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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 9 4422-4427
Copyright © 2004 by The Endocrine Society

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

Carrie M. Brownstein, Ann C. Mertens, Pauline A. Mitby, Marilyn Stovall, Jing Qin, Glenn Heller, Leslie L. Robison and Charles A. Sklar

Departments of Pediatrics (C.M.B., C.A.S.) and Epidemiology and Biostatistics (J.Q., G.H.), Memorial Sloan-Kettering Cancer Center, New York, New York 10021; Department of Pediatrics (A.C.M., P.A.M., L.L.R.), University of Minnesota School of Medicine, Minneapolis, Minnesota 55455; and Department of Radiation Physics (M.S.), University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

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


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
GH deficiency is a common late complication in survivors of pediatric malignancies, particularly those who are treated with radiation (RT) to the hypothalamic-pituitary region. Nonetheless, few reports have assessed final height outcomes in survivors treated with GH. In the present study, we investigated which patient and treatment variables correlate with final height and change in height SD score (SDS) in a large cohort of cancer survivors treated with GH.

We previously identified 361 participants in the multicenter Childhood Cancer Survivor Study who were treated with GH. Final height data were available in 183 survivors (120 males). Diagnoses included: central nervous system tumors (n = 90), acute leukemia (n = 64), soft tissue sarcomas (n = 23), and miscellaneous (n = 6). The median age at diagnosis of the primary cancer was 4.6 yr, and the median age at start of GH treatment was 11.3 yr. Mean height SDS at start of GH therapy was –2.03 ± 0.8, and the mean final height SDS was –1.48 ± 0.10 (P < 0.001). Final height SDS was positively associated with target height and dose of GH but negatively associated with the presence of concomitant endocrinopathies and dose of spinal RT. Change in height SDS (start of GH-final height) was positively associated with male gender, younger bone age at start of GH, and dose of GH; presence of concomitant endocrinopathies and dose of spinal RT were negatively associated with change in height SDS. Risk factors associated with a final height of –2.0 SD or less included lower doses of GH and exposure to higher doses of spinal RT. Thus, to maximize final height, our findings emphasize the importance of beginning GH therapy at the earliest bone age that is clinically feasible; treating with conventional higher doses of GH; and, when possible, minimizing the dose of spinal RT.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
DUE TO IMPROVEMENTS in therapies and supportive care, the survival rates for children and adolescents with a malignancy have increased dramatically over the last 30 yr (1). Because most pediatric cancer patients now can be expected to survive into adulthood, it has become increasingly important to study the long-term consequences and delayed effects of pediatric malignancies and their treatments.

At least one endocrine disturbance can be documented in approximately 40% of survivors, including GH deficiency (GHD). GHD is most often seen after radiation (RT) to the hypothalamic-pituitary region or as a consequence of a tumor in that region of the brain (2). Although GHD is common among survivors of certain pediatric cancers and contributes to adult short stature in this population (3, 4), the determinants of final height in survivors are multifactorial and include both hormonal (e.g. GHD, precocious puberty) and nonhormonal factors (e.g. RT injury to the growth plates of spine, midparental height). Despite the fact that GH has been used in survivors of childhood cancers for more than 25 yr, data on the final height of survivors treated with GH are quite limited (5, 6, 7, 8, 9). Moreover, because of the small size and homogenous nature of most series, it has not been possible to determine the interaction among various patient (e.g. age, gender) and treatment (e.g. spinal RT) variables and how they impact the response to GH.

In the present study, we attempted to overcome some of the aforementioned limitations by determining the variables that contribute to final height and change in height SD score (SDS) (start of GH-final height) in a large and heterogeneous cohort of survivors of childhood cancer treated with GH.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Childhood Cancer Survivor Study (CCSS)

The cohort of patients evaluated in this study is a subset of the patients who are participants in the CCSS, also known to study participants as the Long-Term Follow-Up Study. The methods, objectives, eligibility criteria, and characteristics of study participants for the CCSS have been published in detail previously (10). In brief, the CCSS is a multiinstitutional (see Acknowledgments) retrospective study of 5-yr survivors of childhood cancer diagnosed before age 21 yr, between 1970 and 1986. Subjects with benign tumors, including craniopharyngioma, were excluded from the study. The study was aimed primarily at determining late adverse outcomes that follow treatment for childhood and adolescent cancer. The study was reviewed and approved by the Institutional Review Board at each of the 25 participating clinical centers.

