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Journal of Clinical Oncology, Vol 22, No 15 (August 1), 2004: pp. 3070-3079 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.03.098 Long-Term Cardiac Follow-Up in Relapse-Free Patients After Six Courses of Fluorouracil, Epirubicin, and Cyclophosphamide, With Either 50 or 100 mg of Epirubicin, As Adjuvant Therapy for Node-Positive Breast Cancer: French Adjuvant Study GroupFrom the Centre Oscar Lambret, Lille; Institut Claudius Régaud, Toulouse; Centre Eugène Marquis, Rennes; Centre René Gauducheau, Nantes; Centre Hospitalier de Bretagne Sud, Lorient; Centre Georges-François Leclerc, Dijon; Clinique Saint-Vincent, Besançon; Centre Hospitalier Universitaire Dupuytren, Limoges; Centre Hospitalier Louis Pasteur, Colmar; Centre Hospitalier André Boulloche, Montbéliard; Centre Henri Becquerel, Rouen; Centre Hospitalier, Annecy; and Centre Jean Perrin, Clermont-Ferrand, France Address reprint requests to Jacques Bonneterre, MD, Département de Sénologie, Centre Oscar Lambret, 3 Rue Frédéric Combemale, 59020 Lille Cedex, France; e-mail: j-bonneterre{at}o-lambret.fr
PURPOSE: To evaluate long-term cardiac function in patients without disease who had received six cycles of fluorouracil 500 mg/m2, epirubicin 50 mg/m2, and cyclophosphamide 500 mg/m2 (FEC 50) or the same regimen with epirubicin 100 mg/m2 (FEC 100) as adjuvant chemotherapy for node-positive breast cancer in the French Adjuvant Study Group–05 trial. PATIENTS AND METHODS: One hundred fifty patients (FEC 50, n = 65; FEC 100, n = 85) who were without disease and who gave their informed consent were enrolled for long-term cardiac assessment. The assessment included cardiac events occurring after the end of chemotherapy, vital signs, concomitant disease, ECG, isotopic left ventricular ejection fraction (LVEF), and echographic parameters. Abnormal files were blindly reviewed by cardiologists and oncologists. RESULTS: The median follow-up time was 102 months. After FEC 100, LVEF was less than 50% in five patients (radioisotopic method), and two patients experienced congestive heart failure (CHF) that was possibly related to treatment. Asymptomatic left ventricular dysfunction (LVD) was experienced in 18 patients after FEC 100 and in one patient after FEC 50. In these patients, treatment causality was probable in eight patients. Two additional years after this assessment, all 18 patients were still asymptomatic. CONCLUSION: After more than 8 years of follow-up, the cardiac toxicity observed after adjuvant treatment with FEC 100 comprised two cases of well-controlled CHF and 18 cases of asymptomatic LVD. In the majority of women with primary breast cancer, the benefits of treatment with FEC 100 in terms of disease-free and overall survival outweigh the risks, and cardiac risk factors should be carefully evaluated in patient selection.
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. Although cardiotoxicity occurs infrequently, it can be potentially serious and life-threatening, manifesting in its most severe form as clinically significant congestive heart failure (CHF). The absence of clinical symptoms in the vast majority of patients receiving anthracyclines for the adjuvant treatment of breast cancer is encouraging. Nonetheless, the risks associated with subclinical decreases in left ventricular ejection fraction (LVEF) merit further investigation; concern is warranted regarding late cardiac toxicity or cardiac compromise with a subsequent cardiac event in these patients. The risk of developing cardiotoxicity, particularly CHF, is strongly correlated with the cumulative anthracycline drug dose.2-5 In breast cancer treatment, two anthracyclines are at our disposal: doxorubicin and epirubicin. In the metastatic setting, it has been demonstrated that, at equimolar doses, both anthracyclines had the same efficacy, but epirubicin had a better safety profile, including cardiac safety.6-8 The probability of developing CHF with doxorubicin increases substantially at cumulative doses of 450 to 550 mg/m2 and greater and with epirubicin at cumulative doses of 900 to 1,000 mg/m2 and greater.2,5 The following doxorubicin-to-epirubicin dose ratios that produce 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.9-11 These results prompted the French Adjuvant Study Group (FASG) to choose epirubicin as the standard anthracycline. In 1990, the FASG initiated study FASG 05 to compare six cycles of fluorouracil, epirubicin 50 mg/m2, and cyclophosphamide (FEC 50) every 3 weeks with six cycles of FEC 100 (epirubicin 100 mg/m2) as adjuvant therapy for women with axillary lymph node–positive primary breast cancer.12 At a median follow-up of 67 months, FEC 100 produced a statistically significant improvement in 5-year disease-free survival (66.3% v 54.8%; P = .03) and overall survival (77.4% v 65.3%; P = .007) compared with FEC 50. The risk of clinically significant cardiac events was low, with two cases (0.4%) occurring after adjuvant treatment (one case of myocardial infarction and one decrease in LVEF). Because FEC 100 is emerging as a standard adjuvant treatment for women with early-stage breast cancer, cardiac outcome in long-term survivors merits focused investigation. Therefore, we initiated a prospective study to thoroughly evaluate the cardiac function of disease-free patients who gave their written informed consent in the FASG 05 trial. To our knowledge, it was the first prospective trial designed to evaluate the long-term cardiac function of patients 7 to 10 years after adjuvant epirubicin treatment with FEC 100 or FEC 50 and to study possible prognostic factors predisposing a patient to alterations in cardiac function.
