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Height and Weight in Children Treated for Acute Lymphoblastic Leukemia: Relationship to CNS Treatment

Virginia Kimball Dalton, Montse Rue, Lewis B. Silverman, Richard D. Gelber, Barbara L. Asselin, Ronald D. Barr, Luis A. Clavell, Craig A. Hurwitz, Albert Moghrabi, Yvan Samson, Marshall Schorin, Nancy J. Tarbell, Stephen E. Sallan, Laurie E. Cohen

From the Divisions of Hematology and Oncology and Endocrinology, Department of Medicine, Children’s Hospital; Departments of Pediatric Oncology and Biostatistical Science, Dana-Farber Cancer Institute; Department of Pediatrics, Harvard Medical School; and Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA; Division of Pediatric Hematology/Oncology University of Rochester Medical Center, Rochester, NY; Division of Pediatric Oncology, San Juan, Puerto Rico; Departments of Pediatric Hematology/Oncology, Maine Children’s Cancer Program and Barbara Bush Children’s Hospital at Maine Medical Center, Portland, ME; Division of Pediatric Hematology/Oncology, McMaster University, Hamilton, Ontario; Division of Hematology/Oncology, Hopital Sainte Justine, Montreal; Division of Hematology/Oncology, Le Centre Hospitalier de L’Universite Laval, Quebec City, Quebec, Canada; and Section of Pediatric Hematology Oncology, Tulane Medical School, New Orleans, LA.

Address reprint requests to Virginia M. Kimball Dalton, MS, Department of Pediatric Oncology, Dana-Farber Cancer Institute, 44 Binney St, Dana 355, Boston, MA 02115; email: Virginia_Dalton{at}dfci.harvard.edu.

	ABSTRACT

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Purpose: We evaluated the long-term effects of treatment on height and weight in children with acute lymphoblastic leukemia (ALL) treated with one of the following three different CNS therapies: intrathecal therapy alone, intrathecal therapy with conventional cranial radiation, or intrathecal therapy with twice-daily radiation.

Patients and Methods: Between 1987 and 1995, 618 children treated on two consecutive Dana-Farber Cancer Institute Consortium protocols for ALL were measured for height and weight at diagnosis, and approximately every 6 months thereafter. Patient height, weight, and body mass index (BMI) were converted to z scores for age and sex using the 2000 Centers for Disease Control and Prevention growth charts for the United States.

Results: Children younger than 13 years at diagnosis had a statistically significant decrease in their height z scores and an increase in their BMI z scores, regardless of whether they had received cranial radiation. Young age at diagnosis and increased chemotherapy intensity were major risk factors. Unexpectedly, there was no significant difference in long-term height between children who received radiation and those who did not.

Conclusion: Final height is compromised in survivors of ALL. The detrimental effects on height occur during therapy without the ability for long-term catch-up growth. Although patients became overweight for height, this seemed to be a result of relative height loss with normal weight gain rather than accelerated weight gain. The type of CNS treatment received did not affect changes in height, weight, or BMI.

	INTRODUCTION

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OBESITY AND short stature are commonly observed late effects of therapy for childhood acute lymphoblastic leukemia (ALL).^1–10 Treatment changes to minimize these side effects without compromising efficacy have failed.^1,12 Between 1972 and 1987, the Dana-Farber Cancer Institute (DFCI) ALL Consortium protocols used daily fractionated cranial radiation in all patients to treat asymptomatic CNS leukemia. Based on the experience of others,¹³ from 1987 to 1991, we treated children with standard-risk ALL without cranial radiation. Patients with high-risk disease were treated with either conventionally fractionated or hyperfractionated (twice-daily) cranial radiation to evaluate late toxicity. The biologic rationale for the use of twice-daily radiation was that the proliferating leukemia cells would be more sensitive to a low dose of radiation than the more slowly proliferating neuronal cells.^14,15 In this article, we analyze the long-term effects of treatment on height and weight in children treated for ALL, specifically addressing the relative growth effects of the following three different CNS therapies: intrathecal therapy alone, intrathecal therapy with conventional cranial radiation, and intrathecal therapy with twice-daily radiation.

	PATIENTS AND METHODS

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Treatment Protocols
Patients were treated on one of two previously reported protocols, DFCI ALL Consortium protocol 87–01¹⁶ or 91–01.¹⁷ Both protocols included six-drug induction therapy with doxorubicin, asparaginase, methotrexate (MTX), vincristine, prednisone, and intrathecal cytarabine (ara-C). Distinguishing characteristics of both protocols included postremission consolidation with weekly high doses of asparaginase for all risk groups and postinduction doxorubicin with high-dose corticosteroids for patients with high-risk disease. Standard-risk disease criteria were defined as age between 2 and 9 years; a presenting WBC count lower than 20,000/µL; and absence of T-cell markers, anterior mediastinal mass, and CNS disease. All other patients were classified as high risk, including infants and patients with T-cell disease.

