Chronic Progressive Cardiac Dysfunction Years After Doxorubicin Therapy for Childhood Acute Lymphoblastic Leukemia
http://www.100md.com
《临床肿瘤学》
the Department of Pediatrics, Miller School of Medicine at the Univerity of Miami, Holtz Children's Hospital, and Sylvester Comprehensive Cancer Center, Miami, FL
Department of Pediatric Oncology and Department of Biostatistical Science, Dana-Farber Cancer Institute, Division of Hematology/Oncology and Department of Cardiology, Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA
Department of Biometry and Epidemiology, Medical University of S Carolina, Charleston, SC
ABSTRACT
PURPOSE: Cross-sectional studies show that cardiac abnormalities are common in long-term survivors of doxorubicin-treated childhood malignancies. Longitudinal data, however, are rare.
METHODS: Serial echocardiograms (N = 499) were obtained from 115 doxorubicin-treated long-term survivors of childhood acute lymphoblastic leukemia (median age at diagnosis, 4.8 years; median follow-up after completion of doxorubicin, 11.8 years). Results were expressed as z scores to indicate the number of standard deviations (SDs) above (+) or below (–) the normal predicted value. Median individual and cumulative doxorubicin doses were 30 mg/m2 per dose and 352 mg/m2, respectively.
RESULTS: Left ventricular fractional shortening was significantly reduced after doxorubicin therapy, and the reduction was related to cumulative dose. z scores for fractional shortening transiently improved before falling to –2.76 more than 12 years after diagnosis. Reduced fractional shortening was related to impaired contractility and increasing afterload, consequences of a progressive reduction of ventricular mass, and wall thickness relative to body-surface area. Left ventricular contractility fell significantly over time and was depressed at last follow-up in patients receiving more than 300 mg/m2 of doxorubicin. Systolic and diastolic blood pressures were below normal more than 9 years after diagnosis. Even patients receiving lower cumulative doxorubicin doses experienced reduced mass and dimension. Fractional shortening and dimension at the end of therapy predicted these parameters 11.8 years later.
CONCLUSION: Cardiac abnormalities were persistent and progressive after doxorubicin therapy. Inadequate ventricular mass with chronic afterload excess was associated with progressive contractile deficit and possibly reduced cardiac output and restrictive cardiomyopathy. The deficits were worst after highest cumulative doses of doxorubicin, but appeared even after low doses.
INTRODUCTION
Abnormalities of left ventricular structure and function are common in doxorubucin-treated survivors of childhood leukemia years after therapy.1 We previously reported such abnormalities in 115 survivors of acute lymphoblastic leukemia evaluated at a mean of 6.2 years after completion of therapy.1 Of these survivors, 65 (57%) had increased left ventricular afterload or decreased contractility. Progressive increases in afterload resulting from a thin left ventricular wall seemed to arise from a dose-related failure to increase left ventricular mass commensurate with somatic growth. Cardiotoxicity had two distinct forms: depressed contractility, associated with higher cumulative doxorubicin dose and female sex, and increased afterload, resulting from decreased left ventricular mass and wall thickness. The latter form of cardiotoxicity is related to time since treatment, age at treatment, and doxorubicin dosage.2
The current understanding of late cardiac abnormalities after doxorubicin comes largely from cross-sectional studies, and data about progressive dysfunction have been insufficient to model long-term morbidity. Therefore, in a prospective study, we examined the longitudinal course of left ventricular structure and function in this cohort,1 now followed up for a median of 11.8 years.
METHODS
Patients
The cardiac status of the survivors of childhood acute lymphoblastic leukemia has been periodically assessed at Dana-Farber Cancer Institute and Children's Hospital in Boston, MA.1,2 Eligible patients had completed one of six Dana-Farber pediatric acute lymphoblastic leukemia protocols (72-01, 73-01, 77-01, 80-01, 81-01, or 85-01)3 at least 2 years earlier and were in a first remission. Specifically, eligibility in the echocardiographic evaluation of study patients were being disease-free as of 1989, when this cohort was first assembled,1 and being disease-free 2 years from the end of treatment. Findings in the ineligible patients1,2 did not differ significantly from those included in the study, suggesting that the study population was representative of the larger group.1–3
The children had a total of 736 echocardiograms. Patients with the most impaired cardiac function had the most echocardiograms, and thus including all echocardiograms in the analysis could have biased the results. Therefore, we categorized the echocardiograms and for each patient analyzed one echocardiogram in each category: before doxorubicin therapy, after therapy, the first to assess wall stress, those made from 1987 to 1990 to study left ventricular structure and function, and the most recent, to allow comparison to prior studies on this cohort.1,2 However, these do not correspond to the number of patients by time from diagnosis as noted in Table 1, so that a subject could have been seen more than once in these intervals even though they were seen only once in the echocardiogram grouping before doxorubicin therapy, after therapy, the first to assess wall stress, those made from 1987 to 1990 to study left ventricular structure and function, and the most recent.
The resulting 499 echocardiograms were all remeasured by a single sonographer who was unaware of the clinical data.4 Each echocardiographic study consisted of a complete 2-dimensional echocardiogram and Doppler evaluation with stress-velocity analysis.1,2,5 We used fractional shortening as a measure of overall left ventricular systolic performance, which is influenced by heart rate, preload, afterload, and myocardial contractility. Contractility was measured by the stress-velocity relationship, a load-independent index that incorporates preload and heart rate and varies with afterload.1,2,5 Afterload was assessed as left ventricular end-systolic wall stress, which varies directly with blood pressure and left ventricular dimension and inversely with left ventricular wall thickness.1,2,5
Statistical Methods
To standardize cardiac data by age or body-surface area, to adjust for changes associated with growth, we calculated z scores (the number of standard deviations [SDs] the observed measurement is above [+] or below [–] the predicted value) by dividing the difference between a child's observed cardiac outcome and the normal predicted value by the SD of a distribution of normal cardiac values. The normal predicted value was calculated with a regression model,1,2,5 using data from 285 normal children measured at the same center and in the same manner as the study patients. The normal subjects ranged in body size from 0.2 to 2.2 m2 and were included on the basis of normal height, weight, and height for weight centiles; normal blood pressure; and no evidence of cardiac or other disorders. We adjusted the z scores for mass, afterload, dimension, and wall thickness for body-surface area, and those for fractional shortening, blood pressure, and peak systolic wall stress for age. We plotted z scores over time by repeated-measures regression models in SAS PROC MIXED (SAS, Cary, NC), in which the z score was modeled as a linear, quadratic, and cubic function of time since diagnosis, and we modeled the correlation between z scores measured at a pair of times on the same subject using an autoregressive structure.