Patient Population Between April 1990 and July 1993, 565 women with node-positive operable breast cancer (either > three positive nodes or between one and three positive nodes with histoprognostic grade  2 and hormone receptor negativity), recruited from 20 institutions in France, were randomly assigned to receive one of the following intravenous chemotherapy regimens: fluorouracil 500 mg/m2, epirubicin 50 mg/m2, and cyclophosphamide 500 mg/m2 every 21 days for six cycles (FEC 50) or fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2 every 21 days for six cycles (FEC 100). In postmenopausal patients, tamoxifen 30 mg/d was administered at the first chemotherapy cycle for 3 years. In case of hormone receptor negativity, tamoxifen administration was left to the discretion of the investigators, but the policy had to be similar for both arms in a given center. Locoregional radiotherapy was delivered within 30 days after the last chemotherapy cycle according to standard procedures.12 Before inclusion and initiation of chemotherapy, patients had a cardiac assessment consisting of an ECG and an LVEF measurement at rest by radioisotopic or ultrasonographic methods. To be eligible for chemotherapy, patients had to be free of cardiac dysfunction, with an LVEF value 50%. An ECG was performed before each cycle, and LVEF was assessed at the end of chemotherapy. The long-term cardiac assessment was not prospectively planned at the time the FASG 05 trial commenced. To exclusively study the effects of adjuvant epirubicin-containing chemotherapy, relapse-free patients enrolled onto the FASG 05 trial who agreed to participate in the study were eligible for long-term cardiac assessment. Written informed consent was obtained from each patient in a standard procedure at each participating institution. The study protocol was approved by the ethical committee of the coordinating center according to the French loi Huriet.
Cardiac Assessment
The National Cancer Institute Common Toxicity Criteria (version 2.0, 1998) were used to evaluate the left ventricular function. The cutoff values for normality of measured cardiac parameters, blood pressure, and body mass index (BMI) are shown in Table 1. A peer review committee, which comprised three cardiologists and three medical oncologists who were blinded to adjuvant chemotherapy randomization, was organized at the end of the study. Medical records were reviewed if a patient presented with at least one of the following criteria: a cardiac clinical sign (CHF, rhythm disorders, angina, thromboembolic disease, or hypertensive cardiopathy), a cardiac event between the end of chemotherapy and the present cardiologic consultation, an abnormal ECG, an LVEF less than 50%, a decrease in LVEF
Statistical Methods First, we examined the selected population for the long-term cardiac assessment to determine whether it was representative of the overall FASG 05 patients and whether patients enrolled onto the cardiac assessment study were well balanced among both treatment arms. The analyzed variables were patient and tumor characteristics, adjuvant treatment (chemotherapy, hormonotherapy, and radiotherapy), pretreatment cardiac function, BMI, and blood pressure. For patients included in the long-term cardiac assessment, we compared treatment arms for cardiac clinical signs and cardiac parameters. In patients who presented with left ventricular dysfunction (LVD) according to peer review conclusions, we correlated this event with pretreatment LVEF and comorbid conditions at the time of cardiac assessment (ie, hypertension, hypercholesterolemia, diabetes, side of radiotherapy, age, and BMI).
