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Final Height and Body Mass Index among Adult Survivors of Childhood Brain Cancer: Childhood Cancer Survivor Study

Department of Pediatrics, University of Minnesota (J.G.G., K.K.N., J.A.P., J.P.N., A.C.M., L.L.R.), Minneapolis, Minnesota 55455; Department of Radiation Physics, University of Texas M. D. Anderson Cancer Center (M.S.), Houston, Texas 77030; Departments of Radiation Oncology (S.W.) and Pediatrics (C.A.S.), Memorial Sloan-Kettering Cancer Center, New York, New York 10021; and Departments of Neurology and Pediatrics, Children’s National Medical Center, George Washington University (R.J.P.), Washington, D.C. 20010

Address all correspondence and requests for reprints to: Charles A. Sklar, M.D., Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021. E-mail: sklarc{at}mskcc.org.

	Abstract

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The objectives of this study were 1) to compare final height and body mass index (BMI) between adult survivors of childhood brain cancer and age- and sex-matched population norms, 2) to quantify the effects of treatment- and cancer-related factors on the risk of final height below the 10th percentile (adult short stature) or having a BMI of 30 kg/m² or more (obesity). Treatment records were abstracted and surveys completed by 921 adults aged 20–45 yr who were treated for brain cancer as children and were participants in the multicenter Childhood Cancer Survivor Study. Nearly 40% of childhood brain cancer survivors were below the 10th percentile for height. The strongest risk factors for adult short stature were young age at diagnosis and radiation treatment involving the hypothalamic-pituitary axis (HPA). The multivariate odds ratio for adult short stature among those 4 yr of age or younger at diagnosis, relative to ages 10–20 yr, was 5.67 (95% confidence interval, 3.6–8.9). HPA radiation exposure increased the risk of adult short stature in a dose-response fashion (trend test, P < 0.0001). Adjuvant chemotherapy was not an independent risk factor for adult short stature. BMI distribution in survivors did not differ appreciably from that of population norms; however, in females, young age at diagnosis and HPA radiation dose (trend test, P < 0.001) were associated with risk of obesity. Except for patients treated with surgery only, survivors of childhood brain cancer are at very high risk for adult short stature, and this risk increases with radiation dose involving the HPA. We did not find a corresponding elevated risk for obesity.

	Introduction

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BRAIN CANCERS ARE the most common solid neoplasms that occur in children (1). Survival after a diagnosis of a malignant brain tumor in childhood has improved substantially in the United States over the last several decades. Population-based data from the National Cancer Institute’s Surveillance, Epidemiology, and Ends Results Program show the 5-yr relative survival probability for all brain malignancies combined to be approximately 69% for children diagnosed in 1992 or later (2), although clinical course differs greatly depending on age at diagnosis, tumor site within the brain, and morphological and biological tumor characteristics (3). As reviewed previously (4), survivors of childhood brain cancer are at high risk for a variety of adverse medical, neurocognitive, and psychosocial late effects. Endocrine disorders are prominent among the spectrum of long-term conditions that may afflict brain cancer survivors (5). Many case series have reported on the deleterious effect of treatment for brain cancer on growth patterns in children, but such studies usually were limited by small numbers and highly selective samples (4). In this report from the Childhood Cancer Survivor Study (CCSS), we present results from a comparative analysis of 921 young adult survivors of a childhood brain cancer evaluating final height and body mass index (BMI) to that of same age, same sex population norms in relation to age at diagnosis, histological subtype, GH replacement therapy, and cancer treatment received.