We grouped the 115 patients into three categories by cumulative dose (low, < 300 mg/m2; moderate, 300 to 400 mg/m2; or high, > 400 mg/m2), and then fitted a separate curve for each group. In this study, the patients with poorer heart function were seen more often, and were also followed-up for a longer period of time. In particular, the care providers decided to closely monitor the sicker patients. Since the number of visits and length of follow-up depended on observed data (the heart function at the previous visits), the missing data are missing at random.6 To adjust for the missing at random data, we used the mixed model formulation in SAS PROC MIXED, which ensures that the patients with poor cardiac function who came back most often for repeat testing were not given excessive weight and, did not have a disproportionate influence on the tails of the plots. Since SAS PROC MIXED gives unbiased estimates when missing data are missing at random, we feel confident that the results of this study are not biased in any direction. Data from patients on afterload reduction therapy were censored from blood pressure and afterload analyses when this therapy started.
We also created plots using only the first follow-up observation for each subject, only the last observation for each subject, and the follow-up observation closest to 18 years of age, and found them all to be similar to Figures 1 and 2 (data not shown). We did a sensitivity analysis in which we looked at all possible single observations from each individual interval, and it did not change the results from this article.
In Figure 2, not all z scores were obtained at each time point, so lines for some dose groups contain gaps. All three groups in Figure 2 had at least 10.5 years of follow-up.
To determine whether the z score at the end of treatment predicted long-term cardiac function, we tested linear regression analysis with the latest follow-up z score as the outcome, and three covariates: (1) z score at the end of treatment, (2) time from the end of treatment to latest z score, and (3) cumulative dose group.
RESULTS
Patient Characteristics
Median age at diagnosis was 4.8 years (range, 1.0 to 19.0 years), and the median age at the end of doxorubicin therapy was 5.5 years (range, 2.0 to 21.0 years). Median cumulative doxorubicin dose was 352 mg/m2 (range, 45 to 550 mg/m2), and median dosage was 30 mg/m2 per dose (range, 30 to 52 mg/m2/dose). In the low cumulative dose group, 18 patients (with 50 echocardiograms) received total cumulative doses of 45 mg/m2.
The characteristics of the 115 included patients were compared wth those of the 278 patients who were not included. There were no statistically significant differences in the percentage who were female (50% v 46%), median age after therapy (5.5 v 5.7 years), or median WBC count (9,750 v 7,900 cells/mm3). The median follow-up survival was significantly longer in the included patients (19.5 v 16.5 years). Since most of the patients are still alive, we do not think it indicates that there is a bias by following the patients longer. Because the patients with the highest cumulative doxorubicin doses also had the longest follow-up since higher doses were used in earlier studies (Table 1), we presented the results both for all patients (Fig 1) and by dose category (Fig 2). Age and sex distribution did not significantly differ between cumulative dose groups (Table 1).
Eleven children had early congestive heart failure (before 1 year posttherapy), five of whom also experienced late congestive heart failure. Seven children received cardiac medication during follow-up, including afterload reduction therapy. In the five children with late congestive heart failure, clinical and laboratory findings were consistent with a restrictive cardiomyopathy. These children were often sicker and required earlier heart transplantation than did children with dilated cardiomyopathy at similar levels of systolic dysfunction (data not shown). Two of the 11 children received heart transplants, and another died from cardiac causes while awaiting a heart transplant.
Left Ventricular Structure and Function
Left ventricular contractility. Left ventricular contractility was significantly depressed after doxorubicin therapy, normalized during the next 6 years, and then became significantly depressed at 12 years or more after diagnosis (Table 2, Fig 1A). The change in mean left ventricular contractility over time was statistically significant (P < .001, Fig 1A). The pattern of improvement followed by decline was found in all treatment groups. It varied in severity with cumulative dose, reaching statistical significance at last follow-up in the two higher cumulative dose groups (Table 3, Fig 2A).
Left ventricular end-diastolic dimension. During chemotherapy, the left ventricle was significantly dilated (Table 2), but it returned to normal after therapy (Fig 1B). The change over time in left ventricular dimension approached statistical significance (P = .06). The magnitude of the dilation in left ventricular dimension varied directly with cumulative dose, and while the values for the higher dose groups normalized with time, left ventricular dimension for the low-dose group became significantly lower than normal (Table 3, Fig 2B). At 10.5 years, left ventricular dimension (Fig 2B) differed significantly between the low-dose and moderate-dose groups (P = .027) and between the low-dose and high-dose groups (P = .002).
Left ventricular wall thickness. Mean left ventricular wall thickness relative to body-surface area was significantly reduced at the completion of doxorubicin therapy, became thinner over time, and was significantly less than normal at all points of follow-up beyond 6 years (Tables 2 and 3, Fig 1C). The change in mean left ventricular wall thickness over time was statistically significant (P < .001, Fig 1C). Dose-related differences were not significant (Fig 2C).
Left ventricular mass. Mean left ventricular mass was nearly normal after therapy but decreased over 15 years to more than 1 SD below normal. The difference became significant between 6 and 9 years after diagnosis (Table 2, Fig 1D). The change in mean left ventricular mass over time was significant (P = .049; Fig 1D). Left ventricular mass decreased over time in all dose groups (Fig 2D), and was significantly below normal at last follow-up (Table 3). Left ventricular mass (Fig 2D) differed significantly between the moderate- and high-dose groups (P < .001).