Each participant was required to fill out an extensive baseline questionnaire (complete questionnaire is available at www.cancer.umn.edu/ccss). In addition, detailed medical information was abstracted from the medical record of each participant. Data collected included all treatments for the primary diagnosis, including the initial treatment, treatment for any relapse, and preparatory regimens for bone marrow transplant. Information about cancer treatment included qualitative information on 42 chemotherapeutic agents; quantitative information on 22 selected agents; surgeries performed from the time of diagnosis; and quantitative radiation data on field size, site, and dose.

Survivors treated with GH

From among the first 13,539 participants of the CCSS, we were able to verify that 361 had received treatment with GH (11). From among those 361 subjects treated with GH, 183 had completed their growing and had documented final height data. Final height was defined as the height achieved when serial heights revealed a change of 2 cm or less over a 12-month period or the height recorded when the bone age was 14.5 yr or more for girls and 16 yr or more for boys. Additionally, the charts were reviewed for parental heights, dose of GH, duration of GH therapy, preparation of GH prescribed, bone age at commencement of GH treatment, peak GH value during provocative testing, and treatment with other hormones including GnRH agonists (GnRHa). Results of provocative GH testing were available on 163 of the 183 participants. The peak GH response to provocative testing was less than 10 ng/ml in 156 subjects (68 subjects tested with two agents; 88 subjects tested with one agent) and more than 10 ng/ml in the remaining seven.

A total of 177 patients were known to have received RT; complete radiotherapy records were available for 165 of these patients. Eighty-six received cranial irradiation, 72 craniospinal irradiation, and seven received total body irradiation. Treatment volumes were determined for each patient, based on diagrams and photographs of the patients in treatment position, as found in the records. The absorbed radiation dose was estimated to the hypothalamus-pituitary and the spine; the spine was considered to have been irradiated if at least three fourths of the spine was included in a radiation beam. Standard radiotherapy depth dose data (12) were used to estimate doses to anatomic sites in a beam, and data measured in a water phantom were used for out-of-beam sites (13). For analysis, hypothalamic-pituitary and spinal doses were placed in six categories: 0–10, more than 10–20, more than 20–30, more than 30–40, more than 40–50, and more than 50+ Gy.

Statistical analysis

This was an observational study intended to determine the factors that contribute to final height in survivors of childhood cancer treated with GH, which factors put these children at greatest risk for significant short stature. The covariates, age at diagnosis, age at commencement of GH therapy, bone age at commencement of GH therapy, duration of GH therapy, dose of GH, target height, gender, treatment with chemotherapy, treatment with a GnRHa, treatment with other hormonal agents, dose of pituitary RT, and dose of direct spinal RT were used to explain the variability in the response variables: final height SDS, change in height SDS, and final height SDS dichotomized at –2.0. A linear regression model was used to model the relationship for the first two response variables, and a logistic regression model was used for the third response variable. Stepwise regression was used to find the most significant factors. Pearson’s correlation coefficient was used to measure the association between the self-reported final heights and the documented final heights. The t-statistic was used to test the difference between groups univariately.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
The clinical characteristics of the 183 GH-treated survivors with documented final height data are summarized in Table 1Go.


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  		TABLE 1. Patient characteristics

 
Variables associated with final height and change in height SDS

The change in height SDS from the start of GH therapy to final height was significant (–2.08 ± 0.08 vs. –1.48 ± 0.10, P < 0.0001) (Fig. 1Go). The variables associated with change in height SDS and final height SDS for the multivariate models are summarized in Table 2Go. In the multivariate model, change in height SDS was positively associated with male gender and dose of GH but negatively associated with bone age at start of GH, treatment with other hormones in addition to GH, and dose of spinal RT.



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  		FIG. 1. The height SDS at start of GH and final height. Solid white line represents median height SDS. The boxes represent the 25th and 75th quartiles. Whiskers extend to the upper and lower adjacent values that are 1.5 times or less the interquartile range. *, P < 0.0001.

 

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  		TABLE 2. Results of multivariate analysis for change in height SDS and final height SDS

 
In the multivariate model, final height was positively associated with target height and dose of GH but negatively associated with treatment with other hormones in addition to GH and dose of spinal RT (Table 2Go and Fig. 2Go).



