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Journal of Clinical Oncology, Vol 25, No 24 (August 20), 2007: pp. 3635-3643
© 2007 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2006.09.7451
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Noninvasive Evaluation of Late Anthracycline Cardiac Toxicity in Childhood Cancer Survivors

Melissa M. Hudson, Shesh N. Rai, Cesar Nunez, Thomas E. Merchant, Neyssa M. Marina, Nia Zalamea, Cheryl Cox, Sean Phipps, Ronald Pompeu, David Rosenthal

From the Departments of Hematology Oncology, Biostatistics, Radiological Sciences, and Epidemiology and Cancer Control, and the Division of Behavioral Medicine, St Jude Children's Research Hospital, the University of Tennessee, College of Medicine, Memphis, TN; Department of Pediatrics, M.D. Anderson Cancer Center, Houston, TX; Department of Pediatrics and Cardiology, Stanford University Medical Center, Stanford; and Department of Surgical Education, Santa Barbara Cottage Hospital, Santa Barbara, CA

Address reprint requests to Melissa M. Hudson, MD, St Jude Children's Research Hospital, 332 North Lauderdale, Mailstop 735, Memphis, TN 38105; email: melissa.hudson{at}stjude.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 Appendix
 REFERENCES
 
Purpose Childhood cancer survivors treated with anthracyclines and cardiac radiation are at risk for late-onset cardiotoxicity. The purpose of this study was to delineate the relationship between clinical factors and abnormalities of noninvasive cardiac testing (NICT).

Patients and Methods Participants were recruited from a long-term follow-up clinic. Study measures comprised physical examination, laboratory evaluation, echocardiogram, and ECG. Mean fractional shortening (FS) and afterload were compared for survivors who did (at risk [AR]) and did not (no risk [NR]) receive potentially cardiotoxic modalities, and with values expected for comparable age- and sex-matched controls.

Results The 278 study participants (mean age, 18.1 years; median age, 16.8 years; range, 7.5 to 39.7 years) included 223 survivors AR for cardiotoxicity after treatment with anthracyclines (median dose ± standard deviation [SD], 202 ± 109 mg/m2) and/or cardiac radiation. Mean FS (± SD) was lower for AR (0.33 ± 0.06) compared with NR survivors (0.36 ± 0.05; P = .004) and normative controls (0.36 ± 0.04; P < .001). Mean afterload (± SD) was higher for AR (58 ± 21 g/cm2) compared with NR survivors (46 ± 15 g/cm2; P < .001) and normative controls (48 ± 13 g/cm2; P < .001). The distribution of FS and afterload among NR survivors did not differ from that of controls. After adjustment for age group at diagnosis and time since completion of therapy, anthracycline dose predicted decline in distribution of FS (P < .001) and increase in distribution of afterload (P < .001). Treatment with anthracycline doses ≥ 100 mg/m2 increased the risk of abnormal NICT; survivors who received ≥ 270 mg/m2 had a 4.5-fold excess risk of abnormal NICT (95% CI, 2.1 to 9.6) compared with controls.

Conclusion Childhood cancer survivors treated with anthracycline doses ≥ 270 mg/m2 are at greatest risk for abnormalities of FS and afterload.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 Appendix
 REFERENCES
 
Despite their well-established risk of cardiotoxicity, anthracyclines remain a critical component of treatment for many pediatric malignancies because of their favorable therapeutic benefit.1 Thus, numerous studies have attempted to characterize the clinical predictors, pathogenesis, and natural history of anthracycline-related cardiotoxicity in childhood cancer patients. However, our understanding of cardiotoxicity from an epidemiologic perspective remains inadequate for the following reasons: investigations vary in methodology and definition of cardiotoxicity; published data regarding risk factors are contradictory; longitudinal data on well-defined cohorts, especially those treated with contemporary regimens restricting anthracyclines, are deficient; and the relationship between abnormalities identified by noninvasive cardiac testing (NICT) and clinical status (both present and future) is unknown. In particular, our understanding of the clinical implications of low-dose anthracycline chemotherapy in contemporary treatment regimens on long-term cardiovascular health is limited.2-8 In an effort to increase this knowledge, we describe the results of a study in long-term childhood cancer survivors returning for annual follow-up with the aim of elucidating the relationship of clinical and treatment factors to the risk of cancer-related cardiotoxicity determined through comprehensive noninvasive evaluation of cardiovascular function.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 Appendix
 REFERENCES
 
