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Endocrine Outcomes for Children With Embryonal Brain Tumors After Risk-Adapted Craniospinal and Conformal Primary-Site Irradiation and High-Dose Chemotherapy With Stem-Cell Rescue on the SJMB-96 Trial

Stephen J. Laughton, Thomas E. Merchant, Charles A. Sklar, Larry E. Kun, Maryam Fouladi, Alberto Broniscer, E. Brannon Morris, Robert P. Sanders, Matthew J. Krasin, John Shelso, Zang Xiong, Dana Wallace, Amar Gajjar

From the Division of Neuro-Oncology, Department of Oncology, Division of Radiation Oncology, Department of Radiological Sciences, Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY; and Division of Endocrinology, Department of Biostatistics, St Jude Children's Research Hospital, Memphis, TN

Corresponding author: Amar Gajjar, MD, Division of Neuro-Oncology, Department of Oncology, St Jude Children's Research Hospital, 332 North Lauderdale St, Memphis, TN 38105; e-mail: amar.gajjar{at}stjude.org

	ABSTRACT

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Purpose To estimate the cumulative incidence of specific hormone deficiencies and the influence of hypothalamic-pituitary (HP) axis radiation dose in a cohort of children with embryonal brain tumors treated with risk-adapted craniospinal irradiation (CSI), conformal primary site irradiation, and high-dose chemotherapy.

Patients and Methods Clinical data and HP axis radiation dosimetry data were obtained from 88 eligible children. All patients received regular endocrine follow-up that included screening tests of thyroid function and stimulation testing for growth hormone deficiency (GHD), and adrenocorticotropin hormone deficiency.

Results The cumulative incidence of GHD, thyroid-stimulating hormone (TSH) deficiency, adrenocorticotropic hormone deficiency, and primary hypothyroidism at 4 years from diagnosis was 93% ± 4%, 23% ± 8%, 38% ± 6%, and 65% ± 7%, respectively. Radiation dosimetry to the HP axis was associated only with the development of TSH deficiency; the 4-year cumulative incidence was 44% ± 19% and 11% ± 8% (P = .014) for those receiving more or less than the median dose to the hypothalamus ( 42 v < 42 Gy), respectively. The median dose of CSI for the average-risk (AR) patients was 23.4 and 39.6 Gy (36 to 40.5 Gy) for the high-risk patients. The estimated mean decline in height Z-score after radiation therapy was greater in high-risk patients (–0.65 units/yr) when compared with AR patients (–0.54 units/yr; P = .039).

Conclusion Pediatric patients with CNS embryonal tumors are at high risk for treatment-related hormone deficiencies. GHD and primary hypothyroidism were diagnosed in a majority of subjects relatively soon after the completion of therapy. Radiation dose to the hypothalamus in excess of 42 Gy was associated with an increase in the risk of developing TSH deficiency.

	INTRODUCTION

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Embryonal brain tumors, which include medulloblastoma, primitive neuroectodermal tumors (PNET), and atypical teratoid/rhabdoid tumors, are the most common malignant brain tumors in children. With modern multimodality therapy, the prognosis for newly diagnosed children older than 3 years of age has improved significantly.

The best reported results for children with completely resected, nonmetastatic medulloblastoma show a 5-year overall survival in excess of 80%, whereas those with higher risk disease have a 5-year overall survival approaching 70%.^1,2 Survival outcomes for patients with PNET and atypical teratoid/rhabdoid tumors are less favorable than for medulloblastoma in a comparable age group.^3-6 Improvement in survival seen with this group of tumors has resulted in an increased emphasis on the quality of the long-term survival. Late effects, such as neurocognitive, neurologic, and neuroendocrine deficits, have been extensively reported after successful therapy in these children.^7-10 These effects are likely the result of a complex interaction between the tumor, the different treatment modalities, and individual characteristics in a growing and developing child.^11,12

Endocrine deficits after multimodality therapy for brain tumors in children include growth hormone deficiency (GHD) and resultant impaired linear growth, and thyroid hormone, adrenocorticotropic hormone (ACTH), and sex steroid deficiencies.^12-16 These deficits significantly impact quality of life and require judicious management. Craniospinal irradiation (CSI) has been a long-established component of care in children with embryonal brain tumors, and damage to the hypothalamic-pituitary (HP) axis is an important factor in the development of endocrinopathies. Endocrine sequelae after irradiation depend on total dose and specific clinical factors, including age.^16-19 Previous studies have been either too small, reported on a specific endocrine deficiency, or lacked prospectively collected therapy and endocrine data. Furthermore, long-term endocrine outcomes and their clinical correlates, including HP axis radiation dosimetry, have not been reported in a large cohort of children treated for embryonal brain tumors.