Left ventricular fractional shortening. Mean fractional shortening was significantly depressed after therapy, improved, and then became significantly more depressed (Fig 1E, Table 2). The change after the completion of therapy was statistically significant (P < .001). All cumulative dose groups were nonoverlapping over time (Fig 2E). The degree of depression was dose-dependent (Fig 2E, Table 3). The low-dose group had relatively normal fractional shortening, a finding consistent with our prior work,7 yet, the mean in the high-dose group was nearly 3 SDs below normal at the last follow-up (Fig 2E). Left ventricular fractional shortening (Fig 2E) differed significantly between the low- and high-dose groups (P < .001) and between the moderate- and high-dose groups (P < .001).
Left ventricular afterload. Mean left ventricular afterload was significantly elevated after therapy. Over the next 12 to 14 years, it increased progressively to about 3 SDs above normal (Table 2, Fig 1F). The change over time was statistically significant (P < .001). Afterload was significantly dose-related; at last follow-up, it was normal in the low-dose group and significantly elevated in the moderate- and high-dose groups (Table 3, Fig 2F). Left ventricular afterload (Fig 2F) differed significantly between the low- and moderate-dose groups (P = .002), the low- and high-dose groups (P < .001), and the moderate- and high-dose groups (P < .001).
Systolic blood pressure. Mean systolic blood pressure fell steadily during follow-up, from normal to 1 SD below normal at last follow-up (Table 2, Fig 1G). The change in systolic blood pressure over time was statistically significant (P = .028; Fig 1G). It was significantly depressed beyond 9 years of follow-up for the two higher dose groups (Table 3, Fig 2G).
Diastolic blood pressure. Mean diastolic blood pressure fell rapidly, and significantly so at 9 to 12 years of follow-up (Table 2, Fig 1H). The change over time was statistically significant (P = .012; Fig 1H). It was significantly depressed at latest follow-up in the two higher dose groups (Table 3, Fig 2H).
Left ventricular thickness-dimension ratio. Mean left ventricular thickness-dimension ratio was significantly reduced throughout follow-up; this progressive fall was significant (P < .001; Table 2, Fig 1I). The two highest dose groups were significantly reduced at last follow-up (Table 3, Fig 2I). Left ventricular thickness-dimension ratio (Fig 2I) differed significantly between the low- and moderate-dose groups (P = .045) and the low- and high-dose groups (P = .023).
Predicting late cardiac measurements from those at the end of therapy. The mean z scores at the completion of doxorubicin therapy predicted late follow-up z scores for left ventricular fractional shortening and end-diastolic dimension (P < .001 for each). For fractional shortening, a mean z score below –2 at the end of therapy was associated with a mean z score below –2 an average of 11 years later. A mean z score between –2 and +1 was associated with a later mean z score of –0.67, and a mean z score above 1 was associated with a later mean z score of 0.3. For end-diastolic dimension, mean z scores below 0 after therapy were associated with a mean z score of –0.96 an average of 11 years later. Mean z scores above 0 were associated with a later mean z score of 0.41.
DISCUSSION
Although many of the cardiotoxic effects of doxorubicin therapy for childhood acute lymphoblastic leukemia initially improved after therapy, our longitudinal study showed that cardiac abnormalities are common, persistent, and, for many patients, progressive. Inadequate left ventricular mass with chronic afterload elevation was associated with a progressive contractile deficit. Blood pressures were significantly lower after 9 years, which may indicate reduced cardiac output. The contractile deficit increased with cumulative doxorubicin dose, but even low cumulative dose groups were affected. We did not find a safe dose of doxorubicin that was free of late toxicity.
The abnormalities may portend important problems in the future for anthracycline-treated survivors of childhood cancer. Two studies suggest that the cumulative rate of congestive heart failure rises over time.8,9 In another study, the standardized mortality rate for cardiac death was 8.2 times higher than expected, and the cumulative probability of cardiac death rose 15 to 25 years after diagnosis.10 A study of 5-year survivors found standardized mortality rates of 5.8 for cardiac death and 3.9 for sudden, presumed cardiac death.11 Noncancer deaths increased steadily during the 35 years after treatment.11 In another group of 15-year survivors, increased mortality was related, in part, to doxorubicin and did not decrease during more recent treatment eras.12
The potential effect of these findings is enormous because of the large numbers involved. Of the 12,400 children and adolescents diagnosed with cancer in the United States each year, the overall 5-year survival rate is nearly 80%.13 Approximately one in every 540 adults in the United States aged 20 to 34 years is predicted by the year 2010 to be a survivor of childhood cancer,14 and half of them will have been treated with an anthracycline.15
Cumulative doxorubicin dose affects the development of dilated cardiomyopathy, afterload excess, and late reduction in systolic and diastolic blood pressure. We previously found that at 8 years of follow-up, survivors of childhood cancer who received a cumulative doxorubicin dose of less than 300 mg/m2 have normal left ventricular fractional shortening and dimension.7 Unfortunately, our current data reveal that even patients who received lower cumulative doses, even as low as 45 mg/m2, eventually experienced cardiac abnormalities, including significantly reduced left ventricular mass and dimension. Even low doses are problematic if the goal is to avoid late cardiotoxicity.
In contrast, cumulative doxorubicin dose does not affect the reductions of left ventricular wall thickness and mass (relative to body-surface area), which produce late afterload excess. We previously reported that these late effects are related to a younger age at cancer diagnosis and to longer time since diagnosis2; our current data are consistent with both findings. Cardiac mortality is significantly lower when cancer is diagnosed after age 7 years,10 suggesting that this second type of cardiac dysfunction, with reduced left ventricular wall thickness and mass, may be associated with late cardiac mortality. Abnormal left ventricular volume and pressure overload can lead to chronic afterload excess, resulting in contractile deterioration, in other populations.16
After doxorubicin therapy, the children in our study had a dilated cardiomyopathy (significantly reduced left ventricular fractional shortening and contractility with left ventricular dilation). With time, however, the pattern that appeared was consistent with a developing restrictive cardiomyopathy (normal to reduced left ventricular dimension with significantly reduced left ventricular thickness, fractional shortening, and contractility). These patients experienced a progressive rise in afterload despite a fall in blood pressure. The rise in afterload was secondary to the fall in thickness-dimension ratio, a change that occurred despite the fact that dimension did not increase, emphasizing inadequate left ventricular mass as the primary cause of excess afterload. Progression of this doxorubicin-associated late cardiomyopathy may be slower than for children with dilated cardiomyopathy who were not treated with doxorubicin but nevertheless is unremitting and inexorable during this period of follow-up.
