Female Sex and Higher Drug Dose as Risk Factors for Late Cardiotoxic Effects of Doxorubicin Therapy for Childhood Cancer
Steven E. Lipshultz, M.D., Stuart R. Lipsitz, D.Sc., Suzanne M. Mone, M.S., Allen M. Goorin, M.D., Stephen E. Sallan, M.D., Stephen P. Sanders, M.D., E. John Orav, Ph.D., Richard D. Gelber, Ph.D., and Steven D. Colan, M.D.
Background Late cardiotoxic effects of doxorubicin are increasinglya problem for patients who survive childhood cancer. Cardiotoxicityis often progressive, and some patients have disabling symptoms.Our objective was to identify risk factors for late cardiotoxicity.
Methods We examined echocardiograms from 120 children and adultswho had received cumulative doses of 244 to 550 mg of doxorubicinper square meter of body-surface area for the treatment of acutelymphoblastic leukemia or osteogenic sarcoma in childhood, amean of 8.1 years earlier. Measurements of blood pressure andleft ventricular function, contractility (measured as the stress–velocityindex), end-diastolic posterior-wall thickness, end-diastolicdimension, mass, and afterload (measured as end-systolic wallstress) were compared with sex-specific values from a cohortof 296 normal subjects.
Results All echocardiographic measurements were abnormal atfollow-up a minimum of two years after the end of therapy, withmore frequent and severe abnormalities in female patients. Ina multivariate analysis, female sex and a higher cumulativedose of doxorubicin were associated with depressed contractility(P<0.001), and there was an interaction between these twovariables. Independent and significant associations were foundbetween a higher rate of administration of doxorubicin and increasedafterload (P<0.001), left ventricular dilatation, and depressedleft ventricular function; between a higher cumulative doseand depressed left ventricular function (P<0.001); betweena younger age at diagnosis and reduced left-ventricular-wallthickness and mass and increased afterload; and between a longertime since the completion of doxorubicin therapy and reducedleft-ventricular-wall thickness and increased afterload (P<0.001).
Conclusions Female sex and a higher rate of administration ofdoxorubicin were independent risk factors for cardiac abnormalitiesafter treatment with doxorubicin for childhood cancer; the prevalenceand severity of abnormalities increased with longer follow-up.
There are more than 150,000 survivors of childhood cancer inthe United States,1 a group that is steadily increasing. Bythe year 2010, 1 of every 250 adults from 15 to 45 years ofage in this country may be a survivor of childhood cancer.1Children with common cancers, including sarcomas, and some childrenwith acute lymphoblastic leukemia are frequently treated withthe anthracycline doxorubicin.2 Anthracyclines improve survivalof children with cancer,3,4 but at the expense of cardiotoxicitythat is related to the cumulative dose of these drugs.5 Accordingly,for the past 16 years, treatment protocols have limited cumulativedoses, with the result that congestive heart failure duringtherapy for the initial episode of disease has been rare (<1percent of patients in some studies).2,6,7 Cardiac abnormalitieshave recently been noted to occur years after treatment, however.8,9,10,11,12,13,14,15In an earlier study, we found that 65 percent of survivors ofacute lymphoblastic leukemia in childhood had progressive cardiacabnormalities six years after completing doxorubicin therapy.10Late-onset congestive heart failure, symptomatic arrhythmias,and even sudden death have been noted and are independent ofwhether congestive heart failure occurred during therapy.8,9,10,11,12,13,14,15
Previously, we found that the cumulative dose of doxorubicinwas inversely related to left ventricular contractility, andthe age at diagnosis was inversely related to afterload.10 Unfortunately,other potentially influential factors, such as sex and the rateof administration (dosage) of doxorubicin, could not be evaluatedat that time. We have now extended that study by evaluatinglong-term survivors of either acute lymphoblastic leukemia orosteogenic sarcoma, increasing the study population, and broadeningthe range of dosages and ages at diagnosis. We examined therelations among sex, dosage, cumulative dose, type of cancer,age at the diagnosis of cancer, and length of follow-up, andthe associations of these variables with left ventricular function,loading conditions, and contractility.
