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Journal of Clinical Oncology, Vol 22, No 10 (May 15), 2004: pp. 1864-1871 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.06.033 Subclinical Late Cardiomyopathy After Doxorubicin Therapy for Lymphoma in AdultsFrom the Service of Hematology and Department of Biostatistics Centre Hospitalier Lyon-Sud, Pierre Bénite, France. Address reprint requests to B. Coiffier, MD, Service d'Hématologie, Centre Hospitalier Lyon-Sud, 69495 Pierre-Bénite Cedex; e-mail: bertrand.coiffier{at}chu-lyon.fr
PURPOSE: To assess the cardiac status of the long-term survivors and to estimate the incidence and the features of subclinical cardiotoxicity induced after conventional treatment with doxorubicin for non-Hodgkin's lymphoma or Hodgkin's lymphoma. PATIENTS AND METHODS: We analyzed a group of patients who previously received doxorubicin-based chemotherapy for lymphoma. Echocardiograms were performed at least 5 years after therapy with anthracyclines. Clinical cardiomyopathy was defined by the presence of clinical signs of congestive heart failure (CHF). Subclinical cardiomyopathy was defined by decrease of left ventricular fractional shortening (FS) without clinical signs of CHF. Cumulative dose of doxorubicin, male sex, older age, relapse, radiotherapy (mediastinal or total-body irradiation), autologous stem-cell transplantation, high-dose cyclophosphamide, and cardiovascular risk factors (hypertension, diabetes, hypercholesterolemia, familial history of cardiac disease, being overweight, and smoking history) were evaluated as potential risk factors for the development of cardiac dysfunction. RESULTS: Of 141 assessable patients (median age, 54 years; median cumulative dose of doxorubicin, 300 mg/m2), only one developed CHF. Criteria of subclinical cardiomyopathy were found in 39 patients. In multivariate analysis, factors that contributed to decreased FS were male sex (P < .01), older age (P < .01), higher cumulative dose of doxorubicin or association with another anthracycline (P = .04), radiotherapy (P = .04), and being overweight (P = .04). CONCLUSION: Cardiac abnormalities can occur in patients treated with doxorubicin for lymphoma in the absence of CHF, even in patients who received moderate anthracycline doses. Male sex, older age, higher dose of doxorubicin, radiotherapy, and being overweight were risk factors for the development of cardiomyopathy.
Doxorubicin, which belongs to the anthracycline family of drugs, is a key component of chemotherapy regimens and is the most active agent for the treatment of lymphoma. However, doxorubicin use is limited by its severe cardiotoxicity, including cardiomyopathy and congestive heart failure (CHF), which are late cardiac effects usually occurring after doses greater than 550 mg/m2.1 Early toxicity is rare and includes myocarditis. Late cardiotoxicity after doxorubicin has largely been studied in children2,3 but less often in adults. In children, the principal risk factor for anthracycline-induced cardiomyopathy is highly dependent on cumulative doses.1-4 For adults, a few studies have been performed in the setting of breast cancer with epirubicin5 or doxorubicin,6 of acute myeloid leukemia after idarubicin,7 or after doxorubicin for various hematologic malignancies.8,9 For these patients, an increased risk of developing late cardiotoxicity after anthracycline treatment has been associated with advanced age or with higher cumulative doses.4,9 Most of these studies involved patients who received doses of doxorubicin ranging from 450 to 550 mg/m2. Although risk factors for doxorubicin-induced CHF have been studied, subclinical cardiac toxicity after lower doses of doxorubicin is less understood. Therefore, we studied the occurrence of late cardiac abnormalities by measuring systolic function, left ventricular ejection fraction (LVEF), and fractional shortening (FS) in patients treated with doxorubicin for lymphoma. We evaluated the cardiac function of adults observed for at least 5 years after the successful treatment of the lymphoma with chemotherapy regimens including doxorubicin. The aim of this retrospective study was to estimate the incidence of late cardiotoxicity, to better define cardiac disease characteristics, and to analyze risk factors for development of late cardiotoxicity.
Patient Eligibility and Study Design All patients with a diagnosis of non-Hodgkin's lymphoma or Hodgkin's lymphoma treated at the Hematology Department of Centre Hospitalier Lyon-Sud (Pierre Bénite, France) were eligible if they had received a cumulative dose of doxorubicin more than 250 mg/m2 and if they had received their last administration at least 5 years previously. Patients had to be in complete remission after one or several lines of chemotherapy or at least have stable disease at the time of cardiac evaluation. Patients were excluded from the study if they had active cardiac disease such as CHF or severe arrhythmia before treatment with doxorubicin. All patients had a cardiac evaluation before the onset of chemotherapy (some with echocardiogram), which showed no evidence of cardiomyopathy. After eligibility was determined, informed consent was obtained from all patients. Cardiac evaluation consisted of physical examination, ECG, chest x-ray, and echocardiography.