For all patients with high-risk disease, and for boys with standard-risk disease on protocol 91–01, CNS treatment consisted of cranial radiation delivered in either 10 or 20 fractions (randomized) for a total dose of 18 Gy, always in combination with intrathecal MTX and ara-C. Conventional radiation consisted of 18 Gy delivered in 10 1.8-Gy fractions (one fraction per day over 12 to 14 days). Twice-daily radiation consisted of 18 Gy delivered in 20 0.90-Gy fractions, with a minimum of 6 hours between the twice-daily treatments, over 12 to 14 days. Port and simulation films from all sites were centrally reviewed at the DFCI. Intrathecal therapy dose was based on patient age (< 1 year: MTX 6 mg and ara-C 15 mg; 1 to < 2 years: MTX 8 mg and ara-C 20 mg; 2 to 3 years: MTX 10 mg and ara-C 30 mg; and > 3 years: MTX 12 mg and ara-C 40 mg) and was delivered every 18 weeks after the completion of initial intensive CNS therapy (four therapeutic lumbar punctures over a 2-week period). Girls with standard-risk disease on both protocols and boys on protocol 87–01 were not assigned to receive cranial radiation, but instead, received intrathecal MTX and ara-C delivered every 18 weeks after initial CNS therapy for a total of 2 years from remission.

Patient Population
Between November 1987 and December 1995, 746 children were treated on two previously reported protocols 87–01¹⁶ and 91–01.¹⁷ Both protocols were approved by the investigational review boards at the DFCI and collaborating sites. Patients who had CNS disease at diagnosis (n = 65), Down syndrome (n = 11), or both (n = 2) were excluded from this analysis because those conditions are associated with growth abnormalities. Forty more boys were excluded because they received additional therapy on protocol 87–01 as part of a previously reported patient recall.¹⁶ Of the remaining 628 patients, 618 (98%) had height and weight measurements at diagnosis and approximately every 6 months thereafter available for analysis. For patients who relapsed (n = 90) or who were treated with growth hormone (n = 3) or limb-lengthening therapy (n = 1), height and weight measurements after relapse or initiation of growth hormone or limb-lengthening therapy were excluded from the analysis. All measurements were obtained by chart abstraction.

Growth measurements at age 14 years for girls and age 16 for boys were considered final height measurements because the average child will have reached 98% of their final height at those ages.¹⁸ Bone ages were not available to assess osseous maturation.

Statistical Methods
Patient height, weight, and body mass index (BMI) were converted to z scores, adjusting for age and sex, using Centers for Disease Control and Prevention growth charts for children in the United States.¹⁹ These growth charts were developed with data collected by the National Center for Health Statistics in five cross-sectional, nationally representative health examination surveys from 1963 to 1994. The z score indicates the number of standard deviations (SDs) the measurement is away from the mean for the normal age-sex cohort. As recommended in the growth chart documentation, to obtain the z score for a given measurement, we used the following equation:

where X is the physical measurement (eg, weight, height, or calculated BMI value), and M, S, and L are the median (M), the SD (S), and the power in the Box-Cox transformation (L) from the appropriate table corresponding to the sex and age (in months) of the child.²⁰ Nonlinear mixed-effects models were used to describe changes over time in the height, weight, and BMI z scores, with reference to the z scores at the time of diagnosis.²¹

The associations between changes in the growth z scores and protocol, sex, risk group at diagnosis, age at diagnosis, and type of CNS treatment received were also evaluated. Because children younger than 2 years and those 9 years and older were considered high risk by definition, before including them in the models, the variables of risk group and age at diagnosis were combined into the following six categories: 2 to 4 years and standard risk, 0 to 4 years and high risk, 5 to 9 years and standard risk, 5 to 9 years and high risk, 9 to 12 years, and 13 years and older. For changes in the height and weight z scores, the following nonlinear mixed-effects model was used:

For each subject i, the first equation describes the trajectory over time of the changes in the growth z score with respect to diagnosis. The dependent variable, y_ij, is the difference between the growth z score at time t_j in weeks and the growth z score at diagnosis for each subject i. The _ki, k = 0 to 2, are the coefficients of this nonlinear model for the ith subject. The error terms _ij are independent N(0,²). In the second equation, the parameters _ki are considered as dependent variables and relate each to appropriate patients’ covariates x₁, x₂,. . .,x_m. The coefficients y represent the effects of the covariates associated with the fixed effects of the model or study population averages. The b_ki are the random effects that represent the deviations of the _ki from their population average. The b_ki are independent of _ij and N(0,_b²). For changes in the BMI z scores, the following nonlinear mixed-effects model was used:

These functions allow modeling a response y that approaches a horizontal asymptote (₀) as t and are consistent with the assumption that the effects of the treatment on growth will stabilize as time from diagnosis increases. Parameters ₁ and ₂ are related to the rates of change of the z scores over time and model the short-term changes in the z scores. Parameter estimates statistically significantly different from zero indicate changes in z score over time. Covariates were entered into the model according to a forward selection strategy. Different models were compared with the Akaike Information Criteria to select the best fit.²¹ Several correlation structures for modeling within-subject error dependency were tested.

