GHD after therapeutic cranial irradiation is a treatable late effect of successful cancer therapy that might be reduced or eliminated through careful treatment planning or new methods. Our results suggest that when the mean dose to the hypothalamus can be reduced to less than 16.1 Gy, half the surviving children may be spared from GHD during the first 5 years after treatment. Considering that GHD results from damage to the neurons in the hypothalamus that are considered most sensitive to the effects of irradiation,19
it follows that the incidence of other endocrine deficiencies might also be reduced if and when this threshold dose is observed. Reducing hypothalamic irradiation should be feasible when treating children with brain tumors if the targeted volume is not immediately adjacent to the hypothalamus and when advanced methods of photon or proton therapy are used. That our patients received 30 to 33 fractions of 1.8 Gy over the course of 6 to 6.5 weeks should be considered in the interpretation of these results, since the fractional dose threshold is 0.49 to 0.54 Gy per fraction or 27% to 30% of the prescribed daily dose.
The criteria for diagnosis of GHD vary by institution. Children without any tumor history are often considered to have GHD and qualify for GH therapy when their peak stimulated GH is less than 10 ng/mL. This study provides firm estimates of the radiation dose required to induce GHD by using a more conservative diagnostic level of 7 ng/mL. However, it is clear that other factors in addition to radiation dose contribute to this endocrine deficit. In our study, the incidence of GHD before irradiation was related to CSF shunting, which is standard in the sequelae and treatment of severe hydrocephalus. Pre-existing GHD was also related to tumor diagnosis and tumor location. These variables are often correlated, considering the singular suprasellar location of craniopharyngioma and the fact that the diencephalon or optic pathway is the most commonly irradiated site in childhood low-grade glioma. Because these tumors are intimately associated with the hypothalamus, these patients have a high likelihood of postradiation GHD if it is not already present before irradiation. All factors considered, our data suggest a need for early evaluation and intervention in these patients.
Children with ependymoma often present with obstructive hydrocephalus originating in the posterior fossa. The direct effect of hydrocephalus on the hypothalamus from increased intracranial pressure and expansion of the ventricular system should not be underestimated. Although tumor resection may relieve the obstruction, permanent CSF shunting is required for the most severe cases. In addition to radiation dose to the hypothalamus, CSF shunting is an important risk factor for GHD both before and after irradiation.
Endocrine deficiencies cannot always be predicted by tumor location. This observation highlights the contribution of scattered radiation20
and the need for more accurate estimates of hypothalamic radiation dose. Clinical data describing neuroendocrine effects of irradiation have been derived by using generalized estimates of radiation dose under conditions in which the dose to the hypothalamic-pituitary axis was generally homogeneous and discrete. Examples include patients treated with single-dose or fractionated total-body irradiation (8 to 14 Gy), those given cranial irradiation for acute lymphoblastic leukemia (18 Gy and 24 Gy), and those with tumors of the sella or parasellar region in which the hypothalamic-pituitary axis was uniformly included in the volume of prescribed dose (> 50 Gy). Radiation is a significant contributor to neuroendocrine complications commonly observed after treatment for brain tumors and tumors of the head and neck when the hypothalamus is subtended by the irradiated volume.21
Similar complications are observed when the hypothalamus is incidentally irradiated in the treatment of nasopharyngeal cancer, retinoblastoma, Hodgkin's lymphoma, and pediatric sarcomas of the head and neck.22
For other diseases, the hypothalamus may have been located within the irradiated volume for part or all of the treatment or in the gradient of dose (dose falloff), receiving only a fraction of the daily dose administered. These circumstances make it difficult to assign a dose to the hypothalamus and to determine the risk for late effects. These difficulties are present when the patient is seen by an endocrinologist years after treatment and retrospective dose calculations may be difficult to perform. Newer radiation techniques use 3-dimensional imaging (computed tomography and MRI) and allow for more accurate dose calculation and reporting. Correlated with objective measures of endocrine effects, dosimetry of hypothalamic irradiation will become increasingly valuable in predicting the incidence of specific endocrinopathies.
In pediatric radiation oncology, reducing adverse effects of treatment is an important goal. Reducing adverse effects can be achieved primarily by limiting CNS irradiation to patients for whom the indications are clear and the benefits outweigh the risks. The risk for endocrine-related complications should be carefully considered in planning radiation therapy but should not be used as a reason to avoid curative therapy. Careful follow-up and surveillance will lead to earlier intervention and mitigation of the consequences of cranial radiation.