Echocardiographic Evaluation
Characterization of Clinical Anthracycline-Induced Cardiomyopathy
Characterization of Subclinical Anthracycline-Induced Cardiomyopathy Criteria of subclinical cardiomyopathy include absence of clinical symptoms related to CHF but presence of echocardiographic indexes of cardiomyopathy. In patients previously treated with doxorubicin, various interesting criteria of left ventricular dysfunction have been described. In this study, left ventricular dysfunction was diagnosed if FS was below 25% (without other cardiomyopathy such as valvulopathy or myocardial infarction). This represents the main criterion to define the state of subclinical cardiomyopathy (Table 1). Alternative criteria of subclinical cardiomyopathy were decrease of FS, decrease of ejection fraction, or abnormal wall motion. The presence of at least two of these abnormalities without clinical features of CHF also defined alternative criteria of subclinical cardiomyopathy (Table 1).
Statistical Analysis Fourteen variables were studied for their role in development of doxorubicin cardiomyopathy: cumulative doses of doxorubicin more than 300 mg/m2, age, sex (male), relapse, autologous stem-cell transplantation (ASCT) in first-line therapy or during relapse, radiotherapy (mediastinal radiation or total-body irradiation [TBI]), high-dose cyclophosphamide (> 4,800 mg/m2, which corresponds to four cycles of ACVBP or six cycles of CHOP), treatment with another anthracycline or highest cumulative doses of doxorubicin, hypertension, diabetes, dyslipidemia, being overweight, smoking history, and familial history of cardiac disease.
FS more than or less than 25% and presence or absence of alternative criteria of cardiomyopathy were compared according to the presence or absence of each potential risk factor in univariate analysis by Pearson's Multivariate analysis of the potential effect of all the previously described risk factors on the development of cardiotoxicity (FS with a threshold of 25% or alternative criteria of doxorubicin-induced cardiomyopathy) was made using logistic regression. All tests were two-tailed with a significance when P < .05. All statistics were made using BDMP (BMDP Statistical Software; Statistical Solutions, Saugus, MA) and S-Plus (Math Soft, Statistical Sciences, Seattle, WA).
Population Studied Of 244 patients treated in the department who met the eligibility criteria for enrollment, 103 patients were excluded because of refusal or absence of response after request (73 patients), 22 were lost to follow-up, and eight patients died as a result of noncardiac diseases. No patient presented with anemia or hyperthyroidism at the time of cardiac evaluation. All patients had received their last dose of doxorubicin more than 5 years ago. Characteristics of the 141 patients evaluated are listed in Table 2. Most of patients had non-Hodgkin's lymphoma (128 of 141 patients), with a predominance of diffuse large-cell and follicular lymphomas, and only 13 patients had Hodgkin's lymphoma. The median age at the beginning of chemotherapy with doxorubicin was 47 years (range, 15 to 69 years). The median age at the evaluation by echocardiography was 54 years (range, 26 to 80 years). The median time between diagnosis and cardiac evaluation was 8 years.
At the beginning of chemotherapy, 25 patients (18%) had hypertension but no patient had previous history of CHF, angina, ischemic cardiac disease, or cardiomyopathy. No significant electrocardiographic abnormality was found at the beginning of doxorubicin treatment. Anthracycline regimens consisted of only doxorubicin in most patients (118 of 141 patients). The total dose of doxorubicin ranged from 250 to 550 mg/m2. Twenty-three patients received doxorubicin and epirubicin or mitoxantrone because of relapse of their primary disease. Patients cannot be divided according to the cumulative doses because more than 70% of them received a total doxorubicin dose of 300 mg/m2, only 8.5% patients received a cumulative dose less than 300 mg/m2, and 21% received a dose more than 300 mg/m2 but less than 550 mg/m2 (Table 2). At the time of evaluation, only few patients had poor performance status (9%). Relapse occurred in 55 patients and 35 of them received myeloablative treatment with ASCT. Other previously described potential risk factors were represented by localized mediastinal radiotherapy or TBI (30 of 141) and high-dose cyclophosphamide more than 4,800 mg/m2 (54 of 141). Twenty patients received interferon alfa therapy. Cardiovascular risk factors were recorded in all patients: overweight (defined as body mass index > 30 kg/m2), smoking habit (> 20 cigarettes a day for a period up to 20 years), hypercholesterolemia (> 6.2 mmol/L), family history of cardiac disease (coronary disease or cardiomyopathy), and diabetes were found in three, 18, 18, 13, and 10 patients, respectively (Table 2).