Patient Eligibility and Recruitment
We recruited study participants from long-term childhood cancer survivors in the St Jude Children's Research Hospital (Memphis, TN) After Completion of Therapy Clinic. We targeted enrollment to the following diagnostic groups: acute leukemia, a group receiving low cumulative dosages of anthracycline (100 mg/m2); mediastinal lymphoma, a group with potential cardiovascular injury from anthracyclines and/or thoracic irradiation; sarcoma, a group receiving relatively high cumulative dosages of anthracyclines (300 to 500 mg/m2); and neuroblastoma, a group with cardiac immaturity at anthracycline administration. In addition, a group of survivors (acute lymphoblastic leukemia, Wilms' tumor, and germ cell tumors) not receiving anthracyclines or thoracic irradiation was enrolled as controls. Exclusion criteria included history of congenital heart disease, chronic systemic illness requiring ongoing medical treatment, trisomy 21, and anemia (hematocrit < 28%). Consecutive patients meeting the eligibility criteria were identified and invited to participate. Enrollment was closed for the specific diagnostic groups after reaching the protocol-specified targeted accrual yielding a convenience cohort of study participants. The study was approved by the institutional review boards at St Jude Children's Research Hospital and Stanford University (Stanford, CA). All study participants or their parents provided informed consent.

Clinical Data Collection
We obtained patient demographic, diagnostic, and treatment characteristics by review of the patient's medical records. Cardiac dosimetry was determined by evaluating the original radiation treatment records and portal films.

Cardiac Evaluation
All patients underwent a clinical cardiac assessment by the primary oncologist to evaluate signs of heart failure and assignment to the New York Heart Association class.9 NICT was performed within 24 hours of the clinical assessment and included 12-lead ECG and echocardiography. Echocardiograms consisted of a complete two-dimensional, M-mode, and Doppler evaluation with stress-velocity analysis.10-12 All ECGs and echocardiograms were interpreted by a single cardiologist blinded to treatment (R.P.). Carotid applanation tonometry was performed for determination of ascending aortic pressure and measurement of aortic augmentation index (a measure of vascular compliance).13,14 Fractional shortening (FS) was used as a measure of overall left ventricular systolic performance, and was not age-adjusted, given that it is known to be independent of age in the range of ages in this study.15 Afterload was approximated by the left ventricular end-systolic wall stress.10 Recently, some authors have advocated the use of fiber stress rather than wall stress as a more accurate reflection of true afterload. We chose to use meridional wall stress because of the greater clinical experience with this measure in the setting of anthracycline toxicity.16-18 In addition, as has been noted by Silber,19 in the setting of anthracycline toxicity, the differences between fiber stress and wall stress are small, particularly in the encountered ranges of wall thickness and chamber size. Although contractility index, originally described by Colan et al,20 has been shown to be sensitive in detecting abnormalities in this population, we selected afterload as an end point because of the greater volume of clinical experience with this method.

Statistical Analysis
For the analysis, participants were categorized as at risk (AR) if treatment included anthracyclines or irradiation of some portion of the heart; patients categorized as having no risk (NR) did not receive these treatments. Normative control information was obtained from published data from healthy individuals.15,20-24 Statistics for clinical variables were generated for both groups. Categoric variables were compared using {chi}2 tests.25 Continuous variables were compared using an independent two-sample t test or Wilcoxon rank sum test when the normality assumptions were violated.26 Generalized linear model analysis was used when some predictors were continuous and others categoric. Where data were skewed, log transformation was used to obtain normally distributed values. Raw values for left ventricular diastolic dimension and left ventricular systolic dimension were adjusted for body-surface area (BSA) by dividing by the cube root of BSA, and left ventricular posterior wall diastolic dimension and left ventricular posterior wall systolic dimension values were adjusted by dividing by the square root of BSA.27

