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Obesity in Survivors of Childhood Acute Lymphoblastic Leukemia and Lymphoma

Bassem I. Razzouk, Susan R. Rose, Suradej Hongeng, Dana Wallace, Matthew P. Smeltzer, Margie Zacher, Ching-Hon Pui, Melissa M. Hudson

From the Departments of Hematology/Oncology and Biostatistics, St Jude Children's Research Hospital and the University of Tennessee Health Science Center, Memphis, TN; Department of Endocrinology, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, OH; and the Department of Pediatrics, Mahidol University, Bangkok, Thailand

Address reprint requests to Bassem I. Razzouk, MD, Department of Hematology-Oncology, St Jude Children's Research Hospital, 332 N Lauderdale Ave, Memphis, TN 38105-2794; e-mail: bassem.razzouk{at}stjude.org

	ABSTRACT

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Purpose: We evaluated the long-term effects of treatment on the body mass index (BMI) of children with acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma who received one of three CNS-directed therapies: intrathecal methotrexate with intravenous high-dose methotrexate (1 g/m²), intrathecal methotrexate with 18 Gy cranial radiation, or intrathecal methotrexate with 24 Gy cranial radiation.

Patients and Methods: Between 1979 and 1984, 456 children with newly diagnosed ALL and lymphoma were enrolled onto a single protocol at St Jude Children's Research Hospital (Memphis, TN). The heights and weights of 422 of the children were measured at diagnosis, during treatment, at the end of therapy, and approximately every 6 to 12 months thereafter. Patients who had attained their adult height at the time of analysis (n = 248) were placed in weight categories based on their BMI, BMI percentile, or weight-for-length percentile depending on age.

Results: The overall percentage of survivors who were overweight or obese approximated rates prevalent in the general population of the United States. Young age (< 6 years) and overweight/obesity at diagnosis were the best predictors of obesity at adult height. The rate of BMI increase did not differ significantly between children who received radiation and those who did not, nor between patients who received 18 or 24 Gy of cranial radiation.

Conclusion: BMI weight category at diagnosis, rather than type of CNS treatment received, predicted adult weight in long-term survivors of childhood hematologic malignancies.

	INTRODUCTION

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The number of survivors of childhood cancer has been steadily increasing with progressive improvements in therapy. This expanding population of childhood cancer survivors mandates better characterization of the long-term complications of treatment to improve our understanding of their future health risks. Obesity is a well-recognized late effect in survivors of childhood acute lymphoblastic leukemia (ALL)^1-9 that has important implications for long-term survivors because of its association with increased morbidity and mortality,^10-13 as well as social, psychological, and economic consequences.¹⁴

Several studies have implicated cranial radiotherapy and corticosteroids as treatment variables predisposing to excessive weight gain among ALL survivors.^1-3,8,15-17 However, most of these studies have been limited by lack of comparison groups and a short follow-up. The resultant data inconsistencies have impeded efforts to identify the variables that contribute most to obesity in childhood cancer survivors.^6,18-21 Recently, Oeffinger et al²² compared the prevalence of obesity in a retrospective cohort of 1,765 adult survivors of childhood ALL and 2,565 sibling controls. Treatment with cranial radiation of 20 Gy or more was significantly associated with an increased prevalence of obesity, especially in girls treated at a young age. Conversely, a study from the Dana-Farber Cancer Institute Consortium (Boston, MA) involving 618 children treated for ALL²³ found that children diagnosed at an age younger than 13 years had a significant decrease in their standardized height scores and an increase in their body mass index (BMI) score, regardless of whether they had received cranial radiation.²³

Herein, we report the results of a retrospective longitudinal study of children and adolescents treated for ALL or lymphoma on a single-institutional trial that tested different strategies of CNS treatment based on the risk of relapse. We evaluate the prevalence of overweight and obesity in these long-term cancer survivors and identify contributing clinical and treatment variables.

	PATIENTS AND METHODS

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Treatment Protocol
All study patients were treated in Total Therapy Study X,²⁴ which enrolled 431 children with ALL and 25 with advanced-stage lymphoblastic lymphoma between 1979 and 1984 and tested one of three different intensified therapies, as detailed herein.

Standard-Risk Protocol
Following standard risk assignment, 330 children started induction chemotherapy comprising vincristine, prednisone, asparaginase, and intrathecal methotrexate (MTX); 21 children did not receive further therapy because of parent refusal (n = 4) or failure to achieve remission (n = 17). The remaining 309 patients who attained complete remission were stratified and randomly assigned to receive one of two therapies: 154 received intravenous high-dose MTX (1 g/m²), and intrathecal MTX (12 mg/m² [high-dose intravenous/intrathecal methotrexate arm; IVIT]) periodically during the first 72 of 120 weeks of continuation therapy with mercaptopurine and MTX; 155 received 18 Gy cranial radiation (RT). Systemic and intrathecal therapy was the same as for the IVIT arm, except from weeks 36 to 71, when treatment was interrupted for substitution of two other pairs of drugs: doxorubicin/cyclophosphamide and teniposide/cytarabine.