Incidence of Late Cardiac Toxicity Subclinical cardiomyopathy. Doxorubicin-induced left ventricular dysfunction with decreased FS (< 25%) was found in 39 of 141 patients (27.6%; Table 2). Cardiomyopathy was the direct consequence of anthracycline treatment and no other etiology such as hypertensive or ischemic cardiomyopathy was demonstrated. None of these patients had electrocardiography changes compatible with doxorubicin-induced cardiomyopathy (flattening of the T wave, prolongation of the QT interval, and loss of voltage of the R wave) or any clinical features of cardiomyopathy. When patients had pretreatment echocardiograms, they had been performed by different cardiologists and consequently the only parameter allowing any comparison with echocardiograms at the time of cardiac evaluation was FS. Comparison of mean initial FS was similar between patients who later showed or did not show characteristics of cardiomyopathy. Mean decrease rate of FS was higher in the group of patients with criteria of subclinical cardiomyopathy (41% for the 17 patients evaluated twice) than in patients without criteria of subclinical cardiomyopathy (12% for the 37 patients evaluated twice; Student's t test, P < .0001). With the alternative criteria of cardiomyopathy, we found that 29 patients had two of these criteria, including global hypokinesis, decreased FS (median 21%; range, 11% to 32%), and decreased LVEF (median 47%; range, 30% to 58%) without clinical signs of cardiomyopathy. Among them, 23 have a significant reduction of FS (below 25%) and 82% of them had a concomitant decreased LVEF. A strong association was found between presence of cardiomyopathy with these criteria and major reduction of FS.
Analysis of Risk Factors
Multivariate analysis showed a significant correlation between older age, male sex, radiotherapy, higher cumulative doses of doxorubicin, or association with doxorubicin analogs and left ventricular dysfunction (whatever criteria of cardiomyopathy were retained; Table 4). Among patients who received radiotherapy, there were too few patients who were treated by radiotherapy to the mediastinum to distinguish them statistically from those treated with TBI. In contrast, left ventricular dysfunction was not influenced by other potential risk factors (relapse, ASCT, cumulative doses of doxorubicin > 300 mg/m2, and higher doses of cyclophosphamide). Cardiovascular risk factors (hypertension, diabetes, hypercholesterolemia, being overweight, familial history of cardiac disease, and smoking habit) were analyzed, and only being overweight was significantly associated with decreased FS (P < .05).
Doxorubicin is considered a major drug for treatment of lymphoma but it can induce cardiac morbidity and mortality, even though left ventricular function in long-term survivors previously treated with intermediate doses of doxorubicin is poorly documented. Late anthracycline-induced cardiac dysfunctions may begin with CHF, which usually appears within 1 year to decades after chemotherapy.3,4 Occurrence of CHF is highly related to cumulative doses of anthracyclines, and developed in approximatively 30% of patients who received more than 550 mg/m2 of doxorubicin and decreased to 4% of patients who received a lower cumulative dose (500 to 550 mg/m2).1,3 For patients who received lower doses of doxorubicin, only a few CHFs occurred, but occult ventricular dysfunctions in asymptomatic patients have been described.9,11,12 This was confirmed by endomyocardial biopsy, which showed typical histopathologic changes at lower doses of doxorubicin (< 300 mg/m2).13 Most studies performed to estimate incidence of anthracycline-induced cardiotoxicity and the role of risk factors were realized in children2,3,12 and in adults observed for acute myelogenous leukemia7 or breast cancer.5,6 In adults, few studies have been performed in Hodgkin's lymphoma8,14 or non-Hodgkin's lymphoma.9,15,16 Our study was performed to evaluate incidence and features of asymptomatic cardiomyopathy in adults who underwent successful treatments for lymphoma and who received a cumulative dose of doxorubicin less than 550 mg/m2, which represents the a priori limiting dose for inducing cardiotoxicity. Echocardiography is the most widely used noninvasive evaluation of cardiac function and has been used largely to study anthracycline-induced cardiotoxicity, particularly in children.17 Primary parameters of systolic function are represented by measurements of LVEF and FS; however, measurement of LVEF is limited by a low sensitivity. Evaluation of FS has a higher sensitivity and specificity18,19 and, thereafter, had been chosen as the best index to assess systolic function after anthracycline treatment in routine monitoring.18 In children, FS below 28% or a decrease of 10 percentile units compared with the initial values are criteria of systolic dysfunction.20,21 Because few studies were performed in adults, specific criteria of anthracycline cardiomyopathy are not defined precisely. According to previous studies in asymptomatic left ventricular systolic dysfunction performed apart from the context of chemotherapy,22 