At our institution, we have completed a prospective clinical trial (St Jude Medulloblastoma [SJMB]-96) that examined the efficacy of risk-adapted craniospinal and conformal primary site irradiation, and high-dose chemotherapy with autologous stem-cell support after maximal surgical resection.¹ In this article, we report the cumulative incidence of HP and thyroid dysfunction in this uniformly treated cohort of children with embryonal brain tumors treated prospectively with risk-adapted therapy.

	PATIENTS AND METHODS

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Patients
Between October 1996 and May 2003, 94 children with newly diagnosed, embryonal brain tumors were treated on the SJMB-96 protocol at St Jude Children's Research Hospital (Memphis, TN). Institutional review board approval was received, and written informed consent was obtained from all patients, parents, or legal guardians for trial participation.

Eligibility
Patients between the ages of 3 and 21 years inclusive at the time of diagnosis of their primary CNS embryonal tumor were eligible for the SJMB-96 clinical trial. No prior chemotherapy or radiation therapy (RT) was allowed. Patients were stratified by standard criteria into average risk (AR) or high risk (HR) on the basis of postoperative tumor volume and a modified Chang stage for metastatic disease.^1,20 Patients with extraneural metastatic disease were ineligible for protocol treatment. Those patients who died within 1 year or those without endocrine follow-up beyond 2 years from the start of RT were excluded from our analysis of endocrine outcomes.

RT and Chemotherapy
After surgical resection, AR patients received CSI of 23.4 Gy. Those with infratentorial tumors then received conformal irradiation of the anatomic posterior fossa to 36 Gy, followed by conformal primary site irradiation to 55.8 Gy using a 2-cm clinical-target volume margin on the postoperative tumor bed. Patients with HR disease received CSI of 36 Gy (M0-M1 disease) or 39.6 Gy (M2-M3 disease) followed by conformal primary site irradiation to 55.8 Gy using a 2-cm clinical-target volume margin on the postoperative tumor bed. Where appropriate, metastatic sites were irradiated to 50.4 to 54 Gy. Treatment was administered using conventional fractionation of 1.8 Gy per day, 5 days per week. Chemotherapy was initiated 6 weeks after irradiation. Specific post-RT chemotherapy details have been reported previously and are shown in Figure 1.¹

View larger version (32K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Treatment schema for the SJMB-96 protocol. PBSC peripheral-blood stem cells; CSI, craniospinal irradiation; PF, posterior fossa; G-CSF, granulocyte colony-stimulating factor.

Craniospinal irradiation includes cranial and spinal fields that are conventionally matched at the base of the neck to shield prevertebral cervical soft tissues, including the larynx and, when possible, the thyroid gland. The junction of the field is moved cephalad in 1-cm increments every five fractions during the treatment course to reduce the risk of spinal cord injury. This may increase exposure of part or all of the thyroid gland to the exit dose of the photon spinal field. When in the path of the radiation beam, the thyroid gland typically receives 70% to 80% of the prescribed spinal exit dose; however, the range may vary widely depending on the size of the patient and other parameters, including measures taken to shape the dose to conform to the anterior and posterior curvature of the spinal canal. More accurate assessment of thyroid dosimetry would require that special maneuvers be performed on a daily basis to measure dose at the level of the thyroid and to monitor patient positioning; these maneuvers have not been practical. Based on our assessment, when all or part of the thyroid gland is subtended by the irradiated volume, the thyroid dose in AR and HR patients would be—with large standard deviations—16 and 25 Gy, respectively.