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  		FIG. 2. Final height SDS according to original diagnosis and exposure to direct spinal RT. Solid white line represents median height SDS. The boxes represent the 25th and 75th quartiles. Whiskers extend to the upper and lower adjacent values that are 1.5 times or less the interquartile range. Outliers are individually plotted (horizontal lines). CNS, Central nervous system. *, P < 0.05; **, P < 0.0001.

 
Risk of final height –2.0 SD or less

We calculated the odds ratio for final height –2.0 SD or less for GH-treated survivors stratified by GH dose, bone age at start of GH therapy, dose of spinal RT, and gender (Table 3Go). The odds of final height –2.0 SD or less for survivors treated with spinal RT at a dose of 10 –30 Gy or less were 2.1 times [95% confidence interval (CI), 0.921, 5.095] and those treated with a dose more than 30 Gy were 3.4 times (95% CI, 1.595–7.279; P = 0.004) the odds of final height –2.0 SD or less for survivors treated with spinal doses less than 10 Gy. The odds of final height –2.0 SD or less for survivors treated with GH at a dose greater than 0.3 mg/kg·wk were 0.22 times (95% CI, 0.109, 0.442; P < 0.0001) the odds of final height –2.0 SD or less, compared with those treated with a dose less than 0.25 mg/kg·wk.


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  		TABLE 3. Risk factors associated with final height –2.0 SDS or less

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Studies of final height in childhood cancer survivors treated with GH are important to determine the effectiveness of GH therapy and identify areas in which physicians can intervene to improve final height outcome. Our study provides final height data on the largest cohort of childhood cancer survivors treated with GH reported to date. We were able to identify five variables that were independently associated with an improvement in height SDS: use of lower doses of spinal RT, use of higher doses of GH, initiation of GH therapy at a younger bone age, male gender, and the absence of additional endocrinopathies. Dose of pituitary irradiation, use of GnRHa, exposure to chemotherapy, and duration of GH treatment were not found to have an independent effect on change in height SDS. We found that target height did contribute to final height SDS but not to change in height SDS.

Our results confirm the earlier findings of smaller studies demonstrating the efficacy of GH treatment in survivors of childhood cancer (5, 6, 8, 14, 15, 16). Most recently, Gleeson et al. (9) demonstrated improvements in final height outcomes over 25 yr in childhood brain tumor survivors. These improvements were presumably secondary to more standardized GH schedules, superior dosing regimens (i.e. higher doses spread over 6–7 d/wk), and the use of GnRHa in selected groups of patients.

Additionally, our results concur with the findings of previous studies evaluating children with idiopathic GHD (IGHD), which demonstrated the use of higher doses of GH to be beneficial in maximizing final height (17, 18, 19, 20). We observed an inverse correlation between risk of final height SDS –2.0 or less and GH dose. Previously Radetti et al. (20) observed significantly higher final height SDS and growth velocity SDS in patients treated with GH at 0.3 mg/kg·wk as compared with 0.15 mg/kg·wk. Blethen et al. (18) demonstrated higher final height SDS in IGHD patients treated with recombinant human GH at 0.3 mg/kg·wk, compared with historical controls treated with 0.15–0.19 mg/kg·wk. More recently Cohen et al. (21) reported a dose-response effect of GH both on growth and the serum levels of the growth factors IGF-I and IGF binding protein-3. In the latter study, it appeared that the dose-response curve reached a plateau at around 0.35 mg/kg·wk. At higher doses, there was a greater chance of an elevated IGF-I level but without additional benefit in terms of growth (21).

In the current study, patients were treated with both pituitary-derived GH as well as the recombinant forms of GH. Moreover, the doses used were often lower than the doses that are routinely used currently. Thus, we would anticipate that the height outcomes achieved in the future are likely to be superior to those described in this report.

Our study confirms the well-documented detrimental effect of spinal RT on growth and final height (7, 14, 22). In our study, patients who received more than 30 Gy to the spine had a 3.5 times greater risk of achieving a final height –2.0 SD or less, compared with those treated with less than 10 Gy. Furthermore, when patients were stratified by diagnosis and exposure to direct spinal RT, patients with acute leukemia and central nervous system tumors treated with direct spinal RT had a statistically significant shorter final height SDS than those who did not get spinal RT as part of their treatment.