we had defined cardiomyopathy as a decrease of FS (with a threshold below 25%) and to increase specificity while preserving sensibility, we had studied features of patients with decreased LVEF (below 50%), decreased FS (below 28%), or abnormal wall motion. Among the 141 assessable patients, 39 patients (27.6%) demonstrated decreased FS, whereas 29 patients (20,5%) demonstrated the presence of subclinical cardiomyopathy with the alternative criteria previously described; only one patient developed clinical symptoms of doxorubicin-induced CHF. Most of the patients with cardiomyopathy (respectively, 31 of 39 and 22 of 29 according to the criteria retained) had previously received a total dose of doxorubicin less than 300 mg/m2, which represents the usual treatment for lymphoma. Comparable rates of depressed contractility had been described in adult long-term survivors (range, 14% to 37%) with median cumulative doses of doxorubicin ranging from 200 to 350 mg/m2.8,9,16 In pediatric series of long-term survivors previously treated with comparable cumulative doses of doxorubicin, the overall incidence of systolic abnormalities was similar.2,21,23 Even if no cardiac treatment is required for our asymptomatic patients, an appropriate cardiac follow-up is recommended because evolution of these complications is not known.24 In our series, older age appears to be a risk factor for development of doxorubicin-induced cardiomyopathy, which was confirmed by previous studies.4,9,11 Because median age of our patients at the time of diagnosis was younger than in a large series of lymphoma patients, we have analyzed age as a continuous variable in multivariable analysis. Male sex, which is a risk factor for cardiac disease in general and without the context of neoplasia, also predicts left ventricular dysfunction in our series. The highest cumulative doses of doxorubicin and supplementary chemotherapy with other anthracyclines (mitoxantrone or epirubicin) were considered as a risk factor for developing subclinical cardiomyopathy. Because only 20 patients received total cumulative doses of doxorubicin more than 300 mg/m2, we pooled the patients with highest cumulative doses of doxorubicin and those who received mitoxantrone or epirubicin. In this setting, this parameter was associated with risk of cardiomyopathy. Total cumulative dosage has been found regularly as the major risk factor for development of cardiac dysfunction in previous studies in adults.4,7,9 Few studies reported abnormalities in left ventricular diastolic function15 or in systolic function8 independently of the cumulative doses of anthracycline. Previous radiotherapy to the mediastinum has been described as a risk factor.11,25 In our series, only 13 patients were observed for Hodgkin's lymphoma and only eight received mediastinal radiotherapy. Consequently, there were too few patients for a specific statistical analysis. TBI has also been suspected to induce cardiomyopathy.26 Hypertension, diabetes, and previous history of coronary disease are cardiovascular risk factors but also risk factors for developing CHF.27 Smoking habit is associating with chronotropic incompetence but not directly with CHF. In our series, being overweight was the only cardiovascular risk factor associated with subclinical cardiomyopathy (Table 4). Despite the lower age at diagnosis, the characteristics of our patients regarding histology, treatment, or cumulative doses of anthracycline reflect those of general populations treated for lymphoma. Studies have been performed to decrease or prevent anthracycline-induced cardiotoxicity. For the usual treatment, chemotherapy delivers a cumulative dose of doxorubicin of 300 mg/m2, which corresponds to four cycles of ACVBP (doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone); six cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone); or six cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine). Continuous infusion of doxorubicin was associated with decreased cardiac injury28 but this schedule is used mostly during phase II trials in patients with refractory lymphoma.29 Doxorubicin induces cardiomyopathy by binding with iron to form an intracellular complex catalyzing the generation of highly reactive free radicals, which attack membrane lipids and cause oxidative damage to the myocytes. Dexrazoxane chelates intracellular iron, which may decrease doxorubicin-induced free radical generation and the incidence of cardiotoxicity.30 Recently, the American Society of Clinical Oncology has edited recommendations concerning the use of dexrazoxane in malignancy31: dexrazoxane can be considered for patients with breast cancer who received more than 300 mg/m2 of doxorubicin and who may benefit from continuing doxorubicin-based therapy, and if they have various risk factors including age older than 65 years, hypertension, history of myocardial infarction, or previous mediastinal radiotherapy. Because of the low incidence of CHF observed in our series after the same median dose of doxorubicin, we were unable to suggest recommendations for using dexrazoxane in lymphoma treatment.