Endocrine Assessment
Patients were clinically evaluated at regular intervals by both the primary neuro-oncology team and endocrinology specialists as part of the planned prospective follow-up.¹ Evaluations of the HP axis for evidence of thyroid-stimulating hormone (TSH) deficiency, and GHD and ACTH deficiency were performed. Endocrine screening investigations were undertaken in all patients, and specific stimulation testing occurred on the basis of these testing results or as part of routine clinical management. Standard laboratory techniques were used and institutional normal ranges defined abnormal results. When indicated, by screening tests that demonstrated possible hormonal deficiency, stimulation tests were performed. The arginine tolerance and l-dopa tests were used to evaluate growth hormone (GH) secretory capacity, with peak value less than 10 µg/L defining GHD. A free thyroxine level lower than the normal range, with a normal or low TSH level defined TSH deficiency; a TSH level above the normal range was considered diagnostic of primary hypothyroidism (PHT). ACTH deficiency was diagnosed if a 1-µg ACTH test yielded a 20-minute post-ACTH cortisol level 18 µg/dL, or if a metyrapone test yielded an 11-deoxycortisol level 7 ng/dL.²¹ Growth was monitored at each clinical visit, and height was measured by standard techniques using a stadiometer. Because of the relatively young age of the patient population, we were not able to meaningfully assess leuteinizing hormone and follicular-stimulating hormone status in the current cohort. Three patients had precocious puberty that required treatment with a gonadotrophin-releasing hormone agonist. Four patients had rapid tempo puberty with advanced bone age but did not require medical intervention.

Statistical Considerations
The associations among variables were examined by the Wilcoxon rank sum test or ² test. Exact tests were used when the expected sample size was less than five. The correlation between the dose to the hypothalamus and to the pituitary was based on Pearson's method. The cumulative incidence of a hormone deficiency was estimated from the date of starting RT until the date of the screening test or stimulation test identifying the deficiency. Death was a competing event and patients were censored at the earlier date of starting hormone replacement therapy or the last follow-up date.

The cumulative incidence of hormone deficiency was estimated using the methods proposed by Prentice et al.²² Statistical tests developed by Gray were used to examine the differences in the cumulative incidence of hormone deficiency by radiation dose.²³ Height was converted to age and sex-matched z score using EpiInfo, Version 3.3.2 (Centers for Disease Control and Prevention, Atlanta, GA) and Centers for Disease Control and Prevention 2000 growth reference data. A general linear mixed model was used to estimate the change in patients' height z scores during the time interval from the start of RT to the start of GH replacement therapy or the date of the last height measurement. Given that pubertal production of gonadal and adrenal steroids increase GH secretion, only patients who were Tanner stage 1 were included in this analysis; this only excluded three patients. The analysis was adjusted for patients' age at tumor diagnosis. The differences in the intercepts and slopes of the change in height z scores over time by risk group were examined. Statistical significance was determined at the P .05 level. The significance levels were not adjusted for the number of statistical comparisons made. All statistical analyses were performed using SAS, version 9.1 (SAS Institute, Cary, NC).

	RESULTS

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Study Population
A total of 94 patients were enrolled onto SJMB-96 at St Jude Children's Research Hospital. Five patients died as a result of disease within 1 year of diagnosis. One patient did not receive chemotherapy at parental request and was lost to endocrine follow-up at 1.65 years without any evidence of endocrine deficits, leaving 88 patients for evaluation. Clinical characteristics by risk category are listed in Table 1. Sixteen patients in the cohort have experienced disease progression, with only five receiving additional irradiation at the time of progression as follows: two patients, local RT only; one patient, spinal RT only; and two patients, both local and spinal RT.

View larger version (18K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Cumulative incidence of specific endocrine deficits following radiation therapy. GH, growth hormone; PHT, primary hypothyroidism; ACTH, adrenocorticotropic hormone; TSH, thyroid-stimulating hormone.

View larger version (12K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Cumulative incidence of (A) growth hormone deficiency, (B) thyroid-stimulating hormone (TSH) deficiency, and (C) adrenocorticotropic hormone (ACTH) deficiency by hypothalamic radiation dose divided around the median (42 Gy). XRT, radiation therapy.