In the present study, males appeared to have a better response to GH, compared with females. The reasons for this are not clear, but age and bone age at start of GH therapy were similar between males and females (data not shown). In review of the literature on the affect of gender on height outcome after GH therapy, the data are conflicting and confounded by whether puberty was spontaneous or induced (23, 24). It has been previously demonstrated that females are more likely to develop precocious puberty after cranial irradiation than similarly treated males (25, 26). Thus, it is possible that the propensity for females to enter puberty prematurely may account, at least in part, for their poorer height outcomes. Furthermore, the smaller number of females in this and most other studies make comparisons between males and females difficult. Whereas it is possible that male survivors may respond better to GH, further studies are needed.

The use of a GnRHa has been shown to enhance final height in patients with central precocious puberty (27), those with IGHD without precocious puberty (28, 29, 30), and normal short children with normally timed puberty (31). Recent studies have suggested an augmentation in final height in childhood cancer survivors who were treated with both GH and a GnRHa (5, 9). We did not find that GnRHa therapy was associated with an increase in height SDS in this cohort. It is possible that we did not find an affect of GnRHa on change in final height SDS due to the small number of patients (14 of 183) who received GnRHa in the current study and the fact that GnRHa therapy was not prescribed in a uniform manner in this retrospective study.

Treatment with chemotherapy has been reported to have a significant negative impact on final height (7, 25, 32, 33, 34, 35). In our cohort of survivors, we did not find chemotherapy to independently contribute to final height and change in height SDS. Similarly, in a recent study by Gurney et al. (36), the addition of adjuvant chemotherapy to surgery and cranial irradiation or surgery alone did not impart a greater risk of adult short stature in survivors of childhood brain cancer. This disparity may be due, in part, to the fact that the patients in the present study were treated with GH, as opposed to some of the earlier studies in which patients were not so treated (25, 32, 33, 34, 35). Furthermore, in the study of Ogilvy-Stuart and Shalet (7) in which the subjects were treated with GH, the dose of GH was relatively low and lower than the dose employed in many of the subjects in the present cohort. Thus, it is possible that larger doses of GH may overcome some of the detrimental effects of chemotherapy on growing bones.

Although we did not find that the dose of radiation to the hypothalamus and pituitary was predictive of final height or change in height SDS as documented by earlier studies (37), we did find that the presence of concomitant endocrinopathies was associated with reduced final height and less change in height SDS. Because patients treated with higher doses of hypothalamic-pituitary irradiation are at increased risk of developing more profound GHD and additional anterior pituitary hormone deficiencies (4, 37), the presence of concomitant endocrinopathies is likely a surrogate for radiation dose to the hypothalamic-pituitary axis. Additionally, it is conceivable that suboptimal replacement therapy with other hormones, especially glucocorticoids and sex steroids, independently interferes with growth, as demonstrated by superior final height outcomes in patients with isolated GHD, compared with those with multiple congenital pituitary deficiencies (38).

Whereas recent data support the safety of GH replacement therapy in survivors of childhood cancer in terms of risk of disease recurrence, the issue of risk of subsequent new malignancies remains unresolved (11, 16, 39, 40). Given the data on a possible link between the serum concentrations of IGF-I and IGF binding protein-3 and the common cancers of adulthood (41, 42), the recommendation to monitor serum levels of these growth factors in all children treated with GH seems justified (21). This may be especially important when using doses in the higher ranges.

In conclusion, our data from a large cohort of cancer survivors suggest that improvements in final height can be achieved by initiating GH therapy at the earliest bone age that is clinically feasible, using conventional higher doses of GH and, when possible, minimizing the dose of spinal RT.


