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Radiotherapy hypoglycaemia testing for the evaluation of adrenal function.9 and Laughton et al.14 The


method of evaluation with 1µg of corticotropin used by Patterson et al.22


resulted in higher percentages of


prevalence of central adrenal insufficiency than previously described. Bahl et al. reported only a 3% prevalence of ACTH dysfunction when the standard-dose (250µg) ACTH test was used. These patients were evaluated retrospectively and endocrine assessments were not complete in all patients.15


Different testing methods and strategies of patient selection make it difficult to draw conclusions about the impact of CT planning on the development of ACTH deficiency in survivors of medulloblastoma and ependymoma. Studies using the 1µg ACTH stimulation test show a higher prevalence of ACTH deficiency than those using the insulin tolerance test or the standard-dose ACTH stimulation test. It is not clear from the literature that patients who fail the low-dose test but pass the 250µg test are at increased risk of symptomatic adrenal insufficiency. This test may therefore detect patients with laboratory abnormalities that do not translate into clinical disease. Another important factor to consider when assessing risk of ACTH deficiency is length of follow-up, as there appears to be a longer delay to the onset of ACTH deficiency compared with GH deficiency and primary hypothyroidism.23


Hypogonadism


Based on limited data it is difficult to draw conclusions about the impact of 3D radiation therapy planning on the development of luteinising hormone (LH) and follicle-stimulating hormone (FSH) deficiency. Laughton et al. were not able to assess LH and FSH reliably because of the young age of their patients.14


measured in the study by Bahl et al either.15


These values were not consistently Bahl and colleagues


reported three patients (4%) with gonadotropin deficiency. Future studies should follow these patients through puberty into young adulthood, when gonadotropin deficiency would become apparent.


Conclusions


Survivors of childhood brain tumours who live more than five years have 10- and 15-year survival estimates of 90 and 85%, respectively. These estimates are significantly lower than those of the age- and


1. Rutka JT, Hoffman HJ, Medulloblastoma: a historical perspective and overview, J Neurooncol, 1996;29(1):1–7.


2. Hoffman KE, Yock TI, Radiation therapy for pediatric central nervous system tumors, J Child Neurol, 2009;24(11):1387–96.


3. Packer RJ, Childhood brain tumors: accomplishments and ongoing challenges, J Child Neurol, 2008;23(10):1122–7.


4. Packer RJ, Gajjar A, Vezina G, et al., Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma, J Clin Oncol, 2006;24(25):4202–8.


5. Merchant TE, Li C, Xiong X, et al., Conformal radiotherapy after surgery for paediatric ependymoma: a prospective study, Lancet Oncol, 2009;10(3):258–66.


6. Anderson NE, Late complications in childhood central nervous system tumour survivors, Curr Opin Neurol, 2003;16(6):677–83.


7. Merchant TE, Happersett L, Finlay JL, et al., Preliminary results of conformal radiation therapy for medulloblastoma, Neuro Oncol, 1999;1(3):177–87.


8. Gurney, JG, Kadan-Lottick NS, Packer RJ, et al., Endocrine and Cardiovascular Late Effects among Adult Survivors of Childhood Brain Tumors: Childhood Cancer Survivor Study, Cancer, 2003;97(3):663–73.


9. Livesey EA, Hindmarsh PC, Brook CG, et al., Endocrine disorders following treatment of childhood brain tumours, Br J Cancer, 1990;61(4):622–5.


10. Armstrong G, Long-term survivors of childhood central nervous system malignancies: the experience of the Childhood Cancer Survivor Study, Eur J Paediatr Neurol, 2010;14(4):298–303.


sex-matched US population living during the same time period (survival for 10 years being 99.5% and 99% for 15 years). Eighteen per cent of the mortality seen in these patients was as a result of a medical cause, with death from hormone dysfunction being the most common aetiology.24


These findings underscore the importance of


reducing the risk of endocrine dysfunction where possible and understanding which patients are most at risk of developing dysfunction in order to initiate timely hormone replacement and prevent further morbidity.