High-Risk Protocol
Therapy for the 126 high-risk patients comprised induction chemotherapy with teniposide, cytarabine, prednisone, vincristine, and asparaginase. Prednisone was used at the same dose and for same duration as for the standard-risk protocol. CNS prophylaxis included periodic intrathecal MTX (12 mg/m²) and delayed RT (24 Gy at 1 year). Continuation chemotherapy consisted of mercaptopurine, MTX, teniposide, and cytarabine.

Study Population
Of the 456 patients who were enrolled onto the protocol between May 1979 and December 1984, 422 were eligible for the analysis. By protocol design, heights and weights of patients were measured at diagnosis, during treatment, at end of therapy, and at 6-month to 1-year intervals thereafter. Adult height was defined as the standing height achieved as an adult or when the height measurements increased 1.5 cm per year or less in 2 consecutive years. BMI expressed as kg/m², was used as an indicator of obesity according to the formula [weight/height]² for patients older than 2 years of age. For adult patients (age 20 years), the BMI was used to define weight categories as follows: underweight (BMI < 18.5), normal weight (BMI, 18.5 to 24.9), overweight (BMI, 25.0 to 29.9), or obese (BMI 30).²⁵ BMI z scores for the adults were calculated using normative data from the Second National Health and Nutrition Examination Survey (NHANES II).²⁶ For patients between 2 and 20 years of age, we used an SAS program provided by the Centers for Disease Control (CDC) to calculate BMI z scores and to categorize children and young adults into weight-for-length percentiles or BMI-for-age percentiles based on normative data.^27,28 Based on the calculated percentiles at the last assessment, these patients were categorized as underweight (less than the 10th percentile for age), normal weight (10th to 84th percentile), overweight (85th to 94th percentile), or obese (95th percentile or greater).^29,30 For patients younger than 2 years of age, the anthropometric index of weight-for-length was used to define obesity. Weight-for-length z scores and percentiles based on normative data were provided by the CDC and patients were categorized as underweight, normal weight, overweight, or obese based on the same criteria as BMI for age.

Patients or their legal guardians provided informed consent for participation in the therapeutic clinical trail. The institutional review board approved the therapeutic trial and this retrospective study.

Statistical Methods
This analysis aimed to identify factors predictive of BMI weight category at last assessment and change in BMI z score from diagnosis to last assessment. BMI weight category at last assessment was analyzed as a dichotomous variable in patients classified in two ways: (1) underweight/normal versus overweight/obese and (2) obese versus nonobese. Each dichotomous end point was investigated separately using univariate logistic regression analysis; odds ratios and significance levels were calculated.^31,32 Change in BMI z score from diagnosis to last assessment was investigated univariately using linear regression analysis.

To investigate which factors have independent predictive value, we performed multiple regression analyses for each end point of interest. Each regression model included factors that were significant in the univariate analysis at the alpha = .15 level, as well as sex, cranial radiation (yes or no), treatment arm (IVIT, 18 Gy cranial RT, and 24 Gy cranial RT), and age at diagnosis (< 5, 5 to 9, 10 to 14, and 15 years or < 6 v 6 years).^31,32 Interaction terms were investigated, and their contribution to the model fit was assessed based on R² values and the Shwartz criterion as implemented in SAS Version 9.³¹ Significance levels, R² values, and odds ratios were calculated.^31,32

The effect of treatment group on the change in BMI was examined using a random coefficients model as implemented in PROC MIXED of the SAS Version 9 system.²⁸ The random coefficients model was used to estimate and compare the average rate of change in the BMI among the IVIT, 18 Gy cranial RT, and 24 Gy cranial RT groups. Before analysis, visual inspection and spline smoothing of the scatter plots were performed to investigate nonlinear patterns.

	RESULTS

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Patient Characteristics
At the time of this analysis, 248 patients had achieved adult height. Three patients had an adult height at diagnosis, and, therefore, had only one height measurement. The median age was 5.6 years (range, 0.8 to 18.8 years) at diagnosis and 18.4 years (range, 13.2 to 30.0 years) at last assessment. The median time from diagnosis to last assessment was 11.9 years (range, 0 to 22 years). Of 248 patients, 190 were classified as standard risk (101 in the IVIT group and 89 patients in the 18 Gy RT group) and 55 patients were classified as high risk. Another three standard-risk patients were not randomly assigned because of induction failure. Table 1 summarizes the clinical and treatment features of the study group by weight category at attainment of adult height.

