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Original Article |
Department of Growth and Reproduction (M.S., J.M.) and Pediatric Clinic II (M.S.), Juliane Marie Center; Department of Endocrinology, Abdominal Center (U.F.-R., A.K.R.); Section of Radiation Biology, Department of Oncology (H.S.P.), Finsen Center; and University Hospital, Rigshospitalet, DK-2100 Copenhagen, Denmark
Address all correspondence and requests for reprints to: Marianne Schmiegelow, M.D., Department of Growth and Reproduction 5064, Juliane Marie Center, University Hospital, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. E-mail: mschmiegelow{at}hotmail.com.
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Abstract |
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Thyroid function was evaluated and compared with that in healthy controls (n = 27), measuring TSH, free T4, total T4, total T3, and TRH. The biological effective dose (BED) of radiotherapy, determined for the HP region and spine and expressed in grays (Gy) as BED, gives a means of expressing the biological effects of different dosage schedules in a uniform way. Seventy-one children (45 males and 26 females), less than 15 yr of age when diagnosed between 1970–1997 in the eastern part of Denmark, were included. Twenty-nine had received CSI, and 42 had received CIR only. The median age at time of radiotherapy was 8.4 yr (range, 0.8–14.9). The median length of follow-up was 12.0 yr (range, 2.0–28.0).
There was no significant difference between CSI and the CIR only patients with respect to median BED to the HP region. Primary hypothyroidism was found in 24%, of whom 71% had been treated with CSI and 29% with CIR only; 73% had compensated hypothyroidism, and 27% had overt primary hypothyroidism. Central hypothyroidism was found in 6%. Free T4 and total T3 were significantly lower in the CSI and CIR only groups compared with controls. As the CIR only group had significantly higher median basal TSH levels compared with controls and as the CSI compared with the CIR only group and controls had significantly higher median basal TSH levels, we speculate that this was probably due to scattered irradiation from both cranial and spinal fields to the thyroid gland. There was a significant relation between basal TSH and time of follow-up (rs = -0.39; P = 0.001). Stepwise backward multiple linear regression analysis showed that the best-fit model to predict basal TSH was free T4 (P < 0.0001), the length of follow-up (P = 0.02), and total T3 (P = 0.06). In contrast, age at radiotherapy, BED to the HP region and spine, and whether the patient had been treated with CT were not included in the model. The TRH test showed significantly exaggerated and prolonged TSH responses for the CSI and CIR only groups compared with controls, indicating HP dysfunction.
In conclusion, these data suggest that both CSI and CIR for childhood brain tumor may affect the HP-thyroid axis, resulting in hypothyroidism. CT had no significant influence on HP-thyroid function. We recommend prolonged surveillance of pituitary-thyroid function in long-term survivors of childhood brain tumor and institution of thyroid hormone replacement if the levels of TSH and free T4 are above and below the normal range, respectively, to ensure normal growth and metabolism.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In addition, the possible impact of cranial irradiation (CIR) only vs. craniospinal irradiation (CSI) with or without CT on the HP-thyroid axis has been less well documented. CIR may cause TRH secretory abnormalities if the hypothalamus, in which TRH is synthesized and secreted, lies within the fields of irradiation. The portal hypophyseal vessels form a direct link between the hypothalamus and the anterior pituitary with transfer of TRH to act directly on the pituitary cells, causing synthesis and secretion of TSH from the anterior pituitary. TSH stimulates and regulates the synthesis and secretion of T4 and T3 from the thyroid gland. Central hypothyroidism may thus occur when the HP axis falls within the fields of radiation, resulting in low levels of TSH. CSI may provide irradiation to the thyroid gland if the gland is within the spinal fields of irradiation or as scattered irradiation from the spinal fields. However, CIR may also cause a minor scattered dose to the thyroid gland (10, 11, 12), the impact of which has been less well documented. Thus, when both HP function and primary thyroid function have been disturbed, the degree of central hypothyroidism caused by CIR is difficult to interpret. The effect of CT on the HP region and/or the thyroid gland has been reported in only a few studies (3, 5).
The biological effects of irradiation do not depend simply on the total dose, but on the dose per fraction and on the 
/ß ratio, where and ß are the radiobiological cell survival parameters for the tissue within the treatment volume (13, 14, 15). The biological effective dose (BED) is based on the linear-quadratic model and gives a means of expressing the biological effects of various treatment schedules in a uniform way (13, 14, 15, 16, 17). The adverse effects in late-responding tissues such as neural tissue, which has a low /ß ratio, are critically dependent on dose per fraction, and a small increase in dose per fraction will increase the risk of late effects even at an unchanged total dose (18). Using the BED has enabled us to study a population of children treated during a quarter of a century with very different fractionation schemes and analyze their late effects in relation to BED.