The formula used to calculate BSA was (W0.425 x H0.725) x 0.007184, where W is weight in kilograms and H is height in centimeters.28 Body mass index (BMI) expressed in kilograms per square meter was used as index of obesity according to the formula (weight/height2). For patients younger than age 20 years, we used an SAS program (version 9; SAS Institute, Cary, NC) to categorize into weight-for-length percentiles or BMI-for-age percentiles based on normative data.29 For patients age ≥ 20 years, the BMI is used to define obesity according to the current National Heart, Lung, and Blood Institute definitions as follows: underweight (BMI < 18.5), normal weight (BMI 18.5 to 24.9), overweight (BMI 25 to 29.9), or obese (BMI ≥ 30).30

We used linear regression to assess predictive factors for distribution of FS and afterload. Dependent variables included actual measures of FS and afterload, with abnormal FS defined as less than 0.28, abnormal afterload as more than 74 g/cm2, or either abnormal FS or abnormal afterload. A set of categoric and continuous variables believed to influence the dependent variables were included in multiple regression (linear for actual measures of FS and afterload, and logistic for indicator of abnormal FS and afterload models). We conducted univariable analysis on each individual variable; factors emerging as marginally significant (P < .10) were included in the multivariable analysis. In the multivariable regression, interactions with anthracycline dose exposure and significant factors (from univariable analysis) were explored and retained if effects were still significant. The interaction effect in multivariable logistic regression analysis was not explored because of small event numbers. To adjust the effect of age group (age < 5 v ≥ 5 years) at diagnosis and time since treatment completion, univariable and multivariable analyses always included these two variables in the model. Statistical analyses were performed using SAS software (version 9.1) and S-Plus (version 6.2; Statistical Sciences, Seattle, WA) software.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 Appendix
 REFERENCES
 
Patient Demographics
The 278 patients who agreed to participate in the study represented 22% of the clinic population (n = 1,268); 223 were designated AR and 55 were designated NR based on treatment. Twelve patients declined participation because they were unable to stay for study evaluations. Table 1 summarizes the participants' characteristics. Of 278 cancer survivors who agreed to participate, AR and NR groups did not significantly differ by sex, race/ethnicity, age at cancer diagnosis or age at study evaluation. The time since completion of therapy was significantly longer (P = .003) in survivors in the NR group (median, 11.0 years; range, 4.3 to 21.7 years) compared with those in the AR group (median, 9.0 years; range, 3.0 to 18.0 years). Primary cancer diagnostic groups differed significantly in AR and NR groups, reflecting the use of anthracyclines and thoracic irradiation for specific diagnostic groups. There was also a strong association (P < .001) between disease group and anthracycline dose-intensity (zero, < 50, and ≥ 50 mg/m2/wk).


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  		Table 1. Characteristics of 278 Patients Enrolled Onto the Noninvasive Cardiac Study

 
Clinical Cardiovascular Status
Two patients had a history of a transient cardiac insufficiency during therapy associated with sepsis that resolved following brief inotropic and pressor therapy. None of the patients had clinical cardiac dysfunction at the time of study evaluation. In several patients, aspects of the noninvasive evaluation were technically unsatisfactory and data were not recorded. This was most commonly the result of an inadequate carotid pulse trace. Technically satisfactory data were available to calculate FS, afterload, and QTc in 272, 238, and 273 patients, respectively. Noninvasive assessment identified subclinical cardiovascular dysfunction with FS less than 0.28 in 37 (13.6%) of 272 patients, afterload more than 74 g/cm2 in 33 (13.8%) of 238 patients, or any abnormality in 57 patients (20.9%). In addition, 11 (4.0%) of 273 patients had a prolonged QTc interval.

Cardiotoxic Cancer Treatment
Among the 223 AR patients, potentially cardiotoxic treatment included anthracyclines in 157 patients (67.4%), anthracyclines plus cardiac radiation in 60 patients (25.8%), and cardiac radiation only in six patients (2.6%). There was a broad distribution of anthracycline doses in the AR group (median, 201.8 mg/m2; range, 25 to 510). Of 66 patients who had thoracic irradiation, the treatment field included the whole heart (n = 19) or partial heart (n = 47).

