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Complications in Children Treated for Medulloblastoma or Ependymoma using Radiation Therapy


Table 3: Summary of Studies Evaluating Adrenocorticotropin Hormone Deficiency After Cranial and Craniospinal Irradiation


Author


Laughton et al., 200814


Bahl et al., 200915


Livesey et al., 19909


Rose et al., 200521


Patterson et al., 200922


Patients Enrolled/ Malignancy Patients Tested


88/76 70/unknown 144/90 182/182 41/41


Embryonal brain tumours


Proportion with ACTH Deficiency


43%, 4-year CI 38%


Medulloblastoma (48), 3% ependymoma (22)


Paediatric brain tumour 4% not involving HP axis Central nervous system tumours


Paediatric cancer 24% Comments 1µg corticotropin test or metyrapone used for evaluation 250µg corticotropin test used for evaluation Insulin tolerance test used for evaluation Testing performed in patients referred to endocrinology


with slow growth, fatigue or abnormal pubertal timing 1µg corticotropin test and/or metyrapone test


83% with >40Gy to HP axis, Testing performed in patients referred to endocrinology


50% with 30–39Gy to HP axis, 1µg corticotropin test 12% with 20–29.9Gy to HP axis, 8% with <20Gy to HP axis


ACTH = adrenocorticotropin hormone; CI = cumulative incidence; HP = hypothalamic–pituitary.


examining outcomes with CT planning – and in current clinical practice – remain above the threshold for development of GH deficiency. It is therefore unlikely that a reduction in GH deficiency will be seen in medulloblastoma patients, even with CT planning. On the other hand, more precise delivery of focal radiation will almost certainly have a large impact on the prevalence of GH deficiency in patients who do not require whole-brain radiation delivered as part of the CSI therapy.


Primary Hypothyroidism


The studies describing primary hypothyroidism are presented in Table 2. Primary hypothyroidism is still frequently seen in patients who receive CSI because the thyroid gland is exposed to a portion of the delivered spinal dose. In the studies by Laughton14


and Bahl,15 hypothyroidism occurred with a cumulative incidence of 65 and 52%, respectively.


Studies performed prior to the widespread use of CT planning showed similar prevalences of primary hypothyroidism, with some variability depending on how the patients were selected.8,19,20


Chin et al.19


Thyroid-stimulating Hormone Deficiency In their prospective study, Laughton et al. showed a significant risk of TSH deficiency (10% of patients with a four-year cumulative incidence of 23%)see Table 2.14


Livesy et al.9 and Schmiegelow et al.20 reported TSH


deficiency prevelances of 3.4 and 6%, respectively, in patients treated with radiation for paediatric brain tumour.20,21


The relatively higher


prevalence seen in the Laughton paper may relate, in part, to the fact that the patients were evaluated in a systematic, prospective manner.


It is important to recognise when comparing these studies that the use of different methods of reporting the data may result in different estimates of endocrine dysfunction. For example, in the Laughton study, the ‘prevalence’ of TSH deficiency was 10% but the four-year ‘cumulative incidence’ was 23%. Many of the earlier studies9,20


report


simple prevalence data, which do not account for differences in the length of follow-up and may underestimate the true risk of endocrinopathy. Careful interpretation of study results taking different methodologies into account seems advisable.


reported


a prevalence of 62% of primary hypothyroidism in patients treated with conventionally fractionated CSI for paediatric medulloblastoma. Schmiegelow et al.20 same manner.


diagnosed 41% of patients treated in the


In the CCSS cohort, patients who received a radiation dose of 25Gy or higher to the thyroid gland were more than twice as likely to report primary hypothyroidism than those patients who received lower doses.8


Xu et al.18


reported on the endocrine outcomes in seven young children with medulloblastoma who were treated with 18Gy of craniospinal radiation. Only one patient (14%) developed hypothyroidism in the lower dose group compared with 83% of patients from the same institution who received between 23 and 39Gy of CSI.18


A current


ongoing Children's Oncology phase III trial is evaluating the safety of reduced dose of craniospinal radiation (18 versus 23.4Gy) as well as reduced radiation volume to the post fossa for children with average risk medulloblastoma.


Even with the reduced dose to the hypothalamic pituitary axis from cranial boost doses delivered by IMRT, primary hypothyroidism remains a significant risk as long as CSI is required for successful treatment.


EUROPEAN ONCOLOGY & HAEMATOLOGY


Adrenocorticotropic Hormone Deficiency The studies describing ACTH deficiency are presented in Table 3. There are wide variations in the reported prevalence of ACTH deficiency in the literature. This is likely to be due to the use of different diagnostic tests and selection of patients for evaluation. Most papers report a lower prevalence of central adrenal insufficiency than that reported by Laughton14


incidence of 38%), with figures ranging from 49


(43% with a four-year cumulative to 24%21


treated with radiation for tumours of the central nervous system.


One recent retrospective review described central adrenal insufficiency in patients receiving cranial radiation to the hypothalamic–pituitary axis as part of their treatment.22


The results of the review showed adrenal


insufficiency in 83% of cancer survivors who received >40Gy, 50% of patients who received 30–39Gy, 12% of patients who received 20–29.9Gy and 8% of survivors who received <20Gy. This review only included survivors who had undergone hypothalamic–pituitary–adrenal axis testing, and therefore may not be representative of all brain tumour survivors with cranial radiation.


Livesy et al. reported only 4% of patients with ACTH deficiency after a radiation dose of 48Gy to the hypothalamus, using insulin-induced


51 of patients


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