Original Article
Late Cardiac Effects of Doxorubicin Therapy for Acute Lymphoblastic Leukemia in Childhood
N Engl J Med 1991; 324:808-815March 21, 1991
- Abstract
- Abstract
Background.
Cardiotoxicity is a recognized complication of doxorubicin therapy, but the long-term effects of doxorubicin are not well documented. We therefore assessed the cardiac status of 115 children who had been treated for acute lymphoblastic leukemia with doxorubicin 1 to 15 years earlier in whom the disease was in continuous remission.
Methods.
Eighteen patients received one dose of doxorubicin (45 mg per square meter of body-surface area), and 97 received multiple doses totaling 228 to 550 mg per square meter (median, 360). The median interval between the end of treatment and the cardiac evaluation was 6.4 years. Our evaluation consisted of a history, 24-hour ambulatory electrocardiographic recording, exercise testing, and echocardiography.
Results.
Fifty-seven percent of the patients had abnormalities of left ventricular afterload (measured as end-systolic wall stress) or contractility (measured as the stress—velocity index). The cumulative dose of doxorubicin was the most significant predictor of abnormal cardiac function (P<0.002). Seventeen percent of patients who received one dose of doxorubicin had slightly elevated age-adjusted afterload, and none had decreased contractility. In contrast, 65 percent of patients who received at least 228 mg of doxorubicin per square meter had increased afterload (59 percent of patients), decreased contractility (23 percent), or both. Increased afterload was due to reduced ventricular wall thickness, not to hypertension or ventricular dilatation. In multivariate analyses restricted to patients who received at least 228 mg of doxorubicin per square meter, the only significant predictive factors were a higher cumulative dose (P = 0.01), which predicted decreased contractility, and an age of less than four years at treatment (P = 0.003), which predicted increased afterload. Afterload increased progressively in 24 of 34 patients evaluated serially (71 percent). Reported symptoms correlated poorly with indexes of exercise tolerance or ventricular function. Eleven patients had congestive heart failure within one year of treatment with doxorubicin; five of them had recurrent heart failure 3.7 to 10.3 years after completing doxorubicin treatment, and two required heart transplantation. No patient had late heart failure as a new event.
Conclusions.
Doxorubicin therapy in childhood impairs myocardial growth in a dose-related fashion and results in a progressive increase in left ventricular afterload, sometimes accompanied by reduced contractility. We hypothesize that the loss of myocytes during doxorubicin therapy in childhood might result in inadequate left ventricular mass and clinically important heart disease in later years. (N Engl J Med 1991; 324:808–15.)
Article Activity
- Article
The anthracyclines doxorubicin and daunorubicin are effective antileukemic agents used widely in chemotherapeutic regimens in children for the past 20 years.1 , 2 Dose-related cardiotoxicity is commonly recognized,3 4 5 6 7 8 9 but the late effects on the heart (those occurring more than one year after the administration of doxorubicin) are not known. We therefore evaluated cardiac status in children 1 to 15 years after the successful treatment of acute lymphoblastic leukemia with chemotherapeutic regimens that included doxorubicin.