Predictive Factors for Overweight/Obesity
Univariate logistic regression methods were used to identify the predictive factors for overweight/obesity or obesity alone (Table 3). Only BMI weight category at diagnosis achieved significance (P < .0001). Patients who were overweight or obese at diagnosis were 9.2 times (range, 3.6 to 23.7 times) times more likely to be overweight or obese on attaining adult height and 14.7 times (range, 6.0 to 36.1 times) times more likely to be obese compared with patients who were normal weight at diagnosis.

Predictive Factors for an Increase in the BMI z Score
The relationship of selected variables to the change in BMI z score from diagnosis to last assessment was investigated. By univariate analysis, underweight at diagnosis and younger age at diagnosis were each significantly associated with an increased probability of attaining a higher change in BMI z score (P < .0001 and P = .0001, respectively). In multivariable models evaluating BMI weight category at diagnosis, sex, treatment, and age at diagnosis, underweight at diagnosis, and younger age retained significance as predictors of an increased change in BMI z score (data not shown). Among the patients who were underweight at diagnosis, the mean change in BMI z score was 2.04 standard deviations (SDs) compared with a mean change of only 0.60 SD for the normal group and 0.38 SD for the overweight or obese patients at diagnosis.

Exclusion of Failures
Sixty patients included in the aforementioned analyses either relapsed (n = 56) or experienced treatment failure with therapy (n = 4). When this subgroup was omitted from the regression models, BMI weight category at diagnosis remained the most important predictor of overweight or obesity, with or without adjustment for competing covariates (data not shown).

Longitudinal Analysis
We estimated the longitudinal change in BMI among 304 standard-risk (153 IVIT and 151 18 Gy RT) and 107 high-risk (24 Gy RT) patients and compared the rates of increase in BMI among these three treatment groups. Patients randomly assigned to receive the IVIT or 18 Gy RT were stratified by age at diagnosis and sex, to assure that these variables with a potential impact on BMI were distributed similarly between the two groups. Figure 1 shows a plot of the predicted BMI over time for patients included in the longitudinal analysis for the three study groups (IVIT, 18 Gy RT, and 24 Gy RT). The increase in BMI was similar for all groups (P = .42). The slightly larger BMIs for the 24 Gy group at diagnosis and at 5, 10, and 15 years postdiagnosis may reflect the older age at diagnosis and male sex predominance in this subgroup.

View larger version (18K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Comparison of average rates of change in body mass index (BMI) among the high-dose intravenous/intrathecal methotrexate (IVIT), 18 Gy cranial radiation therapy (RT) and 24 Gy cranial RT subgroup using a random coefficients model.28 Predicted BMIs at 5, 10, and 15 years from diagnosis (with 95% CIs) are included beneath the graph. The model included linear, quadratic, and cubic terms.

	DISCUSSION

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The percentage of survivors of childhood ALL or lymphoma who were overweight or obese in our study is comparable to observations in the general US population. Obviously, a difficult issue in analyses such as ours is the choice of an appropriate reference population. We used an SAS program provided by the CDC²⁷ to categorize patients younger than 20 years of age into BMI-for-age percentiles based on normative data. This program constructs US growth charts from pooled data largely derived from national health surveys including NHANES I-III. Of note, the CDC program excludes data from the NHANES III survey³³ for children 6 years of age or older to avoid underclassification of overweight that might result from the upward shifting of the overweight criteria over the years. Despite this conservative approach, the relatively high obesity rate of 16% in adolescents 13 to 19 years of age was similar to the rate of 15.5% in the 12- to 19- year-olds in a recent national survey.³³ In patients who were 20 years or older at their last assessment, 46.0% were either overweight or obese, compared with 54.9% of the general population.³⁵ Overall, the findings we report follow national trends toward greater rates of excessive weight gain with advancing age.^36,37