Cardiac Structure and Function
Table 2 presents results from a two-sample t test or generalized linear model procedure when adjusting for age group at diagnosis and time since completion of therapy for FS and afterload among the two study groups and normative controls (all values that follow are presented as median ± SD). AR survivors had significantly lower FS (0.33 ± 0.06) than NR survivors (0.36 ± 0.05; P = .004) and healthy controls (0.36 ± 0.04; P < .001). Likewise, AR survivors had significantly higher afterload (58 ± 21 g/cm2) than NR survivors (46 ± 15 g/cm2; P < .001) and healthy controls (48 ± 13 g/cm2; P < .001). The distribution of FS and afterload among NR survivors did not differ from that of controls. Individual cardiac dimensions showed relative left ventricular chamber enlargement and wall thinning in AR compared with NR survivors commensurate with more global measures of FS and afterload (raw cardiac measurements are listed in Appendix Table A1, online only).


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  		Table 2. Comparison of Distribution of Cardiac Function in Study Groups and Normative Controls

 
Clinical Variables Influencing Cardiac Function
Effect of Cumulative Anthracycline. To evaluate the influence of anthracycline dose on cardiac outcome, anthracycline exposure for the 217 anthracycline-treated AR survivors was categorized according to total dose with an attempt to form groups of equal size. Table 3 summarizes the analyses comparing the distribution of FS and afterload between normative controls, individual dose groups, and consecutive dose groups after adjusting for age group at diagnosis and time since completion of therapy. Increasing cumulative anthracycline doses above 100 mg/m2 demonstrated a significantly progressive decrease in FS and increase in afterload. This effect first developed at a dose range of 100 to 174 mg/m2, and continued until the maximum dose range (350 to 510 mg/m2). Comparison between serial groups showed a difference between the 100 to 174 mg/m2 group when compared with the 1 to 99 mg/m2 group, with significantly lower FS (P = .002) and higher afterload (P = .011) in the higher dose group. For subsequent serial comparisons, there were no statistically significant interval changes for FS. However, for afterload, there was also a statistically significant difference between the 270 to 349 mg/m2 group and the next lower dose range (200 to 269 mg/m2), with the higher dose associated with higher afterload (P = .016). None of the other serial dose comparisons indicated any difference in afterload between consecutive dose groups. After adjusting for age group at diagnosis and time since completion of the therapy, survivors who received anthracycline doses ≥ 270 mg/m2 had a 4.4-fold (95% CI, 1.95 to 10.4) and 4.0-fold (95% CI, 1.7 to 9.4) excess risk of abnormal FS and afterload, respectively, compared with controls; the relative risk of either abnormal FS or afterload was 4.5-fold (95% CI, 2.1 to 9.6). Data in Table 4 summarize the relationship of anthracycline dose in patients with abnormal FS or afterload.


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  		Table 3. Distribution of Mean Factional Shortening and Afterload by Anthracycline Dose Groups Compared to Normative Controls

 

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  		Table 4. Relationship of Anthracycline Dose Groups and Abnormal Cardiac Measures

 
Linear Regression Analyses of Predictors of Distribution of Cardiac Outcomes
Results of the univariable and multivariable linear regression analyses performed to evaluate the effect of clinical variables on the distribution of cardiac function measures are summarized in Table 5. Three key demographic variables that were independent predictors of the outcome were included in each regression analysis: sex, age group at diagnosis, and time since completion of therapy. All comparisons were adjusted for age group at treatment and follow-up time. We did not observe a significant interaction between sex and anthracycline dose (P = .21). We also could not demonstrate significant or additive effects of radiation or cyclophosphamide on cardiac toxicity as measured by FS or afterload. Notably, aside from BMI, other modifiable post-treatment cardiovascular disease risk factors and history of endocrinopathy did not influence risk of abnormal FS or afterload. In the multivariable model, increasing anthracycline dose emerged as the only significant predictor of reduced FS (P < .001), and age group at diagnosis was not a significant predictor even though it was significant in the univariable model. Significant predictors of elevated afterload included increasing anthracycline dose (P < .001), age group ≥ 5 years (P = .006), and normal BMI (P = .015). Notably, survivors who were older at diagnosis (≥ 5 years) received significantly higher cumulative anthracycline doses compared with those who were younger (< 5 years) at diagnosis (P < .001).