Methods
Subjects
All children given a diagnosis of acute lymphoblastic leukemia and treated10 11 12 13 14 15 at the Dana–Farber Cancer Institute and Children's Hospital in Boston (Table 1Table 1
Study Population.*) who were in continuous remission and had received their last dose of anthracycline at least one year previously were eligible for the study. The children had been treated according to a number of different protocols, all of which included doxorubicin. In March 1987, all eligible patients were asked to participate in a study of the late cardiac effects of anthracycline therapy. The evaluation consisted of a questionnaire, a 24-hour ambulatory electrocardiographic recording (with a Holter monitor), an exercise test, and echocardiography.The questionnaire was designed to elicit a history of symptoms referable to the cardiovascular system and to assess the patient's and the family's perception of the patient's health. A 24-hour electrocardiographic record was made with a Holter monitor and reviewed for abnormalities of heart rate16 and rhythm. A maximal symptom-limited exercise-tolerance test was performed on either a bicycle ergometer or a treadmill.17
The echocardiographic evaluation consisted of two-dimensional echocardiography and Doppler evaluation with analyses of the stress—velocity and stress—shortening indexes.18 Two-dimensional echocardiography and Doppler cardiography were performed in all patients for the qualitative assessment of left ventricular regional-wall motion, the presence of intracardiac thrombus, and evidence of structural or valvular heart disease. An M-mode echocardiogram directed by two-dimensional echocardiography was recorded simultaneously with a phonocardiogram showing the aortic component of the second heart sound, an indirect carotid or axillary pulse tracing, and an electrocardiogram. Blood pressure was measured with a Dinamap automated vital-signs monitor (Critikon). The M-mode echocardiogram, phonocardiogram, and pulse tracing were analyzed by computer as described previously.18
Previous and subsequent echocardiograms were analyzed in an identical fashion. Analysis was restricted to size, wall thickness, and measurements of cardiac function when data on blood pressure and pulse were not available.
The normal control group for comparison of the echocardiographic data consisted of 370 normal subjects (age, 1 month to 40 years). Data from this normal control group showed that ventricular size and wall thickness were closely related to body size and that adjustment for body-surface area eliminated size-related changes. In contrast, afterload in the control group was more closely related to age. Therefore, values adjusted for body-surface area were used for size and wall thickness, and age-adjusted values were used for wall stress. The normal ranges for afterload, indexes of cardiac function, and the relation between afterload and contractility were determined in these subjects and used for statistical comparisons with the values in the study group.
Statistical Analysis
All analyses were performed both for the entire patient group and for the subgroup of patients who received more than one dose of doxorubicin. Exercise tolerance was expressed as a percentage of normal, according to published standards adjusted for age and sex (for the treadmill) or body-surface area (for the bicycle ergometer).19 , 20 Patients with exercise-tolerance values more than 2 SD below the standards were considered to have reduced exercise tolerance. The relation among reported symptoms, exercise capacity, Holter-monitor findings, and the results of studies of left ventricular function were evaluated with Fisher's exact test. The results of left ventricular-function studies were expressed as means ±SD. Left ventricular size, wall thickness, wall stress, and function were compared with values for the normal controls with use of a two-sample t-test. Paired t-tests were used to evaluate changes in cardiac function over time. The relation between end-systolic wall stress and the velocity of circumferential fiber shortening, adjusted for heart rate,18 was calculated for each subject in relation to the normal range and expressed as the normal deviate (Z score). For each patient, left ventricular contractility was considered to be abnormal if the relation between end-systolic wall stress and the velocity of shortening was less than –2 (i.e., a value for velocity more than 2 SD below the mean for that level of wall stress). Similarly, for each subject, increased afterload was defined as a value for end-systolic wall stress more than 2 SD above the mean for age in the normal population.
The potential effects of sex, age at diagnosis, total dose of doxorubicin, age at evaluation, and length of time from the completion of therapy to evaluation on the incidence of cardiac abnormalities were evaluated with use of logistic-regression models.21 All P values are two-sided.
Results
Study Population
Of 460 potentially eligible patients, 179 patients were excluded because their disease was not in remission (20 patients), they had relapsed (135 patients), or they had died in remission (24 patients). Of the 281 remaining patients eligible for cardiac evaluation (i.e., patients in continuous complete remission from acute lymphoblastic leukemia who had had their last doxorubicin treatment at least one year earlier), 115 (41 percent) underwent noninvasive cardiac testing (Table 1 ) and are the subjects of this report. All received doxorubicin as part of combination chemotherapy; other chemotherapeutic agents used included vincristine, methotrexate, prednisone, mercaptopurine, and L-asparaginase from Escherichia coli. No patient received the potentially cardiotoxic agent amsacrine, or cyclophosphamide in a cardiotoxic dosage. None underwent mediastinal or spinal irradiation. At the time of the cardiac evaluation, no patient had a hematocrit value lower than 30 percent, had known hypothyroidism, or was receiving steroids or cardiotonic therapy.