Methods
Study Population
We studied 120 children and adults who had been treated withbolus doses of doxorubicin in childhood (87 for acute lymphoblasticleukemia and 33 for nonmetastatic osteogenic sarcoma). All thepatients had received their last dose of doxorubicin more thantwo years previously and had received cumulative doses of atleast 244 mg per square meter of body-surface area. We includedonly patients who had undergone echocardiographic evaluationtwo years or more after treatment. No patient was known to havehad heart disease before receiving doxorubicin or to have receivedmediastinal or spinal radiation or chemotherapeutic agents otherthan doxorubicin that are known to be associated with chronicor late cardiotoxic effects. No patient had known anemia orhypothyroidism at the time of the echocardiographic evaluation.This study was approved by the committees on human investigationat Children's Hospital and the Dana–Farber Cancer Institute.
Between 1972 and 1987, children with acute lymphoblastic leukemiawere treated according to one of five protocols that includeddoxorubicin at a dose of 30 mg per square meter or 45 to 60mg per square meter every three weeks.12,16 Patients were eligiblefor the current study if they had entered complete remissionand had not relapsed at the time of the echocardiographic evaluation.Eighty-seven patients (50 percent of those who met the eligibilitycriteria) agreed to participate and underwent echocardiographicevaluation adequate to meet the requirements of the study; these87 are a subgroup of the 115 patients described in our previousreport.10 Of this group, 59 received doxorubicin at a dose of30 mg per square meter every three weeks, and 28 received 45to 60 mg per square meter every three weeks.
Patients with osteogenic sarcoma were treated according to oneof six protocols, all of which included the administration ofboluses of doxorubicin. Twenty patients were treated with 75mg of doxorubicin per square meter every three weeks, eightpatients with 75 mg of doxorubicin per square meter in combinationwith cisplatin every three weeks, and five patients with fourdoses of 50 mg of doxorubicin per square meter followed by twodoses of 90 mg per square meter every three weeks.17,18,19 Thirty-threepatients with osteogenic sarcoma (51 percent of the eligiblepatients) participated in this study.
Echocardiographic Evaluation
Echocardiograms were analyzed by cardiologists who were unawareof each patient's treatment protocol, cumulative dose of doxorubicin,and dosage. The echocardiographic study consisted of a completetwo-dimensional echocardiogram and Doppler evaluation with stress–velocityanalysis, as reported previously.20
For comparison, we used data from 296 normal subjects less than44 years of age who had been studied in our echocardiographylaboratory according to the same protocol.20 Although we foundno association between sex and measures of cardiac function(data not shown), others have described sex-related differencesin cardiac measurements in a normal adult population.21 Therefore,we used sex-specific standardized scores or z scores (expressedas the number of standard deviations above or below the valuefor the normal controls) for each cardiac measurement in thisstudy in order to control for variations in age, sex, and bodysize. We determined age- and sex-specific normal ranges forfractional shortening, contractility (measured as the stress–velocityindex), and afterload (measured as end-systolic wall stress)and used these data to calculate z scores for the study group.We obtained z scores according to body-surface area and sexfor left ventricular end-diastolic dimension, end-diastolicposterior-wall thickness, and mass.
Statistical Analysis
We evaluated the potential effects of sex, age at the diagnosisof cancer, the cumulative dose of doxorubicin, the doxorubicindosage, the length of time since the completion of therapy,and the oncologic diagnosis on cardiac status. In univariateanalyses, we used a two-sample t-test for dichotomous variablesand simple linear regression for continuous variables. In multivariateanalyses, we used linear regression to examine the relationbetween measures of cardiac function and possible predictivevariables. We used a step-down procedure to identify importantpredictors for each outcome variable. That is, we started withall the potential predictive factors and dropped the least significant,one at a time. Predictors were kept in the model if the P valuewas less than 0.05 (the analysis was performed with SAS ProcReg Software). We assessed potential interactions between predictivefactors if there was a biologic justification for doing so.However, because patients with leukemia received doses of 60mg or less of doxorubicin per square meter and patients withosteogenic sarcoma generally received doses of 75 mg or moreper square meter, we were unable to examine the relations ofboth disease and dosage to cardiac outcome. Although the effectof sex on cardiac status was hypothesized a priori,22 the otherpredictors were examined in an exploratory way. Since we didnot adjust the P values for multiple testing, they should beinterpreted cautiously. All P values are two-tailed.