The authors indicated no potential conflicts of interest.
Supported in part by an unrestricted grant from Chiron. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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3. Steinherz LJ, Steinherz PG, Tan CTC: Cardiac toxicity 4 to 20 years after completing anthracycline therapy. JAMA 266:1672-1677, 1991 4. Von Hoff DD, Layard MW, Basa P, et al: Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 91:710-717, 1979 5. Ryberg M, Nielsen D, Skovsgaard T, et al: Epirubicin cardiotoxicity: An analysis of 469 patients with metastatic breast cancer. J Clin Oncol 16:3502-3508, 1998[Abstract] 6. Haq MM, Legha SS, Choksi J, et al: Doxorubicin-induced congestive heart failure in adults. Cancer 56:1361-1365, 1985[CrossRef][Medline] 7. Anderlini P, Benjamin RS, Wong FC, et al: Idarubicin cardiotoxicity: A retrospective study in acute myeloid leukemia and myelodysplasia. J Clin Oncol 13:2827-2834, 1995[Abstract] 8. Aviles A, Arevila A, Diaz Maqueo JC, et al: Late cardiac toxicity of doxorubicin, epirubicin, and mitoxantrone therapy for Hodgkin's disease in adults. Leuk Lymphoma 11:275-279, 1993[Medline]
9. Limat S, Demesmay K, Voillat L, et al: Early cardiotoxicity of the CHOP regimen in aggressive non-Hodgkin's lymphoma. Ann Oncol 14:277-281, 2003 10. Ehler D, Carney DK, Dempsey AL, et al: Guidelines for cardiac sonographer education: Recommendations of the American Society of Echocardiography Sonographer Training and Education Committee. J Am Soc Echocardiogr 14:77-84, 2001[CrossRef][Medline] 11. Bristow MR, Mason JW, Billingham ME, et al: Doxorubicin cardiomyopathy: Evaluation by phonocardiography, endomyocardial biopsy and cardiac catheterization. Ann Intern Med 88:168-175, 1978
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13. Friedman MA, Bozdech MJ, Billingham ME, et al: Doxorubicin cardiotoxicity: Serial endomyocardial biopsies and systolic time intervals. JAMA 240:1603-1606, 1978 14. LaMonte CS, Yeh SD, Straus DJ, et al: Long-term follow-up of cardiac function in patients with Hodgkin's treated with mediastinal irradiation and combination chemotherapy including doxorubicin. Cancer Treat Rep 70:439-444, 1986[Medline] 15. Marchandise B, Schroeder E, Bosly A, et al: Early detection of doxorubicin cardiotoxicity: Interest of Doppler echocardiographics analysis of left ventricular filling dynamics. Am Heart J 118:92-98, 1989[CrossRef][Medline] 16. Haddy TB, Adde MA, McCalla J, et al: Late effects in long-term survivors of high-grade non-Hodgkin's lymphomas. J Clin Oncol 16:2070-2079, 1998[Abstract] 17. Steinhertz LJ, Wexler LH: Prevention of anthracycline cardiomyopathy. Prog Pediatr Cardiol 8:97-108, 1998[CrossRef]
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29. Lichtman SM, Niedzwiecki D, Barcos M, et al: Phase II study of infusional chemotherapy with doxorubicin, vincristine and etoposide plus cyclophosphamide and prednisone (I-CHOPE) in resistant diffuse aggressive non-Hodgkin's lymphoma: GALGB 9255—Cancer and Leukemia Group B. Ann Oncol 11:1141-1146, 2000
30. Swain SM, Whaley FS, Gerber MC, et al: Cardioprotection with dexrazoxane for doxorubicin containing therapy in advanced breast cancer. J Clin Oncol 15:1318-1332, 1997
31. Hensley ML, Schuchter LM, Lindley C, et al: American Society of Clinical Oncology clinical practice guidelines for the use of chemotherapy and radiotherapy protectants. J Clin Oncol 17:3333-3355, 1999 Submitted June 9, 2003; accepted February 25, 2004.
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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. 