The study population consisted of 58 boys and 57 girls. Their mean age at the time of the study was 13.6 years (median, 12.6; range, 3.9 to 31.7). The age at diagnosis ranged from 7 months to 19.1 years (mean, 6.2 years; median, 4.8). The length of time since the completion of therapy was 1 to 15 years (median, 6.4). The total dose of doxorubicin ranged from 45 to 550 mg per square meter of body-surface area; for purposes of this study, the patients were divided according to the cumulative-dose categories 45 mg per square meter (n = 18), 228 to 360 mg per square meter (n = 52), 361 to 475 mg per square meter (n = 42), and more than 500 mg per square meter (n = 3). No patient had a total dose of doxorubicin between 45 and 228 mg per square meter. For the multiple-dose protocols, the rate of administration ranged from 30 to 60 mg per square meter every three weeks (Table 1).
To evaluate possible bias in the selection of patients, we examined the clinical characteristics of the 166 patients who met the study's entrance criteria but who were not enrolled. Specifically, we compared the study group and the group of patients who did not participate with respect to age at diagnosis, sex, specific treatment protocol, total dose of doxorubicin, and length of time since the completion of doxorubicin therapy. We found no significant differences in any of these variables (data not shown).
Acute Doxorubicin Cardiotoxicity
Acute congestive heart failure (defined as failure beginning within one year of the completion of doxorubicin therapy) occurred in 11 of the 115 patients (10 percent). All 11 patients improved with anticongestive therapy, which was eventually discontinued in all cases. Five of the 11 patients subsequently had recurrent congestive heart failure 3.7 to 10.3 years after completing doxorubicin treatment. Two of these five patients underwent cardiac transplantation.
Echocardiography
An echocardiogram was obtained specifically for this study in all 115 patients. Regional wall motion appeared normal in all the study patients. No intracardiac mass (thrombus or vegetation) or structural abnormality was detected in any of the patients.
Left Ventricular Size and Wall Thickness
The mean left ventricular end-diastolic size adjusted for body-surface area for all 115 patients was 4.47±0.58 cm, similar to that in normal controls (4.52±0.29 cm, P = 0.376). In the subset of 97 patients who received more than 45 mg of doxorubicin per square meter, this value was also not significantly different from normal (4.55±0.58 cm). Left ventricular posterior-wall thickness adjusted for body-surface area was lower in recipients of doxorubicin than in normal controls (0.68±0.20 vs. 0.81 ±0.09 cm, P<0.0001). In patients in the higher-dose group, this value was also significantly lower than normal (0.66±0.18 cm).
Left Ventricular Function, Afterload, and Contractility
We used analysis of covariance to compare fractional shortening, velocity of shortening, end-systolic wall stress, and posterior-wall thickness (adjusted for age or body-surface area) in patients who received a single dose of 45 mg of doxorubicin per square meter with the values in those who received a cumulative dose of more than 227 mg per square meter and in the normal control group. For each measure, the group that received the higher cumulative dose had significantly impaired function (P<0.0001), whereas the group that received the single dose was similar to the normal controls.
Specifically, fractional shortening was reduced from normal values in both the overall patient group (30.2±5.7 percent; normal, 33.5±2.5 percent; P<0.0001) and in the subgroup of patients who received more than 45 mg of doxorubicin per square meter (29.1±5.3 percent, P<0.0001). The velocity of shortening was similarly reduced in all patients (0.96±0.18 circumferences per second; normal, 1.05±0.08; P<0.0001) and in the group that received more than 45 mg of doxorubicin per square meter (0.93±0.17 circumferences per second, P<0.0001). Left ventricular end-systolic wall stress was significantly higher in the study group (P<0.0001), ranging from 21 to 129 g per square centimeter (mean, 64.0±22.4; normal, 47.5±7.0), and was even higher in the subgroup that received more than 45 mg of doxorubicin per square meter (67.6±22.2 g per square centimeter, P<0.0001). Wall stress is inversely related to wall thickness, and directly related to left ventricular size and intracavitary pressure. In these patients, size and pressure were normal, and increased wall stress was attributable exclusively to reduced wall thickness.