Treatment with cranial radiation, especially at doses of 20 Gy or higher, has been reported to be a significant predictor of risk for overweight/obesity in previous investigations of childhood ALL.^8,9,22,34 Oeffinger et al²² demonstrated that cranial radiation at 20 Gy or higher was associated with an increased prevalence of obesity, especially in females treated before 5 years of age. This was also observed in children surviving brain tumors who were treated with even higher doses of cranial radiation.³⁸ In the present study, high-risk patients who received 24 Gy of cranial irradiation were more likely to be males and older at diagnosis than were those who received IVIT or 18 Gy cranial irradiation. They also had higher a BMI than those treated with 18 Gy or IVIT; however, the change over time in BMI was not significantly different among patients in the three treatment groups. This finding suggests that factors other than cranial irradiation contributed to the increased risk of obesity in leukemia or lymphoma survivors in our cohort. Likewise, female sex, previously associated with obesity,²² did not predict the risk of obesity in our study. To the contrary, males were more likely to be overweight or obese at the last assessment. In consideration of other treatment factors predisposing to overweight/obesity, it is important to note that corticosteroid doses were comparable in all treatment arms of the study. However, standard-risk patients on our study received much higher doses of intravenous MTX (1 gm/m²) than did patients in the previous studies,^22,23 and high-risk patients received the drug pair cytarabine/teniposide that was not routinely used in previous studies.^22,23 Finally, the racial and ethnic composition of our cohort, which included a slightly greater proportion of black (8.8% v 5.5%) and a lower proportion of Hispanic (0.4% v 2.4%) children than in the Oeffinger study,²² should be considered in the interpretation of our results. However, it seems unlikely that this small difference in racial and ethnic composition could account for the differences in our findings.

Although involving a relatively small number of patients, this study has several strengths. First, all patients were treated at a single institution, on the same treatment protocol, with a long duration of follow-up (median, 11.9 years), permitting us to determine changes in BMI over time. Second, unlike in the study by Dalton,²³ our standard-risk patients were stratified and randomly assigned to receive different forms of CNS-directed therapy, thus compensating for the effects of potential risk factors such as age and sex. Third, all height and weight values used in the BMI determinations were measured during routine clinic visits, and were not self-reported as in the Oeffinger study.²²

There were also several limitations of the study design. In addition to its retrospective nature, we did not compare results with findings in a control group of healthy siblings, which could provide insight into other socioeconomic and familial factors contributing to overweight/obesity. Instead, we used prevalence rates of obesity and overweight in the US population, a method that is subject to errors in comparison depending on the reference data used.^25,35,39 There is also the concern of evolving weight patterns nationwide, with a trend toward an increased prevalence of overweight/obesity in children, adolescents, and adults.^35,37,39,40 Another potential limitation was the inclusion of patients who either experienced treatment failure with induction therapy or relapsed; however, repeat analyses excluding these 60 patients yielded essentially the same results as did the full analysis. The study also included 21 patients with advanced-stage lymphoblastic lymphoma who were treated with the same therapy as the larger group of patients with ALL, a common practice in the late 1970s and early 1980s. This subgroup was considered relevant because it allowed us to show that excessive weight gain is related more to the inherent characteristics of patients than to the primary cancer diagnosis.

In conclusion, this retrospective single-institution study identified the BMI weight category at diagnosis and age at diagnosis as the most important predictors of overweight and obesity in survivors of childhood ALL and lymphoma. Thus, in principle, it may be possible to lower rates of excessive weight gain in this population by early identification of the high-risk groups at diagnosis, followed by prospective dietary education of the patients and families and ongoing dietary and exercise counseling.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The authors indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

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Conception and design: Bassem I. Razzouk, Susan R. Rose, Suradej Hongeng, Ching-Hon Pui, Melissa M. Hudson

Financial support: Ching-Hon Pui

Administrative support: Margie Zacher, Melissa M. Hudson

Provision of study materials or patients: Susan R. Rose, Margie Zacher, Ching-Hon Pui, Melissa M. Hudson

Collection and assembly of data: Bassem I. Razzouk, Suradej Hongeng, Dana Wallace, Matthew P. Smeltzer, Margie Zacher, Melissa M. Hudson

Data analysis and interpretation: Bassem I. Razzouk, Susan R. Rose, Dana Wallace, Matthew P. Smeltzer, Ching-Hon Pui, Melissa M. Hudson

Manuscript writing: Bassem I. Razzouk, Susan R. Rose, Suradej Hongeng, Dana Wallace, Matthew P. Smeltzer, Ching-Hon Pui, Melissa M. Hudson

Final approval of manuscript: Bassem I. Razzouk, Susan R. Rose, Suradej Hongeng, Dana Wallace, Matthew P. Smeltzer, Margie Zacher, Ching-Hon Pui, Melissa M. Hudson

Other: Dana Wallace, Matthew P. Smeltzer

	ACKNOWLEDGMENTS

 
We thank John Gilbert for his expert editorial review.

	NOTES

 
Supported by Grant No. CA 21765 from the National Cancer Institute, by a Center of Excellence Grant from the State of Tennessee, and by the American Lebanese Syrian Associated Charities (ALSAC). C.-H.P. is the American Cancer Society-F.M. Kirby Clinical Research Professor.

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

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Submitted June 16, 2006; accepted December 20, 2006.

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Razzouk, B. I. Articles by Hudson, M. M. Search for Related Content PubMed PubMed Citation Articles by Razzouk, B. I. Articles by Hudson, M. M.