	Subjects and Methods

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CCSS

As previously described (6), CCSS is an ongoing, multicenter, epidemiological, follow-up study of adult survivors of childhood cancer. Inclusion criteria for CCSS were limited to individuals who received their primary treatment at one of 25 collaborating institutions (Table 1) and who survived at least 5 yr after diagnosis of their malignant disease. CCSS eligibility was restricted to those with a primary brain cancer, leukemia, Hodgkin’s disease, non-Hodgkin lymphoma, kidney tumor, neuroblastoma, soft tissue sarcoma, or malignant bone tumor, which was diagnosed between 1970 and 1986 at age 20 yr or younger. Children diagnosed with nonmalignant brain neoplasms, such as craniopharyngiomas, were not eligible for inclusion in CCSS, and thus are not represented in this analysis. The human subjects research review committees at University of Minnesota (the study coordinating center) and each collaborating institution approved CCSS protocols and documents. Each eligible participant or his or her proxy if younger than age 18 yr at interview or if they died after achieving 5-yr survivorship but before being interviewed, provided informed consent for the study and separate consent to allow release and abstraction of medical records, including treatment records. Among the 20,276 5-yr survivors (cases) identified by the collaborating institutions, at the time of this analysis 14,054 were enrolled and completed an interview, 3,132 declined to participate, 2,996 were lost to follow-up and never offered enrollment, and 94 were pending completion of data collection.

Data collection

As part of a baseline survey questionnaire covering a wide range of information on demographic characteristics, health habits, and medical conditions, each participant was asked to report on his or her current height and weight. A copy of the survey instrument is available for review and downloading at www.cancer.umn.edu/ccss. Baseline interviews, completed by mailed questionnaire or in some cases by telephone with a trained interviewer, were conducted primarily in 1995 and 1996. Accordingly, self-reported age- and sex-specific population norms for height, weight, and BMI were derived from the 1995 National Health Interview Survey (NHIS). NHIS is conducted annually by the National Center for Health Statistics of the Centers for Disease Control and Prevention (7). The 1995 NHIS included interviews with 102,467 persons, including 35,331 who were aged 20–45 yr (8), to correspond with the age range at interview of the CCSS cases included in this analysis.

Radiation dosimetry

Radiation dose was quantified by a radiation physicist who evaluated diagrams and photographs taken in the treatment position to determine maximum total brain dose and brain regions exposed. If diagrams were not available, a written description from the medical record was used to estimate the regions included and the dose administered. Radiation exposure assessment included partitioning the brain into four anatomical segments: frontal cortex, posterior fossa, parietal/occipital cortex, and temporal lobe, which includes exposure to the hypothalamic-pituitary axis (HPA). A region was considered to be in a primary radiation field if at least 50% of the segment was included in the radiation volume; otherwise, the segment was considered to have received scatter dose.

Chemotherapy

Seven broad drug classes of adjuvant chemotherapy were identified from treatment records: alkylating agents, alkaloids, platinum-containing agents, antimetabolites, topoisomerase inhibitors, antibiotics, and steroids. The combinations of drugs received were so heterogeneous that no particular agent or combination of agents could be isolated sufficiently to quantify independent risk with confidence. Therefore, adjuvant chemotherapy was incorporated into the treatment group classifications as a yes/no factor. Each person who was treated with chemotherapy also received surgery and cranial radiation.

GH replacement therapy (GHRT)

A previous study was conducted to verify GHRT among CCSS study participants who reported a postdiagnosis history of GH deficiency or GH treatment (9). Among the 921 brain cancer cases eligible for this analysis, 63 had confirmed GHRT, and 27 others reported receiving GHRT, but records were not available to verify the information. In contrast to those who did not receive GHRT, the 27 unverified GHRT cases closely resembled the characteristics of the 63 confirmed GHRT cases. For example, 47.6% with verified GHRT and 48.2% with unverified GHRT had a primitive neuroectodermal tumor vs. 17.0% of those without GHRT. Additionally, 74.6% with verified GHRT and 77.8% with unverified GHRT fell within our definition of adult short stature vs. 35.7% without GHRT. As such, the 27 unverified GHRT cases were combined with the 63 verified cases in the analysis of GHRT effects.

Data analysis

Outcome variables. Age- and sex-specific height and BMI percentile classifications were calculated for each brain cancer case, based on the population norms obtained from the 1995 NHIS. BMI was calculated by dividing weight in kilograms by height in meters squared. For multivariate analyses, adult short stature was defined as a height below the 10th percentile, and a BMI value of 30 or higher was used to define obesity.