Contractility, as assessed by the relation between afterload and the velocity of shortening, was not impaired in the study group overall. When the relations among left ventricular performance, afterload, and contractility were examined, it was apparent that abnormal contractility was the primary or only cause of reduced systolic performance in only a small proportion of patients. To facilitate further analysis, the patients were classified according to afterload and contractility (Table 2Table 2
Echocardiographic Findings in the Patients, According to Various Characteristics.). Forty-nine patients (43 percent) had normal left ventricular contractility and afterload (group 1 in Fig. 1Figure 1
Relation of Rate-Corrected Velocity of Circumferential Fiber Shortening (VCFc, in Circumferences per Second) to End-Systolic Wall Stress (Afterload) for 115 Study Patients at Follow-up at Least One Year after the Completion of Doxorubicin Therapy.). Group 1 included 15 patients who had received only a single dose (45 mg per square meter) of doxorubicin. Left ventricular contractility was reduced in 22 patients (19 percent) (groups 3 and 4 in Fig. 1). End-systolic stress was elevated in 60 patients (52 percent) (groups 2 and 4 in Fig. 1). Contractility was normal in 44 of the 60 patients with increased afterload (high end-systolic stress) (group 2 in Fig. 1) and depressed in the other 16 patients (group 4 in Fig. 1). No relation was found between abnormalities of contractility, afterload, or both and reported symptoms, an abnormal result on exercise stress testing, or an abnormal Holter-monitor recording (Table 3Table 3
Relation of Left Ventricular Function to Reported Symptoms, Results of Exercise Testing, and Results of Holter Monitoring.*).The left ventricular shortening fraction was normal or increased in 83 patients and reduced (more than 2 SD below the mean value for normal controls) in 32 others. The shortening fraction was a poor index of left ventricular contractility at the late evaluation. Of the 32 patients with a reduced shortening fraction, only 19 (59 percent) had decreased contractility. In patients with a reduced shortening fraction but normal contractility, excess afterload fully accounted for the observed reduction in systolic performance.
Serial Echocardiographic Data
A total of 629 echocardiograms, including 220 studies with stress—velocity analysis of cardiac contractility and loading conditions, were available for the 115 patients. Echocardiography was performed before the initiation of doxorubicin therapy in 63 patients.
The mean left ventricular end-diastolic size, adjusted for body-surface area, was within the normal range in all studies, both before and after treatment, for all four patient groups, regardless of ventricular function or loading conditions. The mean left ventricular posterior-wall thickness, adjusted for body-surface area, was normal before doxorubicin therapy in the 63 patients for whom such measurements were available (Fig. 2Figure 2
Relation of Left Ventricular Posterior-Wall Thickness (End-Diastole) to Body-Surface Area in 63 Patients.). As Figure 2 shows, during the period of follow-up, left ventricular posterior-wall thickness increased in proportion to body-surface area in the subjects in whom afterload remained normal (groups 1 and 3). In contrast, the patients who had excess afterload at the time of the evaluation had an increase in wall thickness that was less than would be expected for somatic growth (groups 2 and 4). For those in whom serial values for afterload were available, there was a significant increase in age-adjusted end-systolic stress (afterload) during the follow-up interval (median, 2.9 years) from 52.6± 19.0 g per square centimeter to 69.2±30.8 g per square centimeter (P = 0.005); 24 of 34 patients (71 percent) had higher values on the last study. The relation of end-systolic wall stress to the velocity of circumferential fiber shortening (contractility) was not found to change significantly during the same time interval (-0.91 ±3.0 SD on the first echocardiogram vs. -0.22±2.33 SD on the most recent).Risk Factors