ACTH Deficiency
Seventy-six patients (86%) had sufficient data to determine the status of the HP-adrenal axis. Thirty-three (43%) were diagnosed with ACTH deficiency, with a 4-year cumulative incidence of 38% ± 6% (Fig 2). The cumulative incidence of ACTH deficiency at 4 years is 36% ± 7% and 41% ± 10% in the AR and HR patients, respectively (P = 0.422). ACTH status was not affected by the dose of RT administered to the hypothalamus (median, 42.2 Gy for no ACTH deficiency v 41.3 Gy for ACTH deficiency). Furthermore, there was no association between RT dose to the hypothalamus and the cumulative incidence of ACTH deficiency (Fig 3C).

PHT
PHT was diagnosed in 44 patients (51%) at a median of 1.5 years (range, 0.7 to 3.6 years) from initiation of RT. The 4-year cumulative incidence of PHT was 65% ± 7% (Fig 2). AR patients had a significantly lower cumulative incidence of PHT deficiency when compared with HR patients (4-year cumulative incidence, 54% ± 9% v 89% ± 13%; P = .017).

Growth
Height differences at diagnosis between AR and HR patients was not significant, with estimated z scores of –0.06 and 0.04, respectively. The estimated decline in height z score per year was significantly higher in HR patients (–0.65; 95% CI, –0.75 to –0.54) when compared with AR patients (–0.54; 95% CI, –0.63 to –0.44; P = .039; Fig 4). Age at diagnosis was not significantly associated with the estimated decline.

View larger version (10K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 4. The decline of height z scores by risk group.

	DISCUSSION

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The mean radiation dose to the HP axis in our study was similar to that reported by several other groups who examined HP axis dosimetry in smaller groups of children with medulloblastoma/PNET.^11,17,25 The availability of contemporary imaging-based dosimetry has allowed us to correlate uniquely accurate, patient-based HP axis radiation dosimetry data with endocrine outcomes in our patient population.

We have confirmed the findings of others that GHD is very common in children treated for intracranial brain tumors, where therapy involves significant radiation doses to the HP axis.^{12,13,15-17,26-29} The effect of HP axis radiation dose on the cumulative incidence of GHD could not be examined in the current study because 86 of the 88 patients (98%) received more than 27 Gy to the HP axis, which is the reported threshold for almost certain GH dysfunction.^30,31 Only a small number of AR patients were not diagnosed with GHD, whereas all HR patients developed GHD. These AR patients had normal values of insulinlike growth factor-1 and insulinlike growth factor-binding protein-3 on their screening tests, and had normal growth or had reached their adult height at the time of enrollment onto the study.

The differences in decline in height z score that we observed between the two risk groups may well be due to the differences in radiation doses to the spine between the two groups, given that almost all patients had evidence of GHD and our institutional policy of GH replacement was uniformly applied. The only reported data in children treated with 18 Gy CSI for medulloblastoma indicate GHD requiring GH-replacement therapy in all seven surviving children. However, despite GHD, height was less affected in those treated with 18 Gy CSI compared with children receiving higher dose CSI. Of note, sitting height was relatively preserved in those treated with lower dose CSI, suggesting that the dose of CSI radiation is an important determinant of final height.^16,17 By contrast, Gurney et al,²⁶ in reporting final height data from the Childhood Cancer Survivor Study, did not find that spinal radiation seemed to be an independent predictor of reduced growth once HP axis radiation dose was taken into account. Unfortunately, we did not have data on sitting heights to help determine the differential impact of spinal radiation and HP axis radiation on growth. Given the progressive decline in height over time, timely initiation of GH, especially in those diagnosed at a young age, would appear to be both effective and safe.^27-32

We have reported a 4-year cumulative incidence of ACTH deficiency in 38% of our cohort, which is higher than the incidence reported by others after similar therapy. No cases of central adrenal insufficiency were reported in a small study (n = 20) by Heikens et al (1998).³³ However, insufficiency of the HP-adrenal axis has been reported in up to 29% of patients in cohorts of children treated with cranial irradiation or CSI for brain tumors.^12,34,35 It is possible that our results may be related, at least in part, to differences in the type of tests used to assess HP-adrenal function (eg, ACTH stimulation and oral metyrapone v insulin tolerance testing), and the fact that our patients were studied serially and not just at a single point in time.^35,36