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  		Table 5. Linear Regression of Predictors of Distribution of Fractional Shortening and Afterload

 
Logistic Regression Analyses of Predictors of Abnormal Cardiac Outcomes
Results of the univariable and multivariable logistic regression analyses performed to evaluate predictive factors for abnormal cardiac function are summarized in Table 6. All comparisons were adjusted for age group at treatment and follow-up time. Multivariable logistic regression analysis identified increasing anthracycline dose (P = .033) and diagnosis group (P = .051) as the only factors predicting abnormal FS; increasing anthracycline dose (P = .006) and time since therapy (P = .011) predicted abnormal afterload.


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  		Table 6. Logistic Regression Analysis of Predictors of Abnormal Fractional Shortening and Afterload

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 Appendix
 REFERENCES
 
We observed significantly lower FS and higher afterload compared with healthy controls in a cohort of asymptomatic long-term childhood cancer survivors treated with anthracyclines. Notable results include the relatively large study cohort comprising individuals treated across a broad spectrum of ages at diagnosis and anthracycline dose levels. The majority (83%) received cumulative anthracycline doses restricted to 300 mg/m2 or less, reflective of contemporary treatment regimens for favorable pediatric malignancies. Cardiotoxic treatment was well characterized by cumulative anthracycline dose, anthracycline dose-intensity, and cardiac dosimetry. As observed in previous studies, increasing anthracycline dose predicted subclinical cardiovascular dysfunction affecting both FS and afterload at levels above 100 mg/m2. Survivors receiving doses ≥ 270 mg/m2 had a 4.5-fold excess risk of abnormal FS or afterload (95% CI, 2.13 to 9.55) compared with controls.

Numerous cross-sectional and longitudinal studies indicate that individuals treated with higher anthracycline doses, especially ≥ 300 mg/m2, are at risk of exhibiting subclinical cardiovascular dysfunction and clinically significant cardiomyopathy.1-5,7,8,16,31-42 In a prospectively observed cohort of 830 cancer survivors (median, 7.1 years from therapy), Dutch investigators observed that the risk of anthracycline clinical heart failure increased over time, with an estimated risk of 9.8% at 20 years in those who received anthracycline doses of ≥ 300 mg/m2.43 At a median of 11.8 years (range, 8.3 to 15 years) from therapy, Lipshultz et al44 reported cases of late-onset congestive heart failure associated with cardiomyopathy concurrent with an increasing frequency and severity of subclinical cardiac abnormalities in childhood leukemia survivors. French investigators observed similar results in childhood survivors of solid tumors.37 In that study of 229 survivors evaluated at a median of 15 years (range, 0.3 to 24 years) from therapy, 10% developed congestive heart failure and another 39% exhibited severe cardiac dysfunction or major ventricular overload by noninvasive testing in the absence of clinical symptoms. Similar to our study, cumulative anthracycline dose and time from therapy significantly predicted risk of cardiac toxicity.37,43,44

Survivors in our cohort demonstrated an excess risk of abnormalities of cardiac function after treatment with cumulative anthracycline doses in the range of 100 to 200 mg/m2, which contradicts results reported by other investigators advocating the relative safety of anthracycline therapy when doses are restricted to less than 250 mg/m2.8 Several studies evaluating the long-term impact of lower dose anthracycline exposure indicate that a significant minority of survivors exhibit subclinical changes of cardiac dysfunction.2-8 In an excellent systematic review evaluating subclinical cardiotoxicity in childhood cancer survivors, Kremer et al45 noted a range in incidence of abnormal left ventricular function from 0% to 15.2% in individuals treated with cumulative doses less than 300 mg/m2. Noninvasive assessments in our cohort demonstrated that the distribution of FS and afterload in survivors treated with doses less than 100 mg/m2 did not differ from normative controls. Sorensen et al7,8 observed no deterioration of left ventricular end systolic stress at greater than 10 years in longitudinally monitored survivors of childhood leukemia and Wilms' tumor treated with cumulative anthracycline doses less than 240 mg/m2. Similarly, Rammeloo et al46 did not observe a difference in echocardiographic assessment of FS, wall stress, or other measures of left ventricular function in childhood leukemia patients (median, 14 years from diagnosis) randomly assigned to receive either 100 mg/m2 daunomycin (four doses of 25 mg/m2) or no daunomycin. These data do not support the cardiotoxic potential of cumulative anthracycline doses less than 100 mg/m2. However, in other studies, occurrences of congestive heart failure have been reported in survivors treated with low cumulative doses of anthracyclines, but demographic factors such as age, sex, race, and treatment factors (such as anthracycline dose-intensity or cardiac radiation) may have modified the risk of anthracycline cardiotoxicity.1,31,45