Table 2 shows the relation between potential risk factors and the incidence of cardiac abnormalities (increased afterload or decreased contractility). In univariate logistic-regression analyses including all 115 patients, the following were found to be significant risk factors for the presence of any abnormality: a higher cumulative dose of doxorubicin (P = 0.002), a longer time between the completion of doxorubicin therapy and the study echocardiogram (P = 0.006), and an age of less than four years at the time of treatment (P = 0.04). All three were significant predictors of increased afterload (P<0.01), whereas the cumulative dose of doxorubicin and the length of time since the end of treatment were significant predictors of decreased contractility (P<0.01). In multivariate analyses, the cumulative dose of doxorubicin was a risk factor for both increased afterload and decreased contractility (P<0.003), and age at the time of treatment was a risk factor for increased afterload (P = 0.003). The length of time between the completion of doxorubicin therapy and the study echocardiogram was not a significant factor in any logistic model that included the cumulative dose of doxorubicin. In multivariate models restricted to patients who received at least 228 mg of doxorubicin per square meter, the only significant factors were a higher cumulative dose for predicting decreased contractility (P = 0.01), and an age of less than four years at the time of treatment for predicting increased afterload (P = 0.003).
Ventricular Function at the Completion of Therapy
Echocardiograms were obtained within one year of the completion of doxorubicin therapy in 57 patients, all of whom received more than 45 mg of doxorubicin per square meter. Twenty-seven were found to have a reduced shortening fraction (<28 percent) early after treatment (mean, 20.28±5.55 percent), and 30 had normal fractional shortening (mean, 31.8±7.28 percent). Abnormal fractional shortening at the completion of therapy was 70 percent accurate in predicting the presence of either abnormal contractility or abnormal afterload at follow-up (Table 2) (sensitivity = 64 percent, specificity = 81 percent) and was slightly more accurate in predicting abnormalities of contractility (accuracy = 74 percent, sensitivity = 88 percent, specificity = 68 percent) than abnormalities of afterload (accuracy = 67 percent, sensitivity = 63 percent, specificity = 72 percent).
Questionnaire
Completed questionnaires were available for 91 patients. Thirty-six patients (40 percent) reported symptoms referable to the cardiovascular system, including easy fatigability (16 patients), chest pain (10), shortness of breath (9), palpitations (6), or syncope (4). The relation between reports of easy fatigability or shortness of breath and reduced exercise tolerance on stress testing was not statistically significant (P = 0.26).
Holter-Monitor Recordings
Twenty-four-hour Holter-monitor recordings were available for 89 patients. Four recordings demonstrated ventricular tachycardia. One patient had syncope and two had palpitations at the time ventricular tachycardia was recorded. All four patients had severe ventricular dysfunction, and congestive heart failure developed in all four within the year after the observation of high-grade ventricular ectopy. Abnormalities on the Holter-monitor recordings were not related to perceived symptoms overall (P = 0.13), nor did they specifically relate to a history of palpitations or syncope.
Exercise Testing
Exercise tests were performed by 96 patients, of whom 41 (43 percent) had abnormalities: 33 had abnormal duration of exercise; 8 excess tachycardia; 2 exercise-induced hypotension; 3 atrial ectopy; 12 ventricular ectopy (Lown grade 1 through 4A22); 9 abnormal ST-segment and T-wave changes with exercise23; and 6 symptoms of nausea, excess dyspnea, or leg pain during exercise. Eighty-one exercise tests were completed by patients who had received at least 228 mg of doxorubicin per square meter; 48 percent had abnormalities similar in distribution to those noted for the entire group of patients. When the patients' actual exercise duration was divided by the expected duration, the median value was 80 percent of normal. The exercise-duration ratio was not significantly different for subjects with and without abnormal contractility, afterload, or both (P = 0.38).
