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Complications in Children Treated for Medulloblastoma or Ependymoma using Radiation Therapy


increasingly used intensity-modulated radiation therapy (IMRT) to treat ependymomas and to deliver the posterior fossa boost to patients with medulloblastoma. IMRT uses 3D planning to shape the radiation beams to fit the dimensions of the tumour. This reduces the dose of radiation delivered to healthy tissues and should therefore lead to a reduction in the side effects experienced by these children. It is hoped that newer modalities like proton beam radiation may further spare childhood brain tumour survivors of late effects and decreased quality of life.7


Endocrine Outcomes Prior to the Use of 3D Radiation Planning


There are a number of studies describing the late effects experienced by childhood brain tumour survivors. Many of these studies focus on the most common late effects, namely neurocognitive compromise and endocrine dysfunction.6,8–13


These studies have provided


invaluable data that have guided the development of newer therapies intended to reduce late effects without adversely affecting survival.


In patients diagnosed between 1970 and 1986 and treated for medulloblastoma or ependymoma with surgery and radiation (with or without chemotherapy), growth hormone (GH) deficiency was found in 39% of medulloblastoma patients and 24% of survivors of ependymoma.8


Survivors of childhood brain tumours followed in the Childhood Cancer Survivor Study (CCSS) cohort had a significantly increased risk of endocrine complications, with 43% of patients surviving more than five years from completion of therapy reporting one or more endocrine conditions.8


It is important to keep in mind that data from


significantly more than the average risk group (50.5 versus 38.6Gy; p<0.0001). Ninety-four per cent of the patients tested were diagnosed with GH deficiency at a median of 1.8 years after radiation therapy (0.9–4.3 years), while 10% of patients developed thyroid-stimulating hormone (TSH) deficiency.14


The four-year cumulative incidence of GH


and TSH deficiency was 93 and 23%, respectively. As expected, patients who received higher doses of radiation to the hypothalamus were more likely to develop TSH deficiency and therefore it was more commonly seen in the high-risk group, with a four-year cumulative incidence of TSH deficiency of 31% compared with 17% among average-risk patients (p=0.049).14


Primary hypothyroidism was very


common. It was diagnosed in 44 patients (51%) with a four-year cumulative incidence of 65%. Hypothyroidism developed at a median of 1.5 years from radiation therapy and was also more likely in the high-risk group (four-year cumulative incidence of 89 versus 54% among average-risk patients; p=0.017).


Seventy-six patients (86%) were tested for integrity of the hypothalamic pituitary adrenal axis using the low-dose (1µg) corticotropin stimulation test or the metyrapone test. Adrenocorticotropic hormone (ACTH) deficiency was diagnosed in 43% of the patients tested, with a four-year cumulative incidence of 38±6%.14


The young age of the study patients meant that the authors were not able to consistently evaluate gonadotropin levels.


In this same group of patients, hypothyroidism was seen in 30% of the medulloblastoma patients and 12% of the ependymoma survivors.8


the CCSS are based on patient report and not derived from prospective surveillance for endocrine dysfunction. Retrospective, self-reported information may underestimate the risk of hormone dysfunction, particularly GH deficiency.


Endocrine Outcomes Since the Use of 3D Radiation Planning


Since 3D radiation treatment planning has only been used for the past two decades, few studies have looked at the endocrine late effects in patients treated with CT-based 3D conformal radiation or IMRT.


In one recent study, Laughton et al. examined the endocrine outcomes in 88 children (75 with medulloblastoma) treated for embryonal brain tumours at St Jude Children’s Research Hospital between October 1996 and May 2003.14


The children were treated as


part of the SJMB-96 trial, which included surgical resection followed by CSI and high-dose chemotherapy with autologous stem cell rescue. The radiation dose was given according to risk stratification, with average-risk patients receiving 23.4Gy of CSI, 36Gy of conformal radiation to the posterior fossa and a boost to 55.8Gy at the primary tumour site. High-risk patients received either 36Gy (M0–M1 disease) or 39.6Gy (M2–M3 disease) of CSI followed by conformal radiation therapy to 55.8Gy to the primary tumour site.14


The authors calculated


the mean dose of radiation delivered to the hypothalamus and pituitary gland of all patients. Patients were followed for a median of 5.1 years and were evaluated on a regular basis by an endocrinologist with prospective assessment of endocrine outcomes.15


The median dose of radiation delivered to the hypothalamus in all patients was 44Gy, with those in the high-risk group receiving


EUROPEAN ONCOLOGY & HAEMATOLOGY


Endocrine outcomes were studied in a group of patients treated for medulloblastoma and ependymoma at the Hospital for Sick Children and the Princess Margaret Hospital, both in Toronto, from June 2000 to June 2005. These data are currently published in abstract form.15


During


the study time period, 70 children (48 with medulloblastoma and 22 with ependymoma) were treated with radiation at a median age of six years (range one to 17 years). All radiation fields were constructed using CT planning methods. Twenty-four patients received high-dose CSI (median dose of 36Gy with a range of 30.6–39.6Gy) with a median boost dose to the posterior fossa of 18Gy (range 16.2–23.4Gy).16


The


same number of patients received low-dose CSI (median dose 23.4Gy, range 18–23.4Gy) with a median posterior fossa boost of 30.6Gy (range 30.6–36Gy). Twenty-two patients (20 with ependymoma) received only highly conformal RT to the tumour bed using IMRT at a median dose of 54Gy (range 54–59.4Gy).


In this study, children were not evaluated in a consistent prospective fashion, but were referred to an endocrinologist if there were symptoms or biochemical abnormalities that raised concerns about a particular endocrine disorder, such as poor growth or abnormal thyroid function tests. Thyroid function was performed on a regular basis in the neuro-oncology clinic.15


After a median follow-up period of 5.4 years (range 1.2–8.5 years), 35 children (50%) were diagnosed with an endocrine late effect. The five-year cumulative incidence of endocrine toxicity in children who received CSI was 71% compared with 18% for those children treated with focal radiation alone. In those patients who received CSI, the five- year cumulative incidence was 68% for GH deficiency, 52% for hypothyroidism, and 16% for precocious puberty. No difference was noted in the cumulative incidence of endocrinopathy between children treated with high-dose CSI and those who received low-dose CSI. Only two patients (3%) were diagnosed with ACTH deficiency and three patients (4%) were diagnosed with gonadotropin deficiency.15


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