This study has several limitations that should be considered in the interpretation of results. First, the cross-sectional study design precludes evaluation of the longitudinal impact of cardiotoxic antineoplastic therapy. The variability in time from diagnosis among the cohort could underestimate the ultimate clinical impact of cancer therapy on cardiovascular function. Second, despite estimation of cardiac dosimetry, we had limited ability to evaluate the effect of radiation either alone or in combination with anthracyclines. In contemporary treatment regimens and the treatment of relatively young patients, cardiac radiation exposure is restricted proactively. Lengthy follow-up may be necessary to determine the clinical manifestations of radiation injury. Third, because of suboptimal technical quality of the noninvasive evaluations in some patients, specific cardiac outcomes were not available for all cohort members, which could introduce bias into the analysis. Fourth, the lack of recruitment of survivors with a history of worsening cardiac function or any survivors requiring cardiac medication precluded evaluation of the relationship between clinical signs and abnormalities on noninvasive testing. Finally, the most significant limitation is the lack of understanding regarding the clinical significance of abnormal NICT in individuals without clinically symptomatic cardiovascular disease.

Presently available results from longitudinal studies indicate a definite risk of progressive cardiovascular dysfunction over time, particularly in survivors treated with cumulative anthracycline doses ≥ 300 mg/m2.5,34 Continued monitoring of children treated with contemporary regimens restricting anthracyclines and radiation are critical to establish the true risks and benefits of these therapeutic interventions in newly diagnosed children.


   AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
AUTHOR CONTRIBUTIONS
 Appendix
 REFERENCES
 
The author(s) indicated no potential conflicts of interest.


   AUTHOR CONTRIBUTIONS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
Appendix
 REFERENCES
 
Conception and design: Melissa M. Hudson, Thomas E. Merchant, Neyssa M. Marina, Sean Phipps, David Rosenthal

Financial support: Melissa M. Hudson

Administrative support: Melissa M. Hudson, Shesh N. Rai, Nia Zalamea, David Rosenthal

Provision of study materials or patients: Melissa M. Hudson, Nia Zalamea, David Rosenthal

Collection and assembly of data: Melissa M. Hudson, Cesar Nunez, Thomas E. Merchant, Nia Zalamea, Cheryl Cox, Sean Phipps, Ronald Pompeu, David Rosenthal

Data analysis and interpretation: Melissa M. Hudson, Shesh N. Rai, Cesar Nunez, Thomas E. Merchant, Neyssa M. Marina, Cheryl Cox, Sean Phipps, Ronald Pompeu, David Rosenthal

Manuscript writing: Melissa M. Hudson, Shesh N. Rai, Cesar Nunez, Thomas E. Merchant, Neyssa M. Marina, Cheryl Cox, David Rosenthal

Final approval of manuscript: Melissa M. Hudson, Shesh N. Rai, Cesar Nunez, Thomas E. Merchant, Neyssa M. Marina, Nia Zalamea, Cheryl Cox, Sean Phipps, Ronald Pompeu, David Rosenthal


   Appendix
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 Appendix
REFERENCES
 
Go


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  		Table A1. Comparison of Distribution of Cardiac Dimensions in Study Groups

 


   ACKNOWLEDGMENTS
 
We thank Xin Deng and Kyeongmi Cheon for assistance in preparing the statistical analysis, Diane Brand for efforts in data collection, Les Robison and Kiri Ness for insightful comments regarding the analysis, and Barbara Cruchon for helping with manuscript preparation.