   Acknowledgments
 
Following is the list of CCSS institutions and investigators: Arthur Ablin, M.D.* (University of California-San Francisco, California); Roger Berkow, M.D.* (University of Alabama, Birmingham, Alabama); John Boice, Sc.D.{ddagger} (International Epidemiology Institute, Rockville, Maryland); Norman Breslow, Ph.D.{ddagger} (University of Washington, Seattle, Washington); George R. Buchanan, M.D.*, Kevin Oeffinger, M.D.{ddagger} (University of Texas Southwestern Medical Center at Dallas, Dallas, Texas); Lisa Diller, M.D.*, Holcombe Grier, M.D.{dagger}, Frederick Li, M.D.{ddagger} (Dana-Farber Cancer Institute, Boston, Massachusetts); Zoann Dreyer, M.D.* (Texas Children’s Center, Houston, Texas); Debra Friedman, M.D., M.P.H.*, Thomas Pendergass, M.D.{ddagger} (Children’s Hospital and Medical Center, Seattle, Washington); Daniel M. Green, M.D.*{ddagger} (Roswell Park Cancer Institute, Buffalo, New York); Mark Greenberg, M.B., Ch.B.* (Hospital for Sick Children, Toronto, Canada); Robert Hayashi, M.D.*, Teresa Vietti, M.D.{dagger} (St. Louis Children’s Hospital, St. Louis, Missouri); Melissa Hudson, M.D.*{ddagger} (St. Jude Children’s Research Hospital, Memphis, Tennessee); Raymond Hutchinson, M.D.* (University of Michigan, Ann Arbor, Michigan); Michael P. Link, M.D.*, Sarah S. Donaldson, M.D.{ddagger} (Stanford University School of Medicine, Stanford, California); Anna Meadows, M.D.*{ddagger}, Bobbie Bayton{ddagger} (Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania); John Mulvihill, M.D.{ddagger} (Children’s Hospital, Oklahoma City, Oklahoma); Brian Greffe*, Lorrie Odom, M.D.{dagger} (Children’s Hospital, Denver, Colorado); Maura O’Leary, M.D.* (Children’s Health Care-Minneapolis, Minneapolis, Minnesota); Amanda Termuhlen, M.D.*, Frederick Ruymann, M.D.{dagger}, Stephen Qualman, M.D.{ddagger} (Columbus Children’s Hospital, Columbus, Ohio); Gregory Reaman, M.D.*, Roger Packer, M.D.{ddagger} (Children’s National Medical Center, Washington, DC); A. Kim Ritchey, M.D.*, Julie Blatt, M.D.{dagger} (Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania); Leslie L. Robison, Ph.D.*{ddagger}, Ann Mertens, Ph.D.{ddagger}, Joseph Neglia, M.D., M.P.H.{ddagger}, Mark Nesbit, M.D.{ddagger} (University of Minnesota, Minneapolis, Minnesota); Stella Davies, M.D., Ph.D.{ddagger} (Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio); Kathy Ruccione, R.N., M.P.H.* (Children’s Hospital Los Angeles, Los Angeles, California); Charles Sklar, M.D.*{ddagger} (Memorial Sloan-Kettering Cancer Center, New York, New York); Malcolm Smith, M.D.{ddagger}, Peter Inskip, Sc.D.{ddagger} (National Cancer Institute, Bethesda, Maryland); W. Anthony Smithson, M.D.*, Gerald Gilchrist, M.D.{dagger} (Mayo Clinic, Rochester, Minnesota); Louise Strong, M.D.*{ddagger}, Marilyn Stovall, Ph.D.{ddagger} (University of Texas M. D. Anderson Cancer Center, Houston, Texas); Terry A. Vik, M.D.*, Robert Weetman, M.D.{dagger} (Riley Hospital for Children, Indianapolis, Indiana); Yutaka Yasui, Ph.D.*{ddagger}, John Potter, M.D., Ph.D.{dagger}{ddagger} (Fred Hutchinson Cancer Research Center, Seattle, Washington); Lonnie Zeltzer, M.D.*{ddagger} (University of California-Los Angeles, Los Angeles, California). *, Institutional principal investigator; {dagger}, former institutional principal investigator; {ddagger}, CCSS Steering Committee.


   Footnotes
 
This work was supported by National Institutes of Health Grant (U24-CA55727), the Genentech Foundation for Growth and Development, and the University of Minnesota funding provided by the Children’s Cancer Research Fund.

Abbreviations: CCSS, Childhood Cancer Survivor Study; CI, confidence interval; GHD, GH deficiency; GnRHa, GnRH agonist; IGHD, idiopathic GHD; RT, radiation; SDS, SD score.

Received February 3, 2004.

Accepted May 27, 2004.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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