Cardiac monitoring by echocardiography is useful in this population since cardiac measurements after doxorubicin therapy predicted those at latest follow-up. However, these echocardiographic measurements need to be validated as surrogate markers of clinically important end points.17 Left ventricular fractional shortening and wall thickness predict all-cause mortality years in advance in children with HIV-associated cardiomyopathy,18 which allows prevention and therapy to be targeted to high-risk children.19–23 Unfortunately, echocardiography does not identify patients with the greatest abnormalities of left ventricular wall thickness, mass, and afterload on late follow-up after doxorubicin therapy, perhaps because these abnormalities are related to age at diagnosis and time since treatment, rather than cumulative doxorubicin dose.24–26
The effects on left ventricular contractility may be caused by chronic, excessive afterload,1,2 as well as by irreversible impairment of mitochondrial function27,28 and calcium handling29,30 in the myocardiocytes. Progressive left-ventricular wall thinning may result from the loss of myocardiocytes,1 increased apoptosis,31 and reduced collagen production from doxorubicin toxicity that results in enlargement of remaining myocardiocytes.32
These results call into question the use of doxorubicin in children, especially when alternative therapies are available. More follow-up is needed to determine the natural history and clinical importance of these abnormalities and recommendations for change in current treatment.26 Potential cardioprotectants should be validated and used in conjunction with doxorubicin33–35 to reduce myocardial injury.36,37 Effective preventive and therapeutic strategies must be developed to slow the course of doxorubicin-associated late cardiac dysfunction in long-term survivors of childhood cancer.38-40
Authors' Disclosures of Potential Conflicts of Interest
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. Consultant/Advisory Role: Steven E. Lipshultz, Chiron. Research Funding: Steven E. Lipshultz, Chiron, Pfizer, Roche Diagnostics. For a detailed description of these categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue.
NOTES
Supported by grants from the National Institutes of Health (CA 68484, CA 55576, CA 06516, CA 79060, HL 59837, HR 96041, HL 53392, HL 72705, and HL 69800).
This study was presented in part as an abstract at the American Society of Clinical and Oncology and the American Heart Association annual sessions.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Lipshultz SE, Colan SD, Gelber RD, et al: Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. N Engl J Med 324:808-815, 1991
Lipshultz SE, Lipsitz SR, Mone SM, et al: Female sex and higher drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer. N Engl J Med 332:1738-1743, 1995
Silverman LB, Declerck L, Gelber RD, et al: Results of Dana-Farber Cancer Institute Consortium protocols for children with newly diagnosed acute lymphoblastic leukemia (1981-1995). Leukemia 14:2247-2256, 2000
Lipshultz SE, Easley K, Orav EJ, et al: The reliability of multicenter pediatric echocardiographic measurements of left ventricular structure and function. Circulation 104:310-316, 2001
Colan SD, Parness IA, Spevak PJ, et al: Developmental modulation of myocardial mechanics: Age- and growth-related alterations in afterload and contractility. J Am Coll Cardiol 19:619-629, 1992
Lipsitz SR, Fitzmaurice GM, Ibrahim JG, et al: Parameter estimation in longitudinal studies with outcome-dependent follow-up. Biometrics 58:621-630, 2002
Nysom K, Holm K, Lipsitz SR, et al: Relationship between cumulative anthracycline dose and late cardiotoxicity in childhood acute lymphoblastic leukemia. J Clin Oncol 16:545-550, 1998
Kremer LC, van Dallen EC, Offringa M, et al: Anthracycline-induced clinical heart failure in a cohort of 607 children: Long-term follow-up study. J Clin Oncol 19:191-196, 2001
Green DM, Grigoriev YA, Nan B, et al: Congestive heart failure after treatment for Wilm's tumor: A report from the national Wilm's tumor study group. J Clin Oncol 19:1926-1934, 2001
Mertens AC, Yasui Y, Neglia JP, et al: Late mortality experience in five-year survivors of childhood and adolescent cancer: The Childhood Cancer Survivor Study. J Clin Oncol 19:3163-3172, 2001
Moller TR, Garwicz Barlow L, et al: Decreasing late mortality among five-year survivors of cancer in childhood and adolescence: A population-based study in the Nordic countries. J Clin Oncol 19:3173-3181, 2001
Green DM, Hyland A, Chung CS, et al: Cancer and cardiac mortality among 15-year survivors of cancer diagnosed during childhood or adolescence. J Clin Oncol 17:3207-3215, 1999
Ries LAG, Smith MA, Gurney JG, et al (eds): Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. National Cancer Institute. SEER Program. Bethesda, MD, NIH Publication No 99-4649, 1999
US National Cancer Institute Workshop on Pediatric Oncology Late Effects of Childhood Cancer Networks. June 26, 2002. Niagara-on-the-Lake, Canada
Krischer JP, Epstein S, Cuthbertson DD, et al: Clinical cardiotoxicity following anthracycline treatment for childhood cancer: The pediatric oncology group experience. J Clin Oncol 15:1544-1552, 1997
Borow KM, Colan SD, Neumann A: Altered left ventricular mechanics in patients with valvular aortic stenosis and coarctation of the aorta: Effects on systolic performance and late outcome. Circulation 72:515-522, 1985
Lipshultz SE, Sanders SP, Goorin A, et al: Monitoring for anthracycline cardiotoxicity. Pediatrics 93:433-437, 1994
Lipshultz SE, Easley KA, Orav EJ, et al: Cardiac dysfunction and mortality in HIV-infected children: The prospective P2C2 HIV multicenter study. Circulation 102:1542-1548, 2000