Myocardial Biopsy
We reviewed our experience with cardiac biopsy in survivors of childhood cancer and found eight patients who had undergone myocardial biopsy. Six were treated for leukemia (3 of them were among the 115 patients included in this study), and 2 were treated for sarcoma. All eight had marked elevations in left ventricular wall stress (mean, 124±28 g per square centimeter; range, 62 to 181) with reduced systolic performance (fractional shortening, 13.06±3.56 percent) and reduced contractility. Six had clinical congestive heart failure at the time of the biopsy, congestive heart failure developed in one 10 months after the biopsy, and one had symptomatic ventricular tachycardia on Holter monitoring. These patients had completed doxorubicin therapy 9.5 to 14 years previously. Marked hypertrophy of myocytes with sarcoplasmic and nuclear enlargement was noted in all the biopsy specimens.24
Discussion
Echocardiographically detectable abnormalities of left ventricular afterload and contractility were common 1 to 15 years after the treatment of acute lymphoblastic leukemia in childhood with chemotherapeutic regimens that included doxorubicin. Reduced contractility and, especially, increased afterload progressed with time and were related to the cumulative dose of doxorubicin, the age of the patient at the time of treatment, and the length of follow-up. Patients were usually asymptomatic, and symptoms correlated poorly with echocardiographic indexes and the duration of exercise. Reduced exercise tolerance was common, although it did not predict abnormalities of ventricular function. Serious disturbances of rhythm were uncommon and were found only in patients with severe ventricular dysfunction.
Increased afterload was the most common abnormality in our patients and those of others.25 End-systolic wall stress (afterload) is a function of blood pressure, the size of the ventricular cavity, and wall thickness.18 Blood pressure and the size of the cavity were normal in our patients, and the excess afterload was attributable exclusively to reduced left ventricular wall thickness. Serial studies revealed an increasing disproportion between wall thickness and ventricular size with time. This progression was most striking in patients who had substantial somatic growth.26 The consequences of the prolonged elevation of left ventricular wall stress are uncertain, but excess afterload appears to contribute to the eventual myocardial deterioration associated with left ventricular volume- and pressure-overload lesions.27
Reduced contractility was less common than increased afterload. The majority of patients with reductions in contractility in whom earlier measurements of ventricular function were available had echocardiographic evidence of acute doxorubicin toxicity. These patients appeared to have had severe injury to the myocardium that impaired both the growth potential and the contractile function of the remaining myocardial cells. The data were insufficient, however, to determine whether reduced contractility was a residuum of acute doxorubicin toxicity, the result of prolonged elevation in afterload, or the combined result of both factors.
The three factors that appeared to influence the frequency of cardiac abnormalities years after doxorubicin therapy (cumulative dose, age at treatment, and length of follow-up) were interrelated. The patients who were followed up for the longest time were treated according to earlier protocols, which used the highest cumulative dose of doxorubicin. In addition, more children under four years of age received doxorubicin at the highest dose rates and the highest cumulative doses. Nevertheless, multivariate analyses clearly demonstrated that the cumulative dose of doxorubicin was the most significant predictive factor for both increased afterload and decreased contractility; an age below four years at treatment was also a significant independent predictive factor for increased afterload.
Multivariate analyses restricted to patients who received at least 228 mg of doxorubicin per square meter indicated that the only significant prognostic factors in this group were age at treatment, for increased afterload, and cumulative dose of doxorubicin, for decreased contractility. We hypothesize that afterload was more adversely affected by doxorubicin in younger patients because more myocardial growth is required for young children to reach adult proportions. Thus, the increase in afterload observed at follow-up might be peculiar to patients who received doxorubicin in early childhood. In contrast, decreased contractility at follow-up was more strongly related to both the cumulative dose of doxorubicin and early depression of ventricular function, suggesting that dose-related early cardiotoxicity may persist or recur years later.