To assess the extent of late effects of radiotherapy to the HP-thyroid axis and the effect of CSI vs. CIR only and CT on thyroid function, we measured TSH, free T4, total T4, and total T3 and performed a TRH test. In the present population-based study we assessed the incidence of hypothyroidism after radiotherapy for childhood brain tumor and analyzed the correlation between thyroid hypofunction and BED to the HP region.
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Subjects and Methods |
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The study included all patients who were 1) diagnosed and treated for brain tumor in the eastern part of Denmark, including all counties of Sealand, the Faroe Islands, and Greenland; 2) diagnosed from January 1970 through February 1997; 3) aged less than 15 yr at the time of diagnosis of a primary brain tumor not directly involving the HP axis; 4) treated with cranial or craniospinal radiotherapy and with or without CT; 5) more than 1 yr from end of treatment at the time of follow-up; and 6) in remission at the time of follow-up.
Ninety-one patients met the criteria and were asked to participate in the study. Seventy-six patients (84%) agreed to participate. The 15 nonparticipants did not differ significantly with respect to histological diagnosis of the tumor, age of the child at the time of radiotherapy, total dose of radiotherapy, dose per fraction of radiotherapy, or length of follow-up. Of the 76 patients who met the inclusion criteria and agreed to participate (49 males and 27 females), 2 males were excluded due to hypothyroidism detected at the time of diagnosis, and 1 female was excluded because she had been thyroidectomized due to adenomas of the thyroid gland. Finally, 2 males were excluded because they had not discontinued their T4 medication at time of follow-up. Thus, 71 patients were included (45 males and 26 females). The median age at the time of radiotherapy was 8.4 yr (range, 0.8–14.9 yr), and the median length of follow-up was 12.0 yr (range, 2.0–28.0 yr). The median age at time of follow-up was 16.8 yr (range, 6.2–43.5 yr). The tumor diagnoses were astrocytoma (n = 31), meduloblastoma (n = 22), ependymoma (n = 5), germ cell tumor (n = 3), glioma (n = 3), pinealoma (n = 1), hemangiopericytoma (n = 1), primitive neuroectodermal tumor (n = 1), and nonhistological verified diagnoses (n = 4). These latter 4 patients were assumed to have chiasma glioma according to diagnostic imaging (n = 4). By the WHO classification, 37 patients had benign tumor, and 30 patients had malignant tumor (19). Twenty-eight patients had hydrocephalus at the time of diagnosis to such a degree that they had a shunt operation performed. Sixteen patients were receiving T4 treatment when included in the study. They discontinued their medication 5 wk before testing. The influence of the duration of a T4 withdrawal period before provocative testing has to our knowledge not been evaluated, but we regarded 5 wk a minimum withdrawal period. Twenty-four patients were receiving other hormone replacement treatments, which included GH (n = 20), hydrocortisone (n = 3), and estradiol (n = 6) or testosterone (n = 2). Twelve patients were receiving continuous anticonvulsant treatment.
The controls (n = 27) were healthy individuals from the hospital staff (13 men and 14 women), with a median age at time of investigation of 34 yr (range, 20–64 yr).
Treatment
Surgery. Sixty-seven children had a biopsy or a total or partial resection of the tumor performed in addition to radiotherapy.
Radiotherapy. Fourteen children had been treated with 60Co, and 57 children had been treated with external conventional 4, 6, or 8 megavoltage radiotherapy delivered by a linear accelerator. Twenty-nine children were treated with CSI and received a median of 35 Gy (range, 24–48 Gy) to the spine and a median of 36 Gy (range, 29–56 Gy) to the whole brain, whereas 22 also had a median 18-Gy (range, 7–26 Gy) boost to the tumor for a combined total dose of median 55 Gy (range, 46–56 Gy). Forty-two children were treated with CIR, of whom 13 children received a median of 47 Gy (range, 22–56 Gy) to the whole brain, and 29 children were treated with focal cranial irradiation and received a median of 51 Gy (range, 31–57 Gy). The overall treatment time differed according to the different treatment schedules used from 1970–1997 from 1 fraction every second day to 1 fraction every day, 5 times a week, and the dose per fraction differed from an increment strategy starting at very low doses increasing over the treatment period to the administration of uniform fractions during the whole treatment period.
