypertension, diabetes or hypercholesterolemia. In FASG 05 patients, we previously found that these concomitant diseases were significantly correlated with the occurrence of a LVD [20].
In our analysis, the outcome of patients who developed a LVD was favorable in 81% of cases. While LVEF is not an ideal end point, other methods may be useful for identifying first signs of cardiotoxicity. Patients with brain natriuretic peptide (BNP) and/or troponin I plasma levels could help to diagnose earlier a potential CHF. It has been shown that an increase in troponin I after chemotherapy was predictive of damages in left ventricular function [22]. Furthermore, an elevation of BNP has been found in patients who received anthracyclines and who subsequently developed a LVD [23]. In 1986, when our trials were initiated, these biomarkers were not available. This information should be of interest to interpret our findings. Further investigations using these biological markers in the monitoring of patients receiving anthracyclines are warranted.
Our results showed that the use of epirubicin-based adjuvant chemotherapy in early breast cancer was associated with a low risk of LVD. When epirubicin was delivered within the recommended doses, a favorable benefit/risk ratio was maintained. The closer monitoring of cardiac function must be performed during the first 2 years after chemotherapy completion. This monitoring must be carefully done in patients at risk, i.e. older women and patients who have an elevated BMI. The question of the use of a cardioprotectant such as dexrazoxane could be addressed. In accordance with American Society of Clinical Oncology (ASCO) and National Cancer Institute of Canada (NCIC) recommendations, there is insufficient evidence for the use of dexrazoxane with epirubicin-based regimens in the absence of specific clinical trials [24, 25]. In our analysis, epirubicin was combined mainly in FEC regimens. The combination with new drugs such as taxanes and trastuzumab must be studied with regard to cardiotoxicity. The experience of combinations of doxorubicin with paclitaxel and trastuzumab led to an unexpected number of severe cardiac events [26, 27]. Even if epirubicin is less cardiotoxic when combined with these drugs [28, 29], we have to be very cautious with these new associations.
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Acknowledgements |
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This work was supported by grants from Pfizer, France. We are indebted to Dr Elisabeth Luporsi (Centre Alexis Vautrin, Nancy, France) for her statistical contribution. Isabelle Chapelle-Marcillac provided editorial assistance in the preparation of the manuscript.
Received for publication March 18, 2005. Revision received August 24, 2005. Accepted for publication September 5, 2005.
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References |
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