Results
Study Population
The characteristics of the study patients and their treatmentsare summarized according to diagnosis and sex in Table 1. Thebase-line characteristics of the eligible nonparticipating subjectsand the participants were similar (data not shown). No clinicalcardiotoxic effects were observed in nonparticipants, regardlessof sex, suggesting that our results were not biased becauseof an imbalance of male or female patients with cardiotoxiceffects who did not participate.
Table 1. Characteristics of the Patients According to Oncologic Diagnosis and Sex.
Twelve study patients had had transient early congestive heartfailure during or within one year after completing doxorubicintreatment. Congestive heart failure occurred later in 12 studypatients, 7 of whom had also had early congestive heart failure3 to 16 years previously. In 3 of these 12 patients with latecongestive heart failure, medical treatment failed; one underwentheart transplantation, one underwent heart–lung transplantation,and one died from documented ventricular fibrillation. Fiveof these 12 patients had initial episodes of congestive heartfailure a mean of 10.2 years after completing doxorubicin treatment,including 2 women during the peripartum period and 1 patientduring nonanthracycline chemotherapy for a relapse of cancer.When patients with clinical evidence of cardiotoxicity wereexcluded, the results were similar (data not shown).
Results of Echocardiography
In the entire study cohort, the mean z scores for all echocardiographicend points two or more years after the completion of therapywere significantly abnormal. However, stratification accordingto sex revealed that the increased left ventricular dimension,reduced left ventricular mass, and reduced systolic blood pressurein the cohort were due primarily to abnormalities in femalepatients (Table 2). Reduced left ventricular contractility,wall thickness, and fractional shortening, as well as increasedleft ventricular afterload, were noted in both male and femalepatients. Peak wall stress was also significantly elevated,indicating an inadequate amount of left ventricular mass. Forty-fivepercent of the female patients (28 of 62) had depressed contractility(more than 2 SD below the normal value), as compared with 12percent of the male patients (7 of 58; P<0.001).
Table 2. Echocardiographic Measurements According to Sex.
Predictors of Cardiac Abnormalities
Univariate analyses revealed relations similar to those shownby the multivariate analyses and are not reported here. Table 3shows the relation between potential risk factors and theoccurrence of cardiac abnormalities in the multivariate analyses,described in detail below.
Table 3. Relations between Noncardiac Risk Factors and Cardiac Findings in the Multivariate Analyses, According to Oncologic Diagnosis.
Sex
For both diseases, female patients had a significantly greaterreduction in contractility than did male patients. However,the relation between sex and the cumulative dose of doxorubicinwas interactive; the higher the cumulative dose, the greaterthe difference in contractility between female and male patients(Figure 1).
Figure 1. Probability of Depressed Contractility as a Function of the Cumulative Dose of Doxorubicin in Female and MalePatients.
To produce this plot, we formed a dichotomous response variable that equaled 1 if the z score for contractility (measured as the stress–velocity index) was extreme (less than -2) and 0 if it was not (-2 or more). A logistic-regression model was then fitted to the interrelation between female sex and the cumulative dose of doxorubicin (the risk factors) and abnormal left ventricular contractility (the outcome variable). Although the risk was higher for female patients at all cumulative doses, the difference in risk between female and male patients was greater at the higher cumulative doses. The observed proportions of female and male patients with late depressed contractility at four different ranges of the cumulative doxorubicin dose are superimposed on the logistic-regression curves. The four dose groups were formed by grouping patients into quartiles according to cumulative dose and plotting the median dose in each quartile (shown as open and solid circles).
As Table 3 shows, female patients had significantly lower leftventricular mass than male patients. Although left ventricularmass was decreased in patients of both sexes, the decrease wassignificant only for female patients (Table 2).
Doxorubicin Dosage
Higher-dose regimens of doxorubicin were strongly associatedwith increased afterload and decreased fractional shortening.The reduction in ventricular function was proportional to, andtherefore explained by, the increase in afterload; this relationwas reflected by the fact that contractility was not relatedto the rate at which doxorubicin was administered. Higher-doseregimens of doxorubicin were also associated with increasedleft ventricular end-diastolic dimension.