Chemotherapy. In addition to radiotherapy, 30 children were treated pre- and/or postoperatively with adjuvant CT. Children treated during the late seventies and eighties were given lomustine, vincristine, and methotrexate as single drugs or in combination. Later, in the nineties, children with germinal cell tumor received cisplatin, bleomycin, and etoposide, and children with medulloblastoma received vincristine, carboplatin, endoxan, and etoposide according to the International Society of Pediatric Oncology II protocol (20).
Methods
Hormone analyses. Between 0800–1000 h blood samples were drawn from an antecubital vein for measurement of serum TSH (n = 71), free T4 (n = 68), total T4 (n = 71), and total T3 (n = 71), and 64 of the patients agreed to have a TRH test performed with TSH measurements at 0, 30, 60, and 150 min. Controls had 0 min TSH, free T4, total T4, and total T3 measured and a TRH test performed; however, they had measurements of TSH at 0, 20, and 60 min. The TSH concentrations were expressed in milliunits per liter and were measured by a time-resolved fluoroimmunometric assay (AutoDELFIA hTSH Ultra assay, Wallac, Inc., Turku, Finland). The minimal detectable concentration was 0.005 mU/liter. The intraassay coefficient was 4.6% at 0.045 mU/liter, 2.8% at 0.895 mU/liter, and 1.3% at 17.6 mU/liter. The interassay coefficient of variation was 4.8% at 0.045 mU/ml, 2.2% at 0.895 mU/liter, and 2.2% at 17.6 mU/liter. The reference range was 0.4–4.0 mU/liter. A TRH test was carried out according to a standard protocol; 3–5 µg TRH (Thyrefact)/kg (maximum, 200 µg Thyrefact) were administered iv, and serum samples for TSH were drawn at 0, 30, 60, and 150 min and measured by a time-resolved fluoroimmunoassay (AutoDELFIA hTSH Wallac, Inc.). Serum free T4 and total T4 were measured by a fluorescence polarization immunoassay (AxSYM Total T4, Abbott Laboratories, Chicago, IL). The sensitivity of the AxSYM Total T4 assay was 1.05 µg/dl. The reference range for free T4 was 9–24 pmol/liter, and that for total T4 was 60–140 nmol/liter. Serum total T3 was measured by a microparticle enzyme immunoassay (AxSYM Total T3, Abbott Laboratories). The sensitivity of the AxSYM Total T3 assay was 0.30 ng/ml. The reference range was 0.9–2.7 nmol/liter.
BED. To get a uniform comparison of the different treatment regimens we used the BED of radiotherapy, which gives a means of comparing different radiotherapy schedules (17). BED received by the HP region and spine was determined by the linear quadratic model as previously described (18).
Statistics. Because the data for the patient population had a skewed distribution, we used median and range. Correlations between variables were tested with the nonparametric Spearman’s correlation analysis (rS = correlation coefficient) (21). We performed the Kruskal-Wallis test to analyze the variance by ranks comparing three unpaired groups, and only in the case of a significant difference was a post hoc Mann-Whitney U test performed. The relationship between the independent variables age at time of radiotherapy, time elapsed since radiotherapy, BED to the HP region and spine, and chemotherapy (given = 1, not given = 0) and the dependent variable basal TSH was analyzed by stepwise backward multiple regression analysis. The validity of the regression model was checked using standard tests. These included assessing the distribution of the residuals and testing for normality, and checking the linearity assumptions in the model by means of standard scatter plots. Data analyses were performed with SPSS statistical software (SPSS, Inc., Chicago, IL) (22). Two-sided P < 0.05 was regarded as significant.
Ethics. Adults and children (or their parents when appropriate) gave their informed consent. The study was performed in accordance with the Helsinki Declaration II and was approved by the local ethical committee of Copenhagen, Denmark (approval 01-339/96).
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Results |
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and Table 1). Eleven patients (73%) had mild or compensated primary hypothyroidism with TSH greater than 4 mU/liter and free T4 greater than 9 pmol/liter (9 patients from the CSI group and 2 patients from the CIR group), whereas 4 patients (27%) had overt primary hypothyroidism with TSH greater than 4 mU/liter and free T4 less than 9 pmol/liter (2 patients from the CSI group and 2 patients from the CIR group; Fig. 2). Four patients (6%) had central hypothyroidism with TSH less than 4 mU/liter and free T4 less than 9 pmol/liter (all 4 patients belonged to the CIR group; Fig. 2).