For testing levels, the
Patient Characteristics Two hundred seventy-eight patients were eligible for this study (127 who had received FEC 50 and 151 who had received FEC 100), of whom 150 were enrolled (65 who had received FEC 50 and 85 who had received FEC 100). The main reasons for nonenrollment included patient refusal (FEC 50, n = 32; FEC 100, n = 26), logistical issues (FEC 50, n = 18; FEC 100, n = 26), patient lost to follow-up (FEC 50, n = 7; FEC 100, n = 8), relapse in the time interval (FEC 50, n = 5; FEC 100, n = 5), and death from other cause (FEC 100, n = 1). The median follow-up time was 102 months (range, 79 to 123 months) in both groups. The baseline characteristics of patients enrolled in this long-term cardiac study were representative of the initial population for age, menopausal status, tumor characteristics, and treatment (Table 2). The only exception was number of involved nodes, which was higher in the initial population of the FEC 50 arm (P = .05). As described in Table 2, all the criteria were well balanced between the two groups of eligible patients for cardiac assessment, except for the mean number of involved nodes, which was significantly higher in the FEC 100 arm (seven v five nodes; P = .02).
The main characteristics of the patients at the time of cardiac assessment are described in Table 3. The median age was 59 years for both groups. The BMI was upper normal value (> 27 kg/m2) in 41.7% of patients treated with FEC 50 and 40% of patients treated with FEC 100. For all patients, the mean increase in BMI was 6.8% as compared with baseline value (P < .001), with an increase of 8.3% and 5.7% for FEC 50 and FEC 100, respectively (P = .18). Overall and for each treatment arm, blood pressure had not significantly change compared with baseline conditions. Concomitant diseases and their treatments were well balanced between FEC 50 and FEC 100 treatment groups. At the time of this long-term follow-up, the treatment of concomitant diseases was as follows: hypertension was treated in nine of 33 patients, diabetes was treated in three of six patients, hypercholesterolemia was treated in five of eight patients, and thyroid dysfunction was treated in six of six patients.
Baseline Cardiac Conditions and Cardiac Risk Factors There was no significant difference in cardiac conditions and risk factors between the FASG-05 patients included on the cardiac assessment and the FASG-05 patients not included (Table 4). Furthermore, baseline cardiac characteristics were well balanced between FEC 50 and FEC 100 patients who had a long-term cardiac assessment. Initially, the LVEF was mainly assessed by radioisotopic method (69%) and was not assessed (protocol violation) in 11 patients (FEC 50, n = 4; FEC 100, n = 7). One patient presented with a radioisotopic LVEF below normal value in the FEC 50 arm (patient value = 53%, normal value > 55%). Six patients presented with a cardiac abnormality on ECG (FEC 50, n = 4; FEC 100, n = 2) as follows: auricular fibrillation (n = 2), right auricular dysfunction (n = 1), tachycardia (n = 1), right bundle branch block (n = 1), and T-wave flatness (n = 1). There were no differences between groups in associated cardiovascular risk factors (BMI, blood pressure) available before inclusion in the FASG-05 trial (Table 4).
Clinical Signs and Cardiac Parameters Cardiac clinical signs (during the follow-up period and at the time of long-term cardiac assessment) occurred in 13 patients (20%) treated with FEC 50 and in 12 patients (14.1%) treated with FEC 100 (P = .34; Table 5). Two cases of CHF were described after FEC 100. The first was diagnosed at the time of this long-term cardiac assessment in a patient 73 years of age who presented with hypertension (systolic blood pressure = 210 mmHg; diastolic blood pressure = 120 mmHg). The second case of CHF had occurred 3 years earlier in a patient 70 years of age who presented with uncontrolled diabetes. At the time of this cardiac assessment, the CHF was well controlled with converting enzyme inhibitor, and all of the cardiac parameters were within the normal range. All cardiac parameters determined in this long-term follow-up and any abnormalities are described in Table 5.
LVD and Causality to Adjuvant Chemotherapy Among the 150 patients enrolled, medical records of 67 patients were peer reviewed according to criteria described in Patients and Methods (FEC 50, n = 26 [40%]; FEC 100, n = 41 [48%]). As described in Table 6, the peer review panel diagnosed an LVD in 21 patients. One patient presented with a mild (grade 1) and asymptomatic LVD after FEC 50, for which the causality was doubtful. As described previously, two patients presented with CHF (National Cancer Institute Common Toxicity Criteria grade 3) after FEC 100; in these patients, the causality was possible because of concomitant risk factors (very severe hypertension in one patient and uncontrolled diabetes in the other). Finally, 18 patients presented with an asymptomatic LVD after treatment with FEC 100. Among these 18 patients, the LVD was mild (grade 1) in nine patients (doubtful causality, n = 3; possible causality, n = 3; probable causality, n = 3), and moderate (grade 2) in nine patients (possible causality, n = 4; probable causality, n = 5). The LVEF was less than 50% in five patients as measured by radioisotopic method and in four patients as measured by echographic method; results were consistent between both methods in only one of these patients.
