L-asparaginase as a marker of chemotherapy dose modification in children with acute lymphoblastic leukemia

Authors

  • Jacques Baillargeon Ph.D.,

    Corresponding author
    1. Center for Epidemiology and Biostatistics, University of Texas Health Science Center, San Antonio, Texas
    2. Department of Pediatrics, University of Texas Health Science Center, San Antonio, Texas
    • Center for Epidemiology and Biostatistics, University of Texas Health Sciences Center at San Antonio, 7703 Floyd Curl Drive, MSC 7933, San Antonio TX 78229-3900===

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    • Fax: (210) 562-9025

  • Anne-Marie Langevin M.D.,

    1. Department of Pediatrics, University of Texas Health Science Center, San Antonio, Texas
    2. Division of Pediatric Hematology/Oncology, CHRISTUS Santa Rosa Children's Hospital, San Antonio, Texas
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  • Margaret Lewis M.S.,

    1. Department of Pediatrics, University of Texas Health Science Center, San Antonio, Texas
    2. Division of Pediatric Hematology/Oncology, CHRISTUS Santa Rosa Children's Hospital, San Antonio, Texas
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  • Paul J. Thomas M.D.,

    1. Department of Pediatrics, University of Texas Health Science Center, San Antonio, Texas
    2. Division of Pediatric Hematology/Oncology, CHRISTUS Santa Rosa Children's Hospital, San Antonio, Texas
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  • Judith Mullins M.D.,

    1. Division of Pediatric Hematology/Oncology, Driscoll Children's Hospital, Corpus Christi, Texas
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  • John Dugan B.S.,

    1. Center for Epidemiology and Biostatistics, University of Texas Health Science Center, San Antonio, Texas
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  • Brad H. Pollock M.P.H., Ph.D.

    1. Center for Epidemiology and Biostatistics, University of Texas Health Science Center, San Antonio, Texas
    2. Department of Pediatrics, University of Texas Health Science Center, San Antonio, Texas
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Abstract

BACKGROUND

The objective of the current study was to compare chemotherapy dose modifications in obese (a body mass index [BMI] > 95%) and nonobese (a BMI ≤ 95%) pediatric patients with acute lymphoblastic leukemia (ALL).

METHODS

The study cohort was comprised of 199 pediatric patients diagnosed with ALL who were treated at 1 of 2 South Texas pediatric oncology centers between 1990–2000. The relative chemotherapy dose modification during the induction phase of chemotherapy was calculated as the ratio of 1) the actual administered dose of L-asparaginase and 2) the protocol-calculated dose of L-asparaginase. The extent to which the chemotherapy dose modification varied according to obesity status was assessed using stratified Student t tests and an ordinary least-squares regression analysis.

RESULTS

Obese ALL patients were found to exhibit a 7% decrease in the mean relative modification of L-asparaginase during induction chemotherapy compared with their nonobese counterparts. This finding was statistically significant (P = 0.009), even after adjustment for gender, age, ethnicity, and clinical institution.

CONCLUSIONS

To the authors' knowledge, the current study is the first published report of an obesity-associated chemotherapy dose modification in pediatric patients with ALL, the most common childhood malignancy. It will be important to examine whether these findings are consistent with those observed in future studies, and ultimately to assess the association between obesity-related dose modifications and long-term cancer outcomes. Cancer 2005. © 2005 American Cancer Society.

The prevalence of childhood obesity has increased steadily since 19601 and is associated with several adverse health outcomes, including diabetes, cardiovascular disease, hyperlipidemia, and cancer.2 However, to our knowledge, little information currently exists regarding how the pediatric patient's obesity affects clinical decision-making. The treatment of obese pediatric patients diagnosed with cancer represents an area of particular clinical concern. Many oncologists fear that reliance on conventional body surface area (BSA)-based calculations yields excessively high doses of chemotherapy agents and could possibly result in fatal organ damage.3 Such dose adjustment is increasingly complex in the treatment of children, given that it may occur across a broad range of growth and development. Although it has been speculated that a substantial modification of dose or dose intensity may adversely affect survival outcomes,3–5 to our knowledge to date there is little information to support or refute such dose modification practices in pediatric patients. Therefore, the purpose of the current study was to compare chemotherapy dose calculations in obese versus nonobese pediatric patients with acute lymphoblastic leukemia (ALL).