The administration of doxorubicin appears to impair myocardial growth, as indicated by the inappropriately small increase in left ventricular wall thickness in relation to somatic growth. By six months of age, the adult number of myocytes is present, and subsequent myocardial growth occurs by increase in the size of existing myocytes.28 29 30 The doxorubicin-induced loss of or damage to a critical number of myocytes4 might decrease the number of residual myocardial cells below that required to generate a normal adult myocardial mass, despite a marked increase in the size of the remaining myocytes. This process may take place with or without signs and symptoms of acute toxicity. In support of this hypothesis, we observed marked hypertrophy of myocytes with focal interstitial fibrosis in myocardial-biopsy specimens in conjunction with reduced wall thickness and increased afterload. Similar pathological findings have been reported in children with doxorubicin-induced congestive heart failure.24 , 31 Limited fibrosis may be due to the inhibitory effects of doxorubicin on the proliferation of nonmuscle cells,32 which make up 75 percent of the cells of the heart.33 In our patients, the size of the left ventricular cavity was appropriate for somatic growth, whereas left ventricular wall thickness failed to keep pace and, consequently, left ventricular after-load increased progressively.
Only 41 percent of the eligible patients were evaluated. We therefore considered the possibility that selection bias might have led to an overestimation of the incidence of late cardiac toxicity, since patients with preexisting cardiac disease might have been more likely to participate in the study. The base-line characteristics of the patients who participated were similar to those of the patients who did not, however, and therefore we do not believe that such bias existed. Furthermore, the patients studied in this series were probably at lower risk for doxorubicin cardiotoxicity than some other children who received doxorubicin.24 , 34 35 36 No patient underwent mediastinal irradiation or received high doses of other cardiotoxic chemotherapeutic agents, and patients who relapsed were excluded from the study.
This study could not address whether there is a safe cumulative dose of doxorubicin or a safe age for the treatment of acute lymphoblastic leukemia with doxorubicin. Echocardiography at the completion of doxorubicin therapy appeared to be of value in predicting subsequent reductions in ventricular contractility. However, we did not identify measurements that predicted the more common finding of increased after-load. Certain recreational activities (such as weight-lifting37) or medical interventions to accelerate somatic growth (such as growth hormone-replacement therapy26) might result in rapid increases in afterload and thus need to be evaluated carefully in the light of their potential to cause adverse cardiac effects in this population.
Our results indicate that the treatment for a potentially fatal childhood cancer may cause another serious or even fatal disease. We found an unexpectedly high incidence of late cardiovascular abnormalities in children who received the anthracycline doxorubicin. The contribution of these agents to the cure of children with cancer must be balanced against the later effects of treatment and their influence on the quality of life of the patient.
We are indebted to the collaborating members of our acute lymphoblastic leukemia trials consortium and to Virginia Dalton, R.N., Mia Donnelly, Suzanne Mone, Kelly Strickland, Kristi Thomas, Denise Bryant, and Sharon Thornhill for technical assistance.
Source Information
From the Departments of Cardiology (S.E.L., S.D.C, S.P.S.) and Pathology (A.R.P.-A.) and the Division of Hematology/Oncology (S.E.S.), Children's Hospital; the Department of Pediatric Oncology (S.E.S.) and the Division of Biostatistics and Epidemiology (R.D.G.), Dana–Farber Cancer Institute; the Departments of Pediatrics (S.E.L., S.D.C, R.D.G., S.E.S., S.P.S.) and Pathology (A.R.P.-A.), Harvard Medical School; and the Department of Biostatistics, Harvard School of Public Health (R.D.G.); all in Boston. Address reprint requests to Dr. Lipshultz at the Department of Cardiology, Children's Hospital, 300 Long-wood Ave., Boston, MA 02115. Supported in part by grants (CA34183 and CA06516) from the National Cancer Institute and by a Clinical Investigator Award (HL01816) from the National Heart, Lung, and Blood Institute.
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