Lipshultz SE, Lipsitz SR, Sallan SE, et al: Long-term enalapril therapy for left ventricular dysfunction in doxorubicin-treated survivors of childhood cancer. J Clin Oncol 20:4517-4522, 2002
Grenier M, Fioravanti J, Truesdale S, et al: Angiotensin-converting enzyme inhibitor therapy in infants, children and adolescents: A review. Prog Ped Cardiol 12:91-111, 2000
Simbre VC II, Adams MJ, Deshpande SS, et al: Cardiomyopathy caused by antineoplastic therapies. Curr Treat Options Cardiovasc Med 3:493-505, 2001
Lipshultz SE, Vlach SA, Lipsitz SR, et al: Cardiac changes associated with growth hormone therapy in children treated with anthracyclines. Pediatrics (in press)
Shaddy RE, Olsen SL, Bristow MR, et al: Efficacy and safety of metoprolol in the treatment of doxorubicin-induced cardiomyopathy in pediatric patients. Am Heart J 129:197-199, 1995
Grenier MA, Lipshultz SE: Epidemiology of anthracycline cardiotoxicity in children and adults. Semin Oncol 25:72-85, 1998
Giantris A, Abdurrahman L, Hinkle A, et al: Anthracycline induced cardiotoxicity. Crit Rev Oncol Hematol 27:53-68, 1998
Lipshultz SE: Ventricular dysfunction clinical research in infants, children and adolescents. Prog Ped Cardiol 12:1-28, 2000
Zhou S, Starkov A, Froberg MK, Leino RL, Wallace KB: Cumulative and irreversible cardiac mitochondrial dysfunction induced by doxorubicin. Cancer Res 61:771-777, 2001
Jung K, Reszka R: Mitochondria as subcellular targets for clinically useful anthacyclines. Adv Drug Deliv Rev 49:87-105, 2001
Chugun A, Temma K, Oyamada T, et al: Doxorubicin-induced late cardiotoxicity: Delayed impairment of Ca2+-handling mechanisms in the sarcoplasmic reticulum in the rat. Can J Physiol Pharmacol 78:329-338, 2000
DeBeer EL, Bottone AE, Voest EE: Doxorubicin and mechanical performance of cardiac trabeculae after acute and chronic treatment: A review. Europ J Pharmacol 415:1-11, 2001
Nakamura T, Ueda Y, Juan Y, et al: Fas-mediated apoptosis in adriamycin-induced cardiomyopathy in rats: In vivo study. Circulation 102:572-578, 2000
Muszynska A, Wolczynski S, Palka J: The mechanism for anthracycline-induced inhibition of collagen biosynthesis. Europ J Pharmacol 411:17-25, 2001
Lipshultz SE: Dexrazoxane for protection against cardiotoxic effects of anthracyclines in children. J Clin Oncol 14:328-331, 1996
Lipshultz SE, Rifai N, Dalton VM, et al: The effect of dexrazoxane on myocardial injury in doxorubicin-treated children with acute lymphoblastic leukemia. N Engl J Med 351:145-153, 2004
Herman EH, Zhang J, Rifai N, et al: The use of serum levels of cardiac troponin T to compare the protective activity of dexrazoxane against doxorubicin- and mitoxantrone-induced cardiotoxicity. Cancer Chemother Pharmacol 48:297-304, 2001
Herman EH, Zhang J, Lipshultz SE, et al: Correlation between serum levels of cardiac troponin –T and the severity of chronic cardiomyopathy induced by doxorubicin. J Clin Oncol 17:2237-2243, 1999
Lipshultz SE, Rifai N, Sallan SE, et al: Predictive value of cardiac troponin T in pediatric patients at risk for myocardial injury. Circulation 96:2641-2648, 1997
Lipshultz SE, Colan SD: Cardiovascular trials in long-term survivors of childhood cancer. J Clin Oncol 22:769-773, 2004
Sorensen K, Levitt GA, Bull C, et al: Late anthracycline cardiotoxicity after childhood cancer: A prospective longitudinal study. Cancer 97:1991-1998, 2003
Poutanen T, Tikanoja T, Riikonen P, et al: Long-term prospective follow-up study of cardiac function after cardiotoxic therapy for malignancy in children. J Clin Oncol 21:2349-2356, 2003(Steven E. Lipshultz, Stua)
Department of Pediatric Oncology and Department of Biostatistical Science, Dana-Farber Cancer Institute, Division of Hematology/Oncology and Department of Cardiology, Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA
Department of Biometry and Epidemiology, Medical University of S Carolina, Charleston, SC
ABSTRACT
PURPOSE: Cross-sectional studies show that cardiac abnormalities are common in long-term survivors of doxorubicin-treated childhood malignancies. Longitudinal data, however, are rare.
METHODS: Serial echocardiograms (N = 499) were obtained from 115 doxorubicin-treated long-term survivors of childhood acute lymphoblastic leukemia (median age at diagnosis, 4.8 years; median follow-up after completion of doxorubicin, 11.8 years). Results were expressed as z scores to indicate the number of standard deviations (SDs) above (+) or below (–) the normal predicted value. Median individual and cumulative doxorubicin doses were 30 mg/m2 per dose and 352 mg/m2, respectively.
RESULTS: Left ventricular fractional shortening was significantly reduced after doxorubicin therapy, and the reduction was related to cumulative dose. z scores for fractional shortening transiently improved before falling to –2.76 more than 12 years after diagnosis. Reduced fractional shortening was related to impaired contractility and increasing afterload, consequences of a progressive reduction of ventricular mass, and wall thickness relative to body-surface area. Left ventricular contractility fell significantly over time and was depressed at last follow-up in patients receiving more than 300 mg/m2 of doxorubicin. Systolic and diastolic blood pressures were below normal more than 9 years after diagnosis. Even patients receiving lower cumulative doxorubicin doses experienced reduced mass and dimension. Fractional shortening and dimension at the end of therapy predicted these parameters 11.8 years later.
CONCLUSION: Cardiac abnormalities were persistent and progressive after doxorubicin therapy. Inadequate ventricular mass with chronic afterload excess was associated with progressive contractile deficit and possibly reduced cardiac output and restrictive cardiomyopathy. The deficits were worst after highest cumulative doses of doxorubicin, but appeared even after low doses.