Cancer-related variables. Tumor histology was categorized into four groups: 1) astrocytoma and glioma (astroglial), 2) medulloblastoma/primitive neuroectodermal tumor (PNET), 3) ependymoma, and 4) other tumor type. Cancer treatment was categorized into seven groups: 1) surgery only; 2) surgery and cranial radiation; 3) surgery and craniospinal radiation; 4) surgery, cranial radiation, and chemotherapy; 5) surgery, craniospinal radiation, and chemotherapy; 6) surgery with radiation exposure that could not be characterized; and 7) other therapy. HPA exposure was categorized into six groups: 1) no cranial radiation, 2) less than 20 Gy, 3) 20–39 Gy, 4) 40–59 Gy, 5) 60 Gy or more, and 6) uncertain dose. The uncertain dose group included 90 cases who received radiotherapy but whose records were insufficient to reliably characterize HPA dose. Age at diagnosis was categorized into three groups: 1) 4 yr or younger, 2) 5–9 yr, and 3) 10–20 yr.

Multivariate analyses.

For each of the dichotomous outcome variables of adult short stature and obesity, logistic regression analyses were conducted to simultaneously account for the effects of treatment group, tumor histology, age at diagnosis, and GHRT. Because the height percentiles were matched for age at interview and sex, these variables were not explicitly included in those models. Sex and age at interview were included in the models that evaluated obesity. The other therapy, other tumor type, and uncertain dose groups were included in the models as indicator (dummy) variables, but the heterogeneity within each group precludes drawing meaningful conclusions from the results, so their values were not shown in the outcome tables. The uncertain dose was not included in the Mantel-Haenszel ² test for trend to evaluate HPA dose response.

	Results

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Subject characteristics

The mean age at interview for the 921 study participants was 27.2 yr (median, 27.0), with a range of 20–45 yr; little difference in mean age was observed between males (27.3 yr) and females (27.1 yr). Mean height was 1.69 m (SD = 0.12) for males and 1.58 m (SD = 0.11) for females. Both males and females were shorter, on the average, than would be expected from NHIS data. Comparable age mean height from NHIS was 1.79 m for males (P < 0.001) and 1.65 m for females (P < 0.001). Four (0.8%) males and three (0.7%) females had heights shorter than -4 SD, five (1.0%) males and 11 (2.5%) females had heights between -3 and -4 SD, and 65 (13.3%) males and 32 females (7.4%) had heights between -2 and -3 SD compared with same sex population norms from NHIS. Other characteristics of the study population are shown in Table 2. The age distribution at diagnosis was similar for males and females, with approximately 45% of cases younger than age 10 yr when diagnosed. Astroglial tumors (68%) predominated in the case group, and PNETs accounted for an additional 20% of diagnoses. About 28% of cases were treated with surgery only for their brain cancer, and all but four other cases received radiation. Most cases with HPA exposure received between 40 and 59 Gy. Although not shown in Table 2, the maximum brain radiation dose to any part of the brain among the 656 cases who received radiation therapy was: less than 40 Gy, 6%; 40–49 Gy, 15%; 50–54 Gy, 44%; 55 Gy or more, 22%; and uncertain dose, 13%. More males (11.6%) than females (7.7%) received GHRT.

Height and BMI distributions

Figure 1 provides panels of the distributions of height and BMI, stratified, respectively, by age at diagnosis and treatment modality, compared with same age- and same sex-expected values from NHIS. In each evaluation a large excess of brain cancer cases are below the 5th or 10th percentiles for height, but the distributions for BMI among cases are quite similar to normative values. For instance, 53% of adults who were diagnosed before age 5 yr, 46% of those diagnosed from ages 5–9 yr, and 26% of those diagnosed from ages 10–20 yr, were below the 10th percentile for final height (top panel). Treatment group effects are shown in the lower panel, where the height and BMI distributions for those treated with surgery only are only minimally different from what would be expected for population norms. In contrast, a large proportion of adults treated with radiation, particularly craniospinal radiation, are below the 5th or 10th percentiles of height. Adjuvant chemotherapy did not appreciably alter these distributions, so to enhance visual clarity we did not account separately for chemotherapy in the figure.