   NOTES
 
Supported in part by the Cancer Center Support (CORE) Grant No. CA 21765 from the National Cancer Institute and by the American Lebanese Syrian Associated Charities. Supported by Grant No. R25 CA23944 from the National Cancer Institute (N.Z.).

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 Appendix
 REFERENCES
 
1. 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[Abstract]

2. Bossi G, Lanzarini L, Laudisa ML, et al: Echocardiographic evaluation of patients cured of childhood cancer: A single center study of 117 subjects who received anthracyclines. Med Pediatr Oncol 36:593-600, 2001[CrossRef][Medline]

3. Fukumi D, Uchikoba Y, Maeda M, et al: Longitudinal evaluation of anthracycline cardiotoxicity by signal-averaged electrocardiography in children with cancer. Pediatr Int 44:134-140, 2002[CrossRef][Medline]

4. Levitt GA, Dorup I, Sorensen K, et al: Does anthracycline administration by infusion in children affect late cardiotoxicity? Br J Haematol 124:463-468, 2004[CrossRef][Medline]

5. 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[Abstract/Free Full Text]

6. Smibert E, Carlin JB, Vidmar S, et al: Exercise echocardiography reflects cumulative anthracycline exposure during childhood. Pediatr Blood Cancer 42:556-562, 2004[CrossRef][Medline]

7. Sorensen K, Levitt G, Bull C, et al: Anthracycline dose in childhood acute lymphoblastic leukemia: Issues of early survival versus late cardiotoxicity. J Clin Oncol 15:61-68, 1997[Abstract/Free Full Text]

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9. The Criteria Committee of the New York Heart Association: Nomenclature and Criteria for Diagnosis of Disease of the Heart and Great Vessels (ed 9). Boston, MA, Littlie, Brown & Co, 1994, pp 253-256

10. 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[Abstract]

11. Sahn DJ, DeMaria A, Kisslo J, et al: Recommendations regarding quantitation in M-mode echocardiography: Results of a survey of echocardiographic measurements. Circulation 58:1072-1083, 1978[Abstract/Free Full Text]

12. Schiller NB, Shah PM, Crawford M, et al: Recommendations for quantitation of the left ventricle by two-dimensional echocardiography: American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. J Am Soc Echocardiogr 2:358-367, 1989[Medline]

13. Colan SD, Borow KM, Neumann A: Use of the calibrated carotid pulse tracing for calculation of left ventricular pressure and wall stress throughout ejection. Am Heart J 109:1306-1310, 1985[CrossRef][Medline]

14. Kelly R, Fitchett D: Noninvasive determination of aortic input impedance and external left ventricular power output: A validation and repeatability study of a new technique. J Am Coll Cardiol 20:952-963, 1992[Abstract]

15. Henry WL, Gardin JM, Ware JH: Echocardiographic measurements in normal subjects from infancy to old age. Circulation 62:1054-1061, 1980[Abstract/Free Full Text]

16. 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[Abstract]

17. 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[Abstract/Free Full Text]

18. Silber JH, Cnaan A, Clark BJ, et al: Enalapril to prevent cardiac function decline in long-term survivors of pediatric cancer exposed to anthracyclines. J Clin Oncol 22:820-828, 2004[Abstract/Free Full Text]

19. Silber JH: Comment on "Wall stress misrepresents afterload in children and young adults with abnormal left ventricular geometry." J Appl Physiol 97:2395-2396, 2004; author reply 2396-2397[Abstract/Free Full Text]

20. Colan SD, Borow KM, Neumann A: Left ventricular end-systolic wall stress-velocity of fiber shortening relation: A load-independent index of myocardial contractility. J Am Coll Cardiol 4:715-724, 1984[Abstract]

21. Eidem BW, Tei C, O'Leary PW, et al: Nongeometric quantitative assessment of right and left ventricular function: Myocardial performance index in normal children and patients with Ebstein anomaly. J Am Soc Echocardiogr 11:849-856, 1998[CrossRef][Medline]

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Submitted October 31, 2006; accepted May 29, 2007.


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