INTRODUCTION
Abnormalities of left ventricular structure and function are common in doxorubucin-treated survivors of childhood leukemia years after therapy.1 We previously reported such abnormalities in 115 survivors of acute lymphoblastic leukemia evaluated at a mean of 6.2 years after completion of therapy.1 Of these survivors, 65 (57%) had increased left ventricular afterload or decreased contractility. Progressive increases in afterload resulting from a thin left ventricular wall seemed to arise from a dose-related failure to increase left ventricular mass commensurate with somatic growth. Cardiotoxicity had two distinct forms: depressed contractility, associated with higher cumulative doxorubicin dose and female sex, and increased afterload, resulting from decreased left ventricular mass and wall thickness. The latter form of cardiotoxicity is related to time since treatment, age at treatment, and doxorubicin dosage.2
The current understanding of late cardiac abnormalities after doxorubicin comes largely from cross-sectional studies, and data about progressive dysfunction have been insufficient to model long-term morbidity. Therefore, in a prospective study, we examined the longitudinal course of left ventricular structure and function in this cohort,1 now followed up for a median of 11.8 years.
METHODS
Patients
The cardiac status of the survivors of childhood acute lymphoblastic leukemia has been periodically assessed at Dana-Farber Cancer Institute and Children's Hospital in Boston, MA.1,2 Eligible patients had completed one of six Dana-Farber pediatric acute lymphoblastic leukemia protocols (72-01, 73-01, 77-01, 80-01, 81-01, or 85-01)3 at least 2 years earlier and were in a first remission. Specifically, eligibility in the echocardiographic evaluation of study patients were being disease-free as of 1989, when this cohort was first assembled,1 and being disease-free 2 years from the end of treatment. Findings in the ineligible patients1,2 did not differ significantly from those included in the study, suggesting that the study population was representative of the larger group.1–3
The children had a total of 736 echocardiograms. Patients with the most impaired cardiac function had the most echocardiograms, and thus including all echocardiograms in the analysis could have biased the results. Therefore, we categorized the echocardiograms and for each patient analyzed one echocardiogram in each category: before doxorubicin therapy, after therapy, the first to assess wall stress, those made from 1987 to 1990 to study left ventricular structure and function, and the most recent, to allow comparison to prior studies on this cohort.1,2 However, these do not correspond to the number of patients by time from diagnosis as noted in Table 1, so that a subject could have been seen more than once in these intervals even though they were seen only once in the echocardiogram grouping before doxorubicin therapy, after therapy, the first to assess wall stress, those made from 1987 to 1990 to study left ventricular structure and function, and the most recent.
The resulting 499 echocardiograms were all remeasured by a single sonographer who was unaware of the clinical data.4 Each echocardiographic study consisted of a complete 2-dimensional echocardiogram and Doppler evaluation with stress-velocity analysis.1,2,5 We used fractional shortening as a measure of overall left ventricular systolic performance, which is influenced by heart rate, preload, afterload, and myocardial contractility. Contractility was measured by the stress-velocity relationship, a load-independent index that incorporates preload and heart rate and varies with afterload.1,2,5 Afterload was assessed as left ventricular end-systolic wall stress, which varies directly with blood pressure and left ventricular dimension and inversely with left ventricular wall thickness.1,2,5
Statistical Methods
To standardize cardiac data by age or body-surface area, to adjust for changes associated with growth, we calculated z scores (the number of standard deviations [SDs] the observed measurement is above [+] or below [–] the predicted value) by dividing the difference between a child's observed cardiac outcome and the normal predicted value by the SD of a distribution of normal cardiac values. The normal predicted value was calculated with a regression model,1,2,5 using data from 285 normal children measured at the same center and in the same manner as the study patients. The normal subjects ranged in body size from 0.2 to 2.2 m2 and were included on the basis of normal height, weight, and height for weight centiles; normal blood pressure; and no evidence of cardiac or other disorders. We adjusted the z scores for mass, afterload, dimension, and wall thickness for body-surface area, and those for fractional shortening, blood pressure, and peak systolic wall stress for age. We plotted z scores over time by repeated-measures regression models in SAS PROC MIXED (SAS, Cary, NC), in which the z score was modeled as a linear, quadratic, and cubic function of time since diagnosis, and we modeled the correlation between z scores measured at a pair of times on the same subject using an autoregressive structure.
We grouped the 115 patients into three categories by cumulative dose (low, < 300 mg/m2; moderate, 300 to 400 mg/m2; or high, > 400 mg/m2), and then fitted a separate curve for each group. In this study, the patients with poorer heart function were seen more often, and were also followed-up for a longer period of time. In particular, the care providers decided to closely monitor the sicker patients. Since the number of visits and length of follow-up depended on observed data (the heart function at the previous visits), the missing data are missing at random.6 To adjust for the missing at random data, we used the mixed model formulation in SAS PROC MIXED, which ensures that the patients with poor cardiac function who came back most often for repeat testing were not given excessive weight and, did not have a disproportionate influence on the tails of the plots. Since SAS PROC MIXED gives unbiased estimates when missing data are missing at random, we feel confident that the results of this study are not biased in any direction. Data from patients on afterload reduction therapy were censored from blood pressure and afterload analyses when this therapy started.
We also created plots using only the first follow-up observation for each subject, only the last observation for each subject, and the follow-up observation closest to 18 years of age, and found them all to be similar to Figures 1 and 2 (data not shown). We did a sensitivity analysis in which we looked at all possible single observations from each individual interval, and it did not change the results from this article.
In Figure 2, not all z scores were obtained at each time point, so lines for some dose groups contain gaps. All three groups in Figure 2 had at least 10.5 years of follow-up.
To determine whether the z score at the end of treatment predicted long-term cardiac function, we tested linear regression analysis with the latest follow-up z score as the outcome, and three covariates: (1) z score at the end of treatment, (2) time from the end of treatment to latest z score, and (3) cumulative dose group.