View larger version (28K): [in this window] [in a new window]   FIG. 1. Age- and sex-specific percentiles for height and BMI comparing normative data from the 1995 NHIS to the distribution among surviving brain cancer study participants by age at diagnosis (upper panel) and by treatment modality (lower panel).

The multivariate model quantifying the relative odds of being below the 10th percentile for height, compared with the 10th percentile or higher, is shown in Table 3. This evaluation considers simultaneously the effects of age at diagnosis, tumor histology, treatment group (without accounting for radiation dose), and GHRT. The strongest risk factors for adult short stature were young age at diagnosis and craniospinal irradiation. PNET histology and GHRT were also independent risk factors for adult short stature. After accounting for treatment, histology, and GHRT, adult short stature was 5-fold higher in those diagnosed before age 5 yr and 3-fold higher in those diagnosed from age 5–9 yr compared with those diagnosed at age 10–19 yr. The age effect appears to be considerably stronger among females than males.

As shown in Table 3, younger age at diagnosis and cranial radiation are the only apparent risk factors for obesity, and only in females. The risk for obesity among females, after controlling for the other factors in the model, was 2.7-fold higher for those with age at diagnosis of 4 yr or younger and 3.6-fold higher for those diagnosed at 5–9 yr compared with those diagnosed at older ages. Cranial irradiation among females, regardless of concurrent treatments, increased the risk of obesity 2- to 3-fold above that of treatment with surgery only. No similar effects were seen among the male cases. There did appear to be a dose-response relation between HPA radiation dose and obesity among females (test for trend, P < 0.001), but not among males (test for trend, P = 0.32; Table 4).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In this large epidemiological study of young adults who survived primary brain cancer as a child, we found that a remarkably high proportion, nearly 40%, were very short of stature. These findings are similar to smaller studies of brain cancer survivors in both mean values of final adult height (10) and in lower percentiles of height compared with the normal population (11, 12). We acknowledge that self- reported height and weight are not the gold standard measurements, and that some misclassification undoubtedly is present in these data. Because there is evidence to indicate that males typically overreport their height by 2 in. (5.08 cm) (13), we conducted a sensitivity analysis to estimate the prevalence bounds of short stature among males in our study population. The prevalence of short stature in our study population could range from 22% if the misclassification only occurred in the male NHIS comparisons to 51% if the misclassification occurred only among our brain cancer survivor cases. However, because the population norms we used from NHIS data were also based on self-report, we believe that any errors in height and weight are not likely to systematically differ between the two reporting sources.

Because of the high correlations between age at diagnosis, histological subtype, and treatment modality, it is often difficult to disentangle the independent effects of each individual factor on brain cancer late effects. Our multivariate models provide evidence that the most important single factors predicting adult short stature are young age at diagnosis and radiation exposure to the HPA. Helseth et al. (10) also reported a correlation between young age at the time of treatment and short final height. Evidence of the association between radiation treatment and impaired growth velocity or short final height has been reported in other studies of brain cancer patients (14, 15, 16, 17) and in follow-up studies that examined other types of cancer (9, 18, 19). Children who undergo cranial radiation treatment for brain cancer are at increased risk for short stature, GH deficiency, and for other endocrine abnormalities that were not examined in this analysis, such as precocious puberty, hypogonadism, and hypothyroidism (5, 11, 20, 21, 22, 23, 24, 25).