Linear regression analysis was used to assess the association between patient and treatment characteristics on changes in the growth z scores at final height with respect to the z scores at diagnosis. Stepwise variables selection was used to build the final models. Appropriateness of the models was assessed by analysis of residuals and coefficient of determination R².

	RESULTS

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Patient Characteristics at Diagnosis
Patient clinical and demographic characteristics are listed in Table 1. As of January 2003, the median follow-up time from diagnosis of ALL was 6.1 years, with a range of 0 to 14.4 years.

Patient Characteristics for Children Who Reached Final Height
Table 2 lists characteristics for the 93 children who reached final height. Each of them had growth measurements in the interval 3 months before to 3 months after their 14-year (for girls) or 16-year (for boys) birthday for inclusion. Fifty-four patients were treated on protocol 87–01, and 39 were treated on protocol 91–01. The median follow-up was 7.2 years, with a range of 1.9 to 14.3 years.

Factors Related to Long-Term Growth
Height. Table 3 lists the average changes in growth z scores according to age at diagnosis and risk group at a median follow-up from diagnosis of 6 years. These estimates were obtained using mixed-effects models. For the height z scores, the fitted model and P values are shown in Table 4. Four hundred seventy-four patients were included in this analysis. Because our outcome variable was the difference in z score compared with baseline, patients with only one growth measurement or who did not have one at baseline were not included in the models. Age and risk group at diagnosis were associated with changes in the z scores of height over time. Figure 1 shows the different trajectories of the changes in the height z scores with respect to baseline for age and risk group. All children experienced a decrease in height with respect to the population growth charts, but children 0 to 4 years old with high-risk features at diagnosis were the most affected group.

View larger version (19K): [in this window] [in a new window]   Fig 1. Changes in height z scores from diagnosis.

Protocol, sex, and type of CNS treatment were not significantly associated with changes in the z scores over time. Children who had received radiation, either standard or twice-daily fractions, had slightly decreased z scores with respect to baseline values, but these changes were not significantly different from those experienced by unirradiated children (P = .97 and .41 for once-daily and twice-daily cranial radiation, respectively, when compared with the nonirradiated group, adjusting for age and risk group).

On average, the z scores of children randomly assigned to conventional radiation were +0.14 higher than the z scores of children randomly assigned to hyperfractionated radiation, but this difference was not statistically significant (P = .11, adjusting for age at diagnosis and risk group; total number of randomized patients = 317).

Weight. Tables 3 and 5 and Figure 2 show the results of the mixed-effects model and the trajectory of changes in the weight z scores with respect to baseline. Age and risk group were also associated with the trajectory of the weight z scores over time. For all age and risk groups, the z scores for weight decreased during the first year of therapy, followed by a subsequent increase. At 6 years of follow-up, standard-risk children ages 2 to 4 years and standard-risk children ages 5 to 8 years at diagnosis had z scores 0.34 and 0.41 higher, respectively, than their z scores at diagnosis. All high-risk children had long-term z scores similar to those at diagnosis. Protocol, sex, and type of CNS treatment were not significantly associated with the trajectory of weight z scores over time.

View larger version (15K): [in this window] [in a new window]   Fig 2. Changes in weight z scores from diagnosis.

View larger version (19K): [in this window] [in a new window]   Fig 3. Changes in body mass index z scores from diagnosis.

Patients Who Reached Final Height (age 14 years for girls and 16 years for boys)
Table 7 lists the results of the linear regression model on changes in the growth z scores for children who had measurements at 14 years of age for girls and at 16 years of age for boys; only age at diagnosis and risk group were statistically significant. All high-risk children experienced decreases in the height z scores, but standard-risk children did not. Although the power of this analysis is low because of the small sample size, these results are consistent with the findings for the overall sample when using the mixed-effects models. All standard-risk children experienced increases in the weight z scores, but all high-risk children (including all children 13 years or older) did not. The z scores for BMI increased for all children, except for children 13 years old or older at diagnosis and for high-risk children 5 to 8 years old. The most affected group was standard-risk children 5 to 8 years old, for whom the change in the BMI z score with respect to the z score at diagnosis was more than +1.0. Many studies have concluded that their initial findings need to be assessed with longer follow-up. We performed a separate analysis for children who had achieved final height and substantiated the trends observed in the overall group. Of the patients who achieved final height, age at diagnosis and risk group stratum were significant predictors of changes in height, weight, and BMI.