RESULTS
Patient Characteristics
Median age at diagnosis was 4.8 years (range, 1.0 to 19.0 years), and the median age at the end of doxorubicin therapy was 5.5 years (range, 2.0 to 21.0 years). Median cumulative doxorubicin dose was 352 mg/m2 (range, 45 to 550 mg/m2), and median dosage was 30 mg/m2 per dose (range, 30 to 52 mg/m2/dose). In the low cumulative dose group, 18 patients (with 50 echocardiograms) received total cumulative doses of 45 mg/m2.
The characteristics of the 115 included patients were compared wth those of the 278 patients who were not included. There were no statistically significant differences in the percentage who were female (50% v 46%), median age after therapy (5.5 v 5.7 years), or median WBC count (9,750 v 7,900 cells/mm3). The median follow-up survival was significantly longer in the included patients (19.5 v 16.5 years). Since most of the patients are still alive, we do not think it indicates that there is a bias by following the patients longer. Because the patients with the highest cumulative doxorubicin doses also had the longest follow-up since higher doses were used in earlier studies (Table 1), we presented the results both for all patients (Fig 1) and by dose category (Fig 2). Age and sex distribution did not significantly differ between cumulative dose groups (Table 1).
Eleven children had early congestive heart failure (before 1 year posttherapy), five of whom also experienced late congestive heart failure. Seven children received cardiac medication during follow-up, including afterload reduction therapy. In the five children with late congestive heart failure, clinical and laboratory findings were consistent with a restrictive cardiomyopathy. These children were often sicker and required earlier heart transplantation than did children with dilated cardiomyopathy at similar levels of systolic dysfunction (data not shown). Two of the 11 children received heart transplants, and another died from cardiac causes while awaiting a heart transplant.
Left Ventricular Structure and Function
Left ventricular contractility. Left ventricular contractility was significantly depressed after doxorubicin therapy, normalized during the next 6 years, and then became significantly depressed at 12 years or more after diagnosis (Table 2, Fig 1A). The change in mean left ventricular contractility over time was statistically significant (P < .001, Fig 1A). The pattern of improvement followed by decline was found in all treatment groups. It varied in severity with cumulative dose, reaching statistical significance at last follow-up in the two higher cumulative dose groups (Table 3, Fig 2A).
Left ventricular end-diastolic dimension. During chemotherapy, the left ventricle was significantly dilated (Table 2), but it returned to normal after therapy (Fig 1B). The change over time in left ventricular dimension approached statistical significance (P = .06). The magnitude of the dilation in left ventricular dimension varied directly with cumulative dose, and while the values for the higher dose groups normalized with time, left ventricular dimension for the low-dose group became significantly lower than normal (Table 3, Fig 2B). At 10.5 years, left ventricular dimension (Fig 2B) differed significantly between the low-dose and moderate-dose groups (P = .027) and between the low-dose and high-dose groups (P = .002).
Left ventricular wall thickness. Mean left ventricular wall thickness relative to body-surface area was significantly reduced at the completion of doxorubicin therapy, became thinner over time, and was significantly less than normal at all points of follow-up beyond 6 years (Tables 2 and 3, Fig 1C). The change in mean left ventricular wall thickness over time was statistically significant (P < .001, Fig 1C). Dose-related differences were not significant (Fig 2C).
Left ventricular mass. Mean left ventricular mass was nearly normal after therapy but decreased over 15 years to more than 1 SD below normal. The difference became significant between 6 and 9 years after diagnosis (Table 2, Fig 1D). The change in mean left ventricular mass over time was significant (P = .049; Fig 1D). Left ventricular mass decreased over time in all dose groups (Fig 2D), and was significantly below normal at last follow-up (Table 3). Left ventricular mass (Fig 2D) differed significantly between the moderate- and high-dose groups (P < .001).
Left ventricular fractional shortening. Mean fractional shortening was significantly depressed after therapy, improved, and then became significantly more depressed (Fig 1E, Table 2). The change after the completion of therapy was statistically significant (P < .001). All cumulative dose groups were nonoverlapping over time (Fig 2E). The degree of depression was dose-dependent (Fig 2E, Table 3). The low-dose group had relatively normal fractional shortening, a finding consistent with our prior work,7 yet, the mean in the high-dose group was nearly 3 SDs below normal at the last follow-up (Fig 2E). Left ventricular fractional shortening (Fig 2E) differed significantly between the low- and high-dose groups (P < .001) and between the moderate- and high-dose groups (P < .001).
Left ventricular afterload. Mean left ventricular afterload was significantly elevated after therapy. Over the next 12 to 14 years, it increased progressively to about 3 SDs above normal (Table 2, Fig 1F). The change over time was statistically significant (P < .001). Afterload was significantly dose-related; at last follow-up, it was normal in the low-dose group and significantly elevated in the moderate- and high-dose groups (Table 3, Fig 2F). Left ventricular afterload (Fig 2F) differed significantly between the low- and moderate-dose groups (P = .002), the low- and high-dose groups (P < .001), and the moderate- and high-dose groups (P < .001).
Systolic blood pressure. Mean systolic blood pressure fell steadily during follow-up, from normal to 1 SD below normal at last follow-up (Table 2, Fig 1G). The change in systolic blood pressure over time was statistically significant (P = .028; Fig 1G). It was significantly depressed beyond 9 years of follow-up for the two higher dose groups (Table 3, Fig 2G).
Diastolic blood pressure. Mean diastolic blood pressure fell rapidly, and significantly so at 9 to 12 years of follow-up (Table 2, Fig 1H). The change over time was statistically significant (P = .012; Fig 1H). It was significantly depressed at latest follow-up in the two higher dose groups (Table 3, Fig 2H).
Left ventricular thickness-dimension ratio. Mean left ventricular thickness-dimension ratio was significantly reduced throughout follow-up; this progressive fall was significant (P < .001; Table 2, Fig 1I). The two highest dose groups were significantly reduced at last follow-up (Table 3, Fig 2I). Left ventricular thickness-dimension ratio (Fig 2I) differed significantly between the low- and moderate-dose groups (P = .045) and the low- and high-dose groups (P = .023).