The cumulative incidence of TSH deficiency of 23% ± 8% at 4 years in the current study is somewhat higher than the 4.5% to 6.3% incidence from other series of childhood brain tumor survivors.^14,24 Absolute case numbers in these studies are small, and thus a single case of central hypothyroidism has a significant impact on percentage cumulative incidence. Moreover, our patients were studied serially over time, and thus our numbers more accurately reflect the true incidence of affected patients. We were able to demonstrate a relationship between HP axis radiation dose greater than 42 Gy and the development of TSH, which underscores and reinforces the findings from prior, smaller studies.^14,24

Primary hypothyroidism was seen in 51% of our cohort, with a 4-year cumulative incidence of 65%. These results are similar to the incidence of primary hypothyroidism reported by others after standard-dose CSI for medulloblastoma.^19,37 The incidence of primary hypothyroidism may be underestimated in our study population in those patients who had superimposed central hypothyroidism. Xu et al¹⁷ observed only one case of hypothyroidism in a group of seven surviving children with medulloblastoma treated with 18 Gy CSI. The current, prospective Children's Oncology Group study may help answer whether reduced CSI dose translates into a reduced risk of primary hypothyroidism.

Data from this prospective study accurately estimate the incidence of endocrine deficits associated with therapeutically effective irradiation doses to the HP axis and the craniospinal axis currently used for children with embryonal brain tumors. Efforts to reduce long-term endocrine toxicity in this group of patients will need to focus on better ways to minimize HP axis dose and limit the dose to the thyroid gland.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTSOF INTEREST

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Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: Charles A. Sklar, Novo Nordisk, Genentech, Pfizer Research Funding: None Expert Testimony: None Other Remuneration: None

	AUTHOR CONTRIBUTIONS

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Conception and design: Stephen J. Laughton, Thomas E. Merchant, Charles A. Sklar, Larry E. Kun, Amar Gajjar

Financial support: Amar Gajjar

Administrative support: Amar Gajjar

Provision of study materials or patients: Thomas E. Merchant, Larry E. Kun, Maryam Fouladi, Alberto Broniscer, E. Brannon Morris, Robert P. Sanders, Matthew J. Krasin, John Shelso, Amar Gajjar

Collection and assembly of data: Stephen J. Laughton, Thomas E. Merchant, Charles A. Sklar, John Shelso, Zang Xiong, Dana Wallace, Amar Gajjar

Data analysis and interpretation: Stephen J. Laughton, Thomas E. Merchant, Charles A. Sklar, Larry E. Kun, Maryam Fouladi, Alberto Broniscer, E. Brannon Morris, Robert P. Sanders, Matthew J. Krasin, John Shelso, Zang Xiong, Dana Wallace, Amar Gajjar

Manuscript writing: Stephen J. Laughton, Thomas E. Merchant, Charles A. Sklar, Larry E. Kun, Alberto Broniscer, E. Brannon Morris, Robert P. Sanders, Matthew J. Krasin, John Shelso, Zang Xiong, Dana Wallace, Amar Gajjar

Final approval of manuscript: Stephen J. Laughton, Thomas E. Merchant, Charles A. Sklar, Larry E. Kun, Amar Gajjar

	ACKNOWLEDGMENTS

 
We thank Robert H. Lustig, MD, Susan R. Rose, MD, and Robert K. Danish, MD, for the clinical endocrine care provided to this cohort of patients; and James M. Boyett, PhD, for his insightful critique and review of the manuscript.

	NOTES

 
Supported by the Cancer Center (CORE) support Grant No. CA 21765 from the National Institutes of Health, Musicians Against Childhood Cancer (MACC), the Noyes Brain Tumor Foundation, and the American Lebanese Syrian Associated Charities (ALSAC).

Presented in part at the 12th International Symposium on Pediatric Neuro-Oncology, June 6-9, 2006, Nara, Japan, and at the 40th Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL.

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

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TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
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Submitted July 17, 2007; accepted November 1, 2007.

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