	DISCUSSION

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Cranial radiation has been associated with the development of growth hormone deficiency.^5,6,9,22,23 The delivery of cranial radiation at a dose of 18Gy has been shown not to cause severe growth hormone deficiency.²⁴ Our results indirectly support the findings that growth impairment in childhood ALL survivors is not entirely a result of cranial radiation leading to subsequent growth hormone deficiency.^25,26 Contrary to the findings of others,^{2,9,23,27–29} we did not note a sex difference with respect to height and type of CNS treatment. We found a long-term decrease in height z scores and an increase in weight z scores in children treated for ALL. The first decrease in height was noted 6 months after beginning treatment. This could be a result of suboptimal nutrition or the use of glucocorticoids.³⁰ The role of under nutrition in our study is supported by the fact that most patients lost weight during treatment.

In terms of height, younger high-risk children (0 to 4 years old) were the most severely compromised, with a long-term decrease of approximately 1.3 units in their z score. The standard-risk children in the younger cohort, children treated between the ages of 5 to 8 years regardless of the risk group, and children 9 to 12 years old were also affected but not as severely. The oldest age group, 13 years or older, experienced an initial decrease in the rate of growth during treatment but had almost recovered by the completion of 2 years of therapy. Our data were consistent with previous reports that have found young age at the time of diagnosis to be most influential in affecting long-term height.^10,28,29,31 Because the decrease in z-score that was observed soon after beginning treatment persisted over time, and because growth is more rapid during the first few years of life,³² it is not surprising that the younger children’s height would be more severely affected.

Prior studies have shown that puberty occurs early in female survivors of childhood leukemia but not in males.²³ Early onset of puberty could improve height z-scores at the time of puberty because of acceleration in growth rate, but then it could compromise final height z-scores by decreasing the interval of time available for growth. Although we did not prospectively assess pubertal timing, near final height was defined by age and not by pubertal status. A patient with delayed puberty might not be close to final height; however, they should have an initial decrease in their height z score during the normally timed adolescence. This was not seen and indicates that there is no significant delay in pubertal timing.

Obesity is a well-known consequence among survivors of ALL,^4,33 especially in females.^3,8 At the initiation of therapy, the patients treated on protocol 91–01 were heavier than patients treated on protocol 87–01, which might reflect secular trends in the prevalence of obesity.³⁴ At 6 years of follow-up, we found that standard-risk children between the ages of 2 to 8 years had higher z scores for weight than at diagnosis. All other groups had a weight z score similar to that at diagnosis. Nevertheless, if we take into account that the other groups of children experienced a decrease in their height z scores, then, in fact, the standard-risk group became overweight as indicated by the changes in their BMI z scores (Table 3). The changes in BMI z scores from diagnosis were greater for younger than older children. The type of CNS treatment did not impact changes in weight or BMI. Our results do not support the findings of others^8,30 who reported that cranial radiation was a risk factor for the development of obesity, but they do support that younger age at diagnosis leads to obesity.²⁹ Although the mechanism for persistent obesity in patients treated for ALL remains unclear, we agree with investigators from the Netherlands that corticosteroids most likely cause the obesity.³³ It is noteworthy that our postinduction corticosteroid treatment varied between the two protocols; we used prednisone in protocol 87–01 and dexamethasone in protocol 91–01. However, there was no statistically significant difference in patterns of obesity between the two studies.

We conclude that final height is compromised in survivors of childhood ALL. It was hoped that the delivery of twice-daily radiation would lead to less impairment in growth relative to conventional methods of radiation; however, there seemed to be no difference between conventional and hyperfractionated radiation. In fact, radiation did not seem to significantly contribute to growth impairment or weight gain. Growth seems to be most affected by the loss in height velocity during treatment followed by a lack of catch-up, rather than loss of height velocity thereafter. This indicates that growth-hormone deficiency related to radiation plays a minor role, if any. Although patients became overweight for height, for most patients, this seems to be a result of relative height loss with normal weight gain rather than an accelerated weight gain. Follow-up studies are needed to assess whether interventions, such as improved nutrition during active treatment, will improve final height.

	NOTES

 
Supported in part by grant no. CA 68484 from the National Cancer Institute, National Institutes of Health, Bethesda, MD.

	REFERENCES

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Submitted March 11, 2003; accepted May 14, 2003.

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