Current data suggest that reducing the volume of irradiated brain tissue does not appear to have an adverse effect on progression-free survival in patients with ependymoma.25


The use of conformal radiation is


associated with a lower cumulative incidence of endocrinopathy. Bahl et al. reported a cumulative incidence of only 18% in survivors of ependymoma treated with focal cranial radiation.15


In patients treated for medulloblastoma, trials eliminating irradiation, especially in very young children, are associated with a significantly reduced chance of overall survival.26,27


An ongoing Children’s Oncology


Group trial is testing whether it is safe to further reduce radiation dose and volume for patients with average risk medulloblastoma. With current protocols used, children with medulloblastoma are at high risk of GH deficiency and primary hypothyroidism.14


Patients assessed for endocrinopathies in a prospective, standardised fashion demonstrate high rates of TSH and ACTH deficiency.15


It is


difficult to know which is the most accurate assessment of risk of ACTH deficiency, as many different methods for evaluating the hypothalamic–pituitary–adrenal axis are used in the literature.9,15,21


Even with improved techniques of radiation and dosimetry, children treated for brain tumours remain at risk of endocrine dysfunction. Survivors of childhood brain tumors treated with cranial radiation should receive standardised, serial endocrine assessments. Early identification of hormone deficits and consecutive initiation of effective and safe substitution therapy will prevent further debilitating outcomes of this vulnerable patient population. n


11. Gleeson H, Shalet S, The impact of cancer therapy on the endocrine system in survivors of childhood brain tumours, Endocr Relat Cancer, 2004;11(4):589–602.


12. Muirhead SE, Hsu E, Grimard L, Keene D, Endocrine complications of pediatric brain tumors: case series and literature review, Pediatr Neurol, 2002;27(3):165–70.


13. Constine LS, Woolf PD, Cann D et al., Hypothalamic-pituitary dysfunction after radiation for brain tumors, N Engl J Med, 1993;328(2):87–94.


14. Laughton SJ, Merchant TE, Sklar CA, et al., 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, J Clin Oncol, 2008;26(7):1112–8.


15. Bahl G, Urbach S, Bartels U, et al., Endocrine complications in children treated for medulloblastoma or ependymoma using radiation therapy: Outcomes in the CT-planning era, J Clin Oncol, 2009;27(15S):10064.


16. Melin AE, Adan L, Leverger G, et al., Growth hormone secretion, puberty and adult height after cranial irradiation with 18 Gy for leukaemia, Eur J Pediatr, 1998;157(9):703–7.


17. Giorgiani G, Bozzola M, Locatelli F, et al., Role of busulfan and total body irradiation on growth of prepubertal children receiving bone marrow transplantation and results of treatment with recombinant human growth hormone, Blood, 1995;86(2)825–31.


18. Xu W, Janss A, Packer RJ, et al., Endocrine outcome in children with medulloblastoma treated with 18 Gy of craniospinal radiation therapy, Neuro Oncol, 2004;6(2):113–8.


19. Chin D, Sklar C, Donahue B, et al., Thyroid dysfunction as a late effect in survivors of pediatric medulloblastoma/primitive


neuroectodermal tumors: a comparison of hyperfractionated versus conventional radiotherapy, Cancer, 1997;80(4):798–804.


20. Schmiegelow M, Feldt-Rasmussen U, Rasmussen AK, et al., A population-based study of thyroid function after radiotherapy and chemotherapy for a childhood brain tumor, J Clin Endocrinol Metab, 2003;88(1):136–40.


21. Rose SR, Danish RK, Kearney NS, et al., ACTH deficiency in childhood cancer survivors, Pediatr Blood Cancer, 2005;45(6)808–13.


22. Patterson BC, Truxillo L, Wasilewski-Masker K, et al., Adrenal function testing in pediatric cancer survivors, Pediatr Blood Cancer, 2009;53(7):1302–7.


23. Schmiegelow M, Feldt-Rasmussen U, Rasmussen AK, et al., Assessment of the hypothalamo-pituitary-adrenal axis in patients treated with radiotherapy and chemotherapy for childhood brain tumor, J Clin Endocrinol Metab, 2003;88(7):3149–54.


24. Morris EB, Gajjar A, Okuma JO, et al., Survival and late mortality in long-term survivors of pediatric CNS tumors, J Clin Oncol, 2007;25(12):1532–8.


25. Merchant TE, Mulhern RK, Krasin MJ, et al., Preliminary results from a phase II trial of conformal radiation therapy and evaluation of radiation-related CNS effects for pediatric patients with localized ependymoma, J Clin Oncol, 2004;22(15):3156–62.


26. Chi SN, Gardner SL, Levy AS, et al., Feasibility and response to induction chemotherapy intensified with high-dose methotrexate for young children with newly diagnosed high-risk disseminated medulloblastoma, J Clin Oncol, 2004;22(24):4881–7.


27. Rutkowski S, Bode U, Deinlein F, et al., Treatment of early childhood medulloblastoma by postoperative chemotherapy alone, N Engl J Med, 2005;352(10):978–86.


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EUROPEAN ONCOLOGY & HAEMATOLOGY


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