Predicting late cardiac measurements from those at the end of therapy. The mean z scores at the completion of doxorubicin therapy predicted late follow-up z scores for left ventricular fractional shortening and end-diastolic dimension (P < .001 for each). For fractional shortening, a mean z score below –2 at the end of therapy was associated with a mean z score below –2 an average of 11 years later. A mean z score between –2 and +1 was associated with a later mean z score of –0.67, and a mean z score above 1 was associated with a later mean z score of 0.3. For end-diastolic dimension, mean z scores below 0 after therapy were associated with a mean z score of –0.96 an average of 11 years later. Mean z scores above 0 were associated with a later mean z score of 0.41.
DISCUSSION
Although many of the cardiotoxic effects of doxorubicin therapy for childhood acute lymphoblastic leukemia initially improved after therapy, our longitudinal study showed that cardiac abnormalities are common, persistent, and, for many patients, progressive. Inadequate left ventricular mass with chronic afterload elevation was associated with a progressive contractile deficit. Blood pressures were significantly lower after 9 years, which may indicate reduced cardiac output. The contractile deficit increased with cumulative doxorubicin dose, but even low cumulative dose groups were affected. We did not find a safe dose of doxorubicin that was free of late toxicity.
The abnormalities may portend important problems in the future for anthracycline-treated survivors of childhood cancer. Two studies suggest that the cumulative rate of congestive heart failure rises over time.8,9 In another study, the standardized mortality rate for cardiac death was 8.2 times higher than expected, and the cumulative probability of cardiac death rose 15 to 25 years after diagnosis.10 A study of 5-year survivors found standardized mortality rates of 5.8 for cardiac death and 3.9 for sudden, presumed cardiac death.11 Noncancer deaths increased steadily during the 35 years after treatment.11 In another group of 15-year survivors, increased mortality was related, in part, to doxorubicin and did not decrease during more recent treatment eras.12
The potential effect of these findings is enormous because of the large numbers involved. Of the 12,400 children and adolescents diagnosed with cancer in the United States each year, the overall 5-year survival rate is nearly 80%.13 Approximately one in every 540 adults in the United States aged 20 to 34 years is predicted by the year 2010 to be a survivor of childhood cancer,14 and half of them will have been treated with an anthracycline.15
Cumulative doxorubicin dose affects the development of dilated cardiomyopathy, afterload excess, and late reduction in systolic and diastolic blood pressure. We previously found that at 8 years of follow-up, survivors of childhood cancer who received a cumulative doxorubicin dose of less than 300 mg/m2 have normal left ventricular fractional shortening and dimension.7 Unfortunately, our current data reveal that even patients who received lower cumulative doses, even as low as 45 mg/m2, eventually experienced cardiac abnormalities, including significantly reduced left ventricular mass and dimension. Even low doses are problematic if the goal is to avoid late cardiotoxicity.
In contrast, cumulative doxorubicin dose does not affect the reductions of left ventricular wall thickness and mass (relative to body-surface area), which produce late afterload excess. We previously reported that these late effects are related to a younger age at cancer diagnosis and to longer time since diagnosis2; our current data are consistent with both findings. Cardiac mortality is significantly lower when cancer is diagnosed after age 7 years,10 suggesting that this second type of cardiac dysfunction, with reduced left ventricular wall thickness and mass, may be associated with late cardiac mortality. Abnormal left ventricular volume and pressure overload can lead to chronic afterload excess, resulting in contractile deterioration, in other populations.16
After doxorubicin therapy, the children in our study had a dilated cardiomyopathy (significantly reduced left ventricular fractional shortening and contractility with left ventricular dilation). With time, however, the pattern that appeared was consistent with a developing restrictive cardiomyopathy (normal to reduced left ventricular dimension with significantly reduced left ventricular thickness, fractional shortening, and contractility). These patients experienced a progressive rise in afterload despite a fall in blood pressure. The rise in afterload was secondary to the fall in thickness-dimension ratio, a change that occurred despite the fact that dimension did not increase, emphasizing inadequate left ventricular mass as the primary cause of excess afterload. Progression of this doxorubicin-associated late cardiomyopathy may be slower than for children with dilated cardiomyopathy who were not treated with doxorubicin but nevertheless is unremitting and inexorable during this period of follow-up.
Cardiac monitoring by echocardiography is useful in this population since cardiac measurements after doxorubicin therapy predicted those at latest follow-up. However, these echocardiographic measurements need to be validated as surrogate markers of clinically important end points.17 Left ventricular fractional shortening and wall thickness predict all-cause mortality years in advance in children with HIV-associated cardiomyopathy,18 which allows prevention and therapy to be targeted to high-risk children.19–23 Unfortunately, echocardiography does not identify patients with the greatest abnormalities of left ventricular wall thickness, mass, and afterload on late follow-up after doxorubicin therapy, perhaps because these abnormalities are related to age at diagnosis and time since treatment, rather than cumulative doxorubicin dose.24–26
The effects on left ventricular contractility may be caused by chronic, excessive afterload,1,2 as well as by irreversible impairment of mitochondrial function27,28 and calcium handling29,30 in the myocardiocytes. Progressive left-ventricular wall thinning may result from the loss of myocardiocytes,1 increased apoptosis,31 and reduced collagen production from doxorubicin toxicity that results in enlargement of remaining myocardiocytes.32
These results call into question the use of doxorubicin in children, especially when alternative therapies are available. More follow-up is needed to determine the natural history and clinical importance of these abnormalities and recommendations for change in current treatment.26 Potential cardioprotectants should be validated and used in conjunction with doxorubicin33–35 to reduce myocardial injury.36,37 Effective preventive and therapeutic strategies must be developed to slow the course of doxorubicin-associated late cardiac dysfunction in long-term survivors of childhood cancer.38-40
Authors' Disclosures of Potential Conflicts of Interest
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. Consultant/Advisory Role: Steven E. Lipshultz, Chiron. Research Funding: Steven E. Lipshultz, Chiron, Pfizer, Roche Diagnostics. For a detailed description of these categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue.
NOTES
Supported by grants from the National Institutes of Health (CA 68484, CA 55576, CA 06516, CA 79060, HL 59837, HR 96041, HL 53392, HL 72705, and HL 69800).
This study was presented in part as an abstract at the American Society of Clinical and Oncology and the American Heart Association annual sessions.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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