MATERIALS AND METHODS

Study Cohort

The study cohort was comprised of a consecutive sample of 199 pediatric patients diagnosed with B-precursor ALL who were treated at 2 South Texas Pediatric Minority-Based Community Clinical Oncology Program (STP-MB-CCOP) institutions. Because the Centers for Disease Control and Prevention (CDC) recommends that body mass index (BMI) growth charts be used beginning at 2 years of age (when an accurate stature can be determined),6 we excluded all children who were younger than 2 years at the time of diagnosis. All data were obtained by reviewing existing patient records. Patients were treated primarily as per Pediatric Oncology Group (POG) legacy protocols (P9000, P9400, and P9900 series) following the National Cancer Institute (NCI) definition for standard or high risk based on their age and leukocyte count at the time of diagnosis.7 Patients received either three-drug or four-drug induction regimens comprised of prednisone, L-asparaginase, and vincristine, with or without daunorubicin. The POG legacy protocols did not provide dose reduction guidelines based on obesity status. This study was formally reviewed and approved by the institutional review boards at both of the institutions from which patient records were reviewed.

Measurements

The patient's BMI was calculated using the formula: weight (kg)/height (m)2. The BMI is considered to be the best single anthropometric measure in both children and adults with regard to independence of height, correlation with body fat, and prediction of mortality.8, 9 Ethnicity was assigned on the basis of parental report, according to NCI categories.

Chemotherapy dose modification was calculated by obtaining the ratio of 1) the administered dose of L-asparaginase at the time of chemotherapy induction to 2) the dose that was determined using the conventional BSA algorithm (the square root (height in cm × weight in kg)/3600). All patients in the study cohort received either three-drug or four-drug induction regimens comprised of prednisone, L-asparaginase, and vincristine, with or without daunorubicin. L-asparaginase served as the sole indicator of chemotherapy dose modification for the following reasons: 1) both prednisone and vincristine had upper dose limits that could not be exceeded even in cases of extreme obesity and 2) daunorubicin was not used in a substantial proportion of the study cohort. Because L-asparaginase did not have an upper dose limit and was used in the entire study cohort, it served as the best overall indicator of dose modification. Focusing exclusively on dose modifications that occurred during the induction period permitted the assessment of clinical decision-making that was based on body size and not other toxicity-limiting considerations that are more likely to impact therapy beyond the induction period.

Statistical Methods

Age-standardized and gender-standardized BMI z-scores were calculated for each study patient using height, weight, gender, and age data based on the CDC National Center for Health Statistics (NCHS) growth curves.1, 6 The z-score indicates the number of standard deviations the actual BMI measurement is away from the mean for the normal age-specific and gender-specific general population cohort. Obesity status was defined as a BMI z-score greater than or equal to the 95th percentile and overweight status was defined as a BMI z-score ranging from the 85th to the 95th percentile. Both definitions are based on the recommendations of an expert panel on childhood obesity10 and are in accordance with previous studies.11–13 Variations in chemotherapy dose modification according to obesity status was assessed using stratified, two-sample Student t tests as well as simple general linear modeling (ordinary least-squares regression analysis).

RESULTS

Table 1 presents the demographic characteristics of the study cohort according to BMI percentile categories. Overall, a total of 16.2% of the study cohort was obese (a BMI ≥ 95%) at the time of diagnosis. Males and patients ages 10–18 years were found to have elevated rates of being either overweight or obese. Obesity status was found to be distributed evenly between Hispanic and non-Hispanic patients. Of the 26 non-Hispanic patients in the study cohort, 22 were white, 2 were African American, and 2 were Asian. A total of 10 patients exhibited a BSA greater than 2.0 m2. Of these, nine patients were classified as obese.

Table 1. Study Cohort Characteristic Percentages by Obesity Status
 Nonobese (BMI < 95th percentile)Obese (BMI ≥ 95th percentile)
  1. BMI: body mass index.

Overall (n = 199)83.816.2
Gender  
Male (n = 125)80.219.8
Female (n = 74)89.710.3
Age group  
2-9 yrs (n = 144)88.511.5
10-18 yrs (n = 55)56.743.3
Ethnicity  
Hispanic (n = 173)83.516.5
Non-Hispanic (n = 26)85.214.8
Institution  
A (n = 70)84.315.7
B (n = =129)83.716.6