At least two mechanisms exist for growth impairment from high dose craniospinal radiation: GH deficiency from the effects on the HPA (26), and direct arrest of vertebral body growth from radiation to the spine (27). A recent clinical study of 25 children treated with cranial radiation for a brain tumor showed that GH levels declined over a 12-month period after treatment, and that the level of GH deficiency was dependent on hypothalamic radiation dose and volume (28). The effect on GH levels was dose dependent and was consistent with the HPA dose effects on final height that we observed in our study. Other studies also have shown radiation doses in the range of 40–60 Gy to be associated with a significant risk of GH deficiency (27, 28, 29). Children may benefit from GH replacement therapy for correction of this element of their growth impairment (11, 30); however, in our study treatment with GH did not eliminate the risk for adult short stature. In fact, after accounting for HPA radiation dose and other relevant factors, the male participants who received GHRT had a 3-fold higher likelihood of adult short stature than the male participants not so treated. We were unable to evaluate the etiology of this seemingly paradoxical finding, but it is likely that the patients treated with GHRT reflect those with the most severe growth retardation. Although GHRT was not entirely successful in normalizing their final height, GHRT is reported to be both safe (9, 31, 32) and effective in improving growth velocity (33) in children with radiation-induced GH deficiency. Unfortunately, GH replacement cannot correct the direct bone damage that occurs from radiation exposure to the spine (30, 34). Irradiation of the growing spine may compromise final height by impairing growth of the vertebrae. We found that study participants who received craniospinal irradiation were at higher risk of adult short stature than participants treated with cranial radiation not involving the spine; however, the enhanced effect was weak and not statistically significant once HPA dose was taken into account.

Adjuvant chemotherapy has been reported to be associated with risk of short final height (35, 36) and appeared to impart risk above that of cranial radiation in our study for adult short stature. However, adjuvant chemotherapy was not associated with risk for short stature once HPA radiation dose was taken into account in the analysis.

A novel finding in this study is that although there was a high propensity for brain cancer survivors to be below the 10th percentile in height, cases tended to be proportional in height to weight. This observation contrasts with several previous small studies of brain cancer survivors (33, 37), and with one large study of acute lymphoblastic leukemia survivors treated with lower doses of cranial radiation, who were at high risk for both short stature and significant obesity (38). The risk of severe obesity in patients surviving craniopharyngiomas is well established, but could not be assessed in our study because these patients were not eligible for inclusion. The overall distribution of BMI among participating survivors in our study was similar to that of same age, same sex population norms. The number of obese patients was significantly lower than that of population norms in males and was similar to population norms in females. Among females, but not males, the risk of obesity was increased by HPA radiation exposure in a dose-response fashion and by age at diagnosis of younger than 10 yr. In a retrospective analysis of 156 children who survived a brain tumor for at least 5 yr after therapy, Lustig et al. (39) identified hypothalamic damage from any source of treatment, but particularly from radiation doses of 51 Gy or higher, as the primary risk factor for obesity.

This follow-up study of a large and diverse clinical population confirms and illustrates an important long-term effect of brain cancer and its treatment among those fortunate enough to survive into adulthood, that of substantial short stature. As cure rates for childhood brain tumors continue to improve, so must our understanding of the impairments related to the disease and the consequences of the necessary treatment interventions. Clinical and epidemiological research in the area of cancer survivorship and late effects (40, 41), although difficult to conduct because of feasibility challenges with follow-up, must continue to focus on long-term medical outcomes and how they influence the future physical and psychosocial health of the affected children and their families (42).

	Footnotes

 
This work was supported by National Cancer Institute Grant U24-CA-55727 and the Children’s Cancer Research Fund at University of Minnesota.

Abbreviations: BMI, Body mass index; CCSS, Childhood Cancer Survivor Study; 95% CI, 95% confidence interval; GHRT, GH replacement therapy; HPA, hypothalamic-pituitary axis; NHIS, National Health Interview Survey; OR, odds ratio; PNET, primitive neuroectodermal tumor/medulloblastoma; SDS, SD score.

Received May 1, 2003.

Accepted July 14, 2003.

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				S. E. Lipshultz, S. A. Vlach, S. R. Lipsitz, S. E. Sallan, M. L. Schwartz, and S. D. Colan Cardiac Changes Associated With Growth Hormone Therapy Among Children Treated With Anthracyclines Pediatrics, June 1, 2005; 115(6): 1613 - 1622. [Abstract] [Full Text] [PDF]

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				C. M. Brownstein, A. C. Mertens, P. A. Mitby, M. Stovall, J. Qin, G. Heller, L. L. Robison, and C. A. Sklar Factors That Affect Final Height and Change in Height Standard Deviation Scores in Survivors of Childhood Cancer Treated with Growth Hormone: A Report from the Childhood Cancer Survivor Study J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4422 - 4427. [Abstract] [Full Text] [PDF]

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