At time of long-term cardiac assessment, the correlation between the occurrence of LVD and other coexisting conditions showed that LVD is significantly associated with concomitant disease (hypertension, hypercholesterolemia, or diabetes). Twelve (57.1%) of the 21 patients with LVD had a concomitant disease, whereas 36 (27.9%) of 129 patients not developing LVD had a concomitant disease (P = .008). With regard to the side of radiotherapy (ie, right chest v left chest), there was more radiotherapy to the left side in patients who developed LVD (15 [71.4%] of 21 patients) than in patients not developing LVD (70 [54.3%] of 129 patients), even if not significant (P = .14). The BMI was above normal in 57.1% of patients presenting with LVD, compared with 37.9% of patients not presenting with LVD (P = .10). Age was similar among patients who developed LVD versus those who did not develop LVD (median, 59 years; P = .62). At baseline, the pretherapeutic LVEF was not predictive of the occurrence of LVD: the pretreatment mean value in patients who developed LVD was 64.2% versus 63.7% in those who did not (P = .80).
Outcome of LVD
This study is the first to evaluate prospectively and extensively long-term cardiac toxicity more than 8 years after chemotherapy. We undertook this study to thoroughly evaluate cardiac function when doubling the epirubicin dose from 50 to 100 mg/m2 in the FEC regimen, taking into consideration coexisting conditions in relapse-free surviving patients treated in our FASG-05 adjuvant trial.12 After more than 8 years of follow-up in 150 patients who were free of relapse after adjuvant treatment with FEC 50 or FEC 100 in the FASG 05 trial, only two patients experienced symptomatic CHF that was possibly related to treatment with FEC 100. An additional 18 patients experienced clinically asymptomatic LVD, which was not severe (grade 1) in nine of the patients; 72% of these patients had a normal LVEF as measured by radioisotopic method. None of these asymptomatic patients developed further cardiac symptoms. In our population, the main coexisting conditions to develop LVD was concomitant disease usually associated with cardiovascular disease (high blood pressure, diabetes, and hypercholesterolemia).15 The other recognized risk factors, such as advanced age,2,16 radiation therapy to the mediastinal/pericardial area,17-20 and an elevated BMI,15 were not significantly correlated with the occurrence of LVD. Similarly, in a prospective pharmacologic evaluation of age-related toxicity of adjuvant anthracycline-based chemotherapy (four cycles of doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2), Dees et al21 found no evidence of a sizable difference in cardiotoxicity in older patients compared with younger patients. Interestingly, though not statistically significant, there seemed to be a correlation between the incidence of LVD and increased BMI. Although irradiation to the left chest wall was not significantly correlated with LVD, it also may have contributed to increased damage to the myocardium in these patients. One of the issues in the monitoring of cardiac function, before and during the follow-up of patients treated with an anthracycline-based chemotherapy, is the choice of the method used to monitor cardiac function. To assess cardiac function, we used two recognized methods to diagnose long-term cardiac lesions in asymptomatic patients: echocardiography and isotopic LVEF. Noteworthy, in our trial, the LVEF variations between baseline and long-term value must be interpreted carefully: materials and operators were different, which could have explained the increase in LVEF observed with FEC 50 treatment. However, the difference in LVEF variations observed between 50 and 100 mg/m2 of epirubicin shows that biases have affected both treatment arms equally. Lipshultz et al22 showed that the shortening fraction evaluated by echocardiography had a sensitivity of 64% and a specificity of 81% in diagnosing either a contractility abnormality or an afterload abnormality during long-term follow-up. The sensitivity and reliability of isotopic angiography are greater than those of echocardiography, with reproducible and earlier results.23 Surprisingly, in the present study, of the nine patients with LVD and an LVEF measurement less than 50%, concomitantly low isotopic and echographic LVEF measurements were observed in only two patients. The evolution of measurement techniques together with differences observed in a same patient between echocardiographic and isotopic determinations and proportion of patients who remain asymptomatic despite an abnormal LVEF show that other parameters should be measured. Although LVEF is not an ideal end point, other methods, such as brain natriuretic peptide and/or troponin I plasma