Cumulative Dose of Doxorubicin
In addition to the sex-specific effect of higher cumulativedoxorubicin doses on left ventricular contractility, highercumulative doses were associated with reduced fractional shortening.The latter effect could be explained by the reduced contractility,since there was no association between cumulative dose and afterload.
Age at Diagnosis
A younger age at the time of diagnosis was associated with asignificantly thinner than normal left ventricular posteriorwall at end-diastole and with reduced left ventricular mass.Younger age was also an important predictor of excess left ventricularafterload. As with the doxorubicin dosage, the increased afterloadin patients who were younger at the time of diagnosis accountedfor the significantly diminished fractional shortening.
Years since Doxorubicin Therapy
Patients with longer follow-up periods since the completionof therapy were more likely to have reduced left-ventricular-wallthickness and secondary increases in left ventricular afterload.
Oncologic Diagnosis
The effects of sex and doxorubicin treatment on left ventriculardimension, mass, and fractional shortening appeared to varywith the oncologic diagnosis. Because the age at diagnosis andthe dosage were different for the two diseases, however, wecould not determine whether the differences in the echocardiographicfindings were due to the disease, the dosage, or the age atthe initiation of doxorubicin treatment. For other cardiac abnormalities,the relations appeared to be the same for both diseases.
Discussion
Among patients treated with doxorubicin for cancer during childhood,female sex and a higher-dose doxorubicin regimen were independentrisk factors for abnormalities of cardiac mechanics and werealso independent of the cumulative dose and age at the timeof therapy, which have previously been shown to be risk factorsfor cardiac abnormalities.10 Both the prevalence and the severityof abnormalities of cardiac growth and mechanics increased withlonger follow-up. The risk factors for abnormal contractility(sex and cumulative dose) were different from those for reducedwall thickness and mass (dosage, age at the time of therapy,time since the completion of treatment, and oncologic diagnosis),suggesting separate mechanisms for these two types of toxicity.
Sex
Female patients appear to be more vulnerable to the adverseeffects of treatment of childhood cancer, and male patientsmay need more intensive treatment than female patients to achievea similar rate of cure.23 Girls treated for childhood leukemia24or other types of cancer25,26,27 are more likely to remain inremission than boys. However, they also appear to have morecardiotoxic effects.2,28,29,30,31 Our preliminary work suggestedthat most doxorubicin-treated survivors of childhood leukemiawho had late depressed contractility were female22 and thatfemale patients have nearly twice as high a risk of early clinicalcardiotoxicity as male patients.2 Two recent studies of childrendemonstrated more abnormalities on exercise testing and nuclearangiography at rest and during exercise in girls than in boysduring and after chemotherapy that included anthracyclines.30,31These findings are difficult to interpret, however, since similarsex-related differences in the cardiac responses of supine patientsto exercise, as assessed by radionuclide angiography, have alsobeen documented in normal persons.32
We do not understand why doxorubicin affects left ventricularcontractility more profoundly in female patients than in malepatients. Possible mechanisms include differences in oxidativestress, differential expression of the multidrug-resistancegene, and body composition.
Differences in body composition between girls and boys33,34could influence drug toxicity by altering the metabolism orthe volume of distribution of doxorubicin. Doxorubicin doesnot reach a high concentration in fat,35,36,37 and its clearanceis reduced with increased body fat.37 Consequently, if girlshave more body fat than boys with the same body-surface area,equivalent doses of doxorubicin could lead to higher concentrations,for a longer time, in nonadipose tissue (including the heart)in girls.
Prednisone therapy also increases the percentage of body fat.The children treated for leukemia also received prednisone andappeared to have more late cardiac abnormalities than thosetreated for osteogenic sarcoma, who did not receive prednisone.That prednisone therapy increases the risk of subsequent cardiotoxiceffects of doxorubicin by increasing the percentage of bodyfat is a hypothesis that should be tested.
Dose of Doxorubicin
Most treatment programs establish upper limits for cumulativedoses of doxorubicin that result in less depressed contractilityduring treatment; however, many protocols for childhood cancersinclude intensified therapy, with high dose rates.4,17,18,19Our findings suggest that even when the cumulative dose is limited,higher dose rates are an important predictor of increased afterloadand depressed left ventricular function years after treatment.Presumably, higher bolus doses produce higher levels of doxorubicinin blood and tissue that affect subsequent left ventricularmass and result in the increased afterload and depressed leftventricular function that we observed.