Table 2 presents the mean chemotherapy dose modification in ALL patients according to obesity status. Overall, nonobese patients (n=166) had a mean chemotherapy relative modification value of 1.00 (standard deviation [SD] of 0.04), indicating that the administered dose of L-asparaginase at the time of induction was approximately the same as the dose that was determined using the protocol-based BSA algorithm. By contrast, obese patients (n=33) had a value of 0.93 (SD of 0.11), indicating that the administered chemotherapy dose was 7% lower than the protocol-determined dose. The two groups had significantly different levels of dose modification (P < 0.001, using the Student t test). Stratified analyses demonstrated that statistically significant differences in the mean relative chemotherapy dose modification between obese and nonobese patients persisted across all levels of the stratifying variables: gender, age, ethnicity, and clinical institution. However, it is interesting to note that the dose modification differential between obese and nonobese patients was substantially greater in those patients ages 10–18 years (a difference of 11%) compared with the patients ages 2–9 years (a difference of 3%). Figure 1, a percentage histogram, presents the distribution of L-asparaginase dose modification scores in obese versus nonobese ALL patients. Table 3 presents the linear regression analysis results, which indicate that the association between obesity and chemotherapy dose modification (P < 0.0001) persisted even after simultaneously adjusting for age, gender, ethnicity, and clinical institution.

Table 2. Mean Relative Chemotherapy Dose Modification According to Obesity Status
 Nonobese, mean (SD)Obese, mean (SD)Student t testP value
  1. SD: standard deviation.

Overall (n = 199)1.00 (0.04)0.93 (0.11)3.650.009
Gender    
Male (n = 125)1.00 (0.03)0.94 (0.10)2.770.01
Female (n = 74)1.00 (0.04)0.90 (0.13)2.280.06
Age    
2–9 yrs (n = 144)1.00 (0.04)0.97 (0.06)2.060.05
10-18 yrs (n = 55)1.00 (0.03)0.89 (0.13)3.100.007
Ethnicity    
Hispanic (n = 173)1.00 (0.03)0.94 (0.11)3.660.0009
Non-Hispanic (n = 26)1.00 (0.03)0.93 (0.12)3.700.0001
Institution    
A (n = 70)1.01 (0.03)0.93 (0.09)2.320.04
B (n = 129)1.00 (0.04)0.93 (0.12)2.860.01
Figure 1.

Plot of L-asparaginase dose reduction according to obesity status.

Table 3. Ordinary Least-Squares Regression Analysis Predicting Chemotherapy Dose Modification
CovariateParameter estimateSEStudent t test valueP value
  1. SE: standard error.

Obesity status−0.060.01−5.45< 0.0001
Age−0.00020.00008−3.400.0008
Gender0.0030.0080.320.75
Hispanic ethnicity0.0030.0110.260.79
Institution−0.010.01−1.230.21

DISCUSSION

The treatment of cancer patients who are already obese at the time of diagnosis represents a particular concern among oncologists for several reasons. First, little evidence can be gleaned from the literature that addresses how to appropriately adjust doses of chemotherapy for obese cancer patients. Oncologists generally determine the appropriate dose of chemotherapy agents based on the patient's actual body weight or BSA. However, in treating obese patients, many clinicians fear that reliance on these conventional calculations yields excessively high doses that could result in significant end-organ damage.3 As a result, doses for obese cancer patients are often reduced by using the patient's ideal body weight to calculate the BSA or by capping the BSA at specified level.4, 14 Dose modification practices in treating pediatric patients may be complicated by the patient's physical growth and development and associated biologic changes.

To our knowledge, little published information exists to date regarding obesity-related dose modifications in pediatric and adult cancer patients. In their study cohort of patients with breast cancer, Madarnas et al.4 reported that obese women had a greater reduction in chemotherapy dose compared with nonobese patients. Likewise, in their retrospective study of patients with acute myeloid leukemia, Lange et al.15 reported that obese patients were significantly more likely to have received a dose reduction of ≥ 10% compared with nonobese patients. The findings of the current study indicate that among children with ALL, obese patients exhibited a 7% decrease in the mean relative dose modification of L-asparaginase at the time of induction compared with nonobese patients. This effect persisted even after adjustment for patient age, gender, ethnicity, and clinical institution. It is interesting to note that the dose modification differential was greater among children ages 10–18 years than among those ages 2–9 years. It is possible that the increased frequency of obesity-driven dose modification noted among older patients is because of higher BSAs and associated chemotherapy dose values. It will be important for future investigations to explore the extent to which this finding persists in different patient populations, to better characterize the specific decision-making methodology whereby such dose reductions occur, and to examine whether dose modification is associated with adverse outcomes, particularly with regard to survival.

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