levels and heart rate variability analysis, may be useful for identifying first signs of cardiotoxicity; however, further careful investigation is warranted.24-26 Another issue in anthracycline-based chemotherapy for patients with operable breast cancer is the choice of the anthracycline, doxorubicin or epirubicin, and its dose to maintain a favorable benefit/risk ratio. Regarding anthracycline, the better cardiac toxicity profile of epirubicin, as compared with doxorubicin, has been clearly established in vivo,27 on endomyocardial biopsy,10,11 and in clinical trials.6-8 However, the true incidence of cardiotoxicity remains uncertain. With doxorubicin, 0.4% to 9% of myocardial injury has been reported, which is strongly correlated with the cumulative dose.2,28-32 A recent analysis shows that the risk of doxorubicin-related CHF occurs with greater frequency and at a lower cumulative dose than previously reported: the analysis indicated that an estimated cumulative 26% of patients would experience doxorubicin-related CHF at a cumulative dose of 550 mg/m2.33 With epirubicin, few adjuvant trials reported cardiac events. The FASG presented the results of a retrospective analysis concerning symptomatic cardiac events occurring in eight adjuvant trials that included 3,577 assessable patients.34 After a 7-year median follow-up, the risk to develop clinically symptomatic LVD was 1.36% (95% CI, 0.06 to 0.36) in the 2,553 patients who received epirubicin-based chemotherapy, and one patient died from CHF (0.04%). In the present trial, we demonstrated a quite low and acceptable risk of cardiotoxicity with an adjuvant FEC regimen. Although it is a prospective and exhaustive study of the cardiac function in anthracycline-treated patients, we did not find more complications than in published studies (Table 7). 34-39 In these trials of epirubicin-based adjuvant polychemotherapy, the rate of CHF ranged from 0% to 2.0%, with no associated risk of mortality. Of note, our study was designed to address long-term cardiotoxicity, with 102 months of follow-up, whereas the median follow-up in these trials was shorter, and cardiotoxicity was assessed as part of the routine toxicity evaluation.
In women receiving potentially curative adjuvant anthracycline-containing chemotherapy, long-term follow-up is especially important in risk assessment. Not only does this apply to women with axillary lymph node–positive early disease, but also to those with node-negative disease, because anthracyclines are being used increasingly to treat these women. Indeed, we believe that the low risk of cardiac toxicity is worth the benefit of the long-term benefit we observed and that replacing doxorubicin with epirubicin is an important strategy for increasing the therapeutic index of anthracyclines. The epirubicin-based FEC 100 regimen as adjuvant therapy has positively impacted the treatment of women with poor-prognosis, operable breast cancer. The 10-year update of the FASG-05 trial, recently presented, showed that FEC 100 remained significantly superior to FEC 50 in terms of disease-free (P = .036) and overall survival (P = .038), and this advantage was not counterbalanced by long-term toxicity.40 Concomitant cardiac risk factors, including a preexisting LVD or concurrent disease, seem to increase the risk of anthracycline-associated cardiac toxicity and should be considered in patient selection for FEC 100. With appropriate patient selection, the risk of cardiotoxicity with the FEC 100 regimen is acceptable and does not lead to adverse cardiac sequelae that would outweigh the expected benefits.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Owns stock (not including shares held through a public mutual fund): Isabelle Chapelle-Marcillac, Pfizer. Performed contract work within the past 2 years: Isabelle Chapelle-Marcillac, Pfizer. Received more than $2,000 per year from a company for either of the past 2 years: Isabelle Chapelle-Marcillac, Pfizer.
We thank Jean-Bernard Alexandre (Clinique des Hauts-de-Seine, Chatenay-Malabry, France), Serge Chiffoleau (Nantes, France), Bernard Escudier (Institut Gustave Roussy, Villejuif, France), Philippe Gautier (Centre Oscar Lambret, Lille, France), Didier Palsky (Paris, France), and Bruno Panier (Paris, France) for their cardiac expert assessment. The Phillips Group Oncology Communications Company provided editorial assistance in the preparation of the manuscript.
Supported by grants from Pharmacia SA, Saint-Quentin en Yvelines, France. Presented at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18-21, 2002 (abstract 154; poster display/discussion). Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test was used to compare categoric variables, and continuous variables were compared using analysis of variance.