Age at Diagnosis and Time since Doxorubicin Therapy
Patients who were younger at the time of diagnosis had the greatestreductions in left ventricular mass and the most profound increasesin afterload. As we have previously suggested,10 this differencecould be due to the inhibition of myocardial growth by doxorubicin,which would be accentuated in younger children, whose left ventricularmass is smaller. Perhaps higher levels of doxorubicin in tissueand blood occurred in younger patients because of their higherpercentage of body fat.33,34
Because time is required for somatic growth to outstrip myocardialgrowth, the myocardial effects of doxorubicin on left ventricularmass and afterload become more obvious over time, and progressivecardiac abnormalities may occur. The effect of the length offollow-up and of sex on cardiac growth and function may be clinicallyapparent only after prolonged observation. For example, femalesurvivors of childhood cancer were less likely to die than malesurvivors if the disease was diagnosed when they were between12 and 20 years old; before 12 years of age, there was no difference.38Among patients in whom cancer was diagnosed during adolescence,Byrne et al. found that the survival advantage of female patientsextended beyond the immediate treatment period but diminishedwith increasing follow-up and was no longer significant beyond30 years of age.38 We do not know how many patients in thatseries were treated with anthracyclines. However, if the studygroup was representative of groups studied in pediatric oncologyprotocols in the United States,2 the effect of sex on late cardiotoxicitymay have a role in the eventual neutralization of the survivaladvantage among female patients treated for cancer during adolescenceand may contribute to the lack of a survival advantage amonggirls treated before 12 years of age. Female sex has also beenassociated with a higher risk of potentially life-threateningcardiac arrhythmias after drug treatment for cardiovasculardisease, a fact that may also contribute to the reduction ofthe survival advantage in female patients with time.39 The prognosisafter myocardial damage from infarction or congestive heartfailure is probably worse for women, among whom higher mortalityrates have been observed than among men,40 again suggestingthat substantial myocardial damage after treatment with doxorubicinmay reduce survival more in women.
In conclusion, limiting the cumulative dose of doxorubicin maynot suffice to prevent late cardiotoxic effects in patientstreated for cancer during childhood. At a minimum, sex and thedosage of doxorubicin should also be considered when treatmentprotocols are designed. For the many current survivors of childhoodcancer who received bolus doses of anthracyclines, careful evaluationis necessary to detect subclinical cardiac abnormalities. Girlswho were treated with high cumulative doses of anthracyclinesor with regimens of high individual doses, as well as patientsof both sexes who were relatively young at the time of treatmentor have had long periods of follow-up since doxorubicin therapy,appear to be at the highest risk for late cardiotoxic effects.
Supported in part by grants from the National Institutes ofHealth (CA34183, CA06516, CA55576, and HL48012) and the DavidB. Perini, Jr., Quality of Life Program, and by a Clinical InvestigatorAward (HL01816) from the National Heart, Lung, and Blood Institute.
We are indebted to Cynthia Barber, M.P.H., and Tracie L. Miller,M.D., for editorial assistance and to Nancy Borden, Stacie Cohen,Emily Flynn-McIntosh, Greta Knapschaefer, Virginia Kimball,R.N., Michael Parzen, D.Sc., and Mia Donnelly for technicalassistance.
Source Information
From the Department of Cardiology (S.E.L., S.M.M., S.P.S., S.D.C.) and the Division of Hematology–Oncology (A.M.G., S.E.S.), Children's Hospital; the Department of Pediatrics, Harvard Medical School (S.E.L., A.M.G., S.E.S., S.P.S., R.D.G., S.D.C.); the Department of Pediatric Oncology (A.M.G., S.E.S.) and the Division of Biostatistics (S.R.L., R.D.G.), Dana–Farber Cancer Institute; the Department of Biostatistics, Harvard School of Public Health (S.R.L., E.J.O., R.D.G.); and the Department of Medicine, Brigham and Women's Hospital (E.J.O.) — all in Boston.
Address reprint requests to Dr. Lipshultz at the Department of Cardiology, Children's Hospital, 300 Longwood Ave., Boston, MA 02115.
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