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and Table 1
). There was a significant difference between levels of total T3 in the CSI group and the CIR group compared with controls, but there was no significant difference between levels of total T3 in the CSI group compared with the CIR group (Table 1).
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]. The CIR group also had significantly higher median basal TSH levels compared with controls [1.78 mU/liter (range, 0.56–7.99 mU/liter) vs. 1.51 mU/liter (range, 0.53–2.6 mU/liter); P = 0.02]. There was an inverse significant relation between basal TSH and time of follow-up (rs = -0.39; P = 0.001); however, there was no significant relation between basal TSH (rs = -0.18) and age at radiotherapy.
There was no significant difference with respect to free T4, total T4, total T3, basal TSH, and TSH at 30, 60, and 150 min between the 12 patients receiving anticonvulsants and the other patients.
There was no significant difference between the CSI and the CIR group of patients with respect to median BED to the HP region [63 Gy (range, 0–94 Gy) vs. 76 Gy (range, 46–89 Gy); Table 1]. There was no significant relation between BED to the HP region and basal TSH (rs = 0.0) or peak TSH (rs = -0.02), respectively, at 30 min.
In the CSI group the median BED to the spine was 55 Gy (range, 27–78 Gy), but there was no significant relation between BED to the spine and free T4 (rs = 0.16) or basal TSH (rs = 0.22), respectively. However, there was a significant relation between BED to the spine and total T3 (rs = 0.43; P = 0.03).
Patients treated with CT in addition to radiotherapy (n = 30) compared with patients treated with radiotherapy only (n = 41) had significantly higher basal TSH levels [median, 3.10 mU/liter (range, 0.85–22.5 mU/liter) vs. 2.07 mU/liter (range, 0.56–7.99 mU/liter); P = 0.02]. However, in the CSI group (n = 29) 22 patients had been treated with CT in addition to CSI. If we compared these 22 patients with the remaining CSI patients without CT (n = 7), we found no significant difference with regard to median TSH levels [median, 3.69 mU/liter (range, 0.89–22.5 mU/liter) vs. 3.35 mU/liter (range, 0.87–4.64 mU/liter)]. Patients treated with CT in addition to CIR (n = 8) compared with patients treated with CIR without CT (n = 34) also had no significant difference with regard to median TSH levels [median, 1.69 mU/liter (range, 0.85–5.1 mU/liter) vs. 1.92 mU/liter (range, 0.56–7.99 mU/liter)].
Stepwise backward multiple linear regression analysis showed that the best-fit model to predict basal TSH was free T4 (P < 0.0001), length of follow-up (P = 0.02), and total T3 (P = 0.06), with all three variables included in the model. In contrast, age at radiotherapy, BED to the HP region and spine, and whether the patient had been treated with CT were not included in the model (Table 2).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We found primary hypothyroidism in 24% of the total cohort, of whom 71% had been treated with CSI, whereas 29% had been treated with CIR only. Of the patients with hypothyroidism, 73% had mild or compensated hypothyroidism, and 27% had overt primary hypothyroidism. Central hypothyroidism was found in 6% of the cohort. We found significantly lower levels of free T4 in the CSI group and the CIR only group compared with controls; however, there was no significant difference between free T4 in the CSI group compared with the CIR group. These results emphasize that the thyroid should be shielded during both CSI and CIR due to scatter irradiation from the cranial fields.
There was no significant difference between the CSI and CIR only groups with respect to BED to the HP axis, indicating that the same degree of radiotherapy-induced central hypothyroidism would be expected in the two groups. The interaction between central and primary hypothyroidism in the present study is probably also why BED was not significantly correlated to the endocrinological end points, as other reports have shown significant BED response correlations (18).
We found a significant inverse relationship between basal TSH and time of follow-up; however, there was no significant relation between basal TSH and age at radiotherapy. This is in very good accord with the pathophysiology of radiation-induced changes in neural tissue. Over time a decline is seen due to both vascular changes with degeneration and mitotic cell death of capillary endothelial cells, which fail to nourish the neural tissue resulting in parenchymal cell loss. With a median length of follow-up in the present study of 12 yr we would expect to have established the number of patients with thyroid dysfunction; however, as longer term results of children with brain tumors are not yet available, we suggest that thyroid function should be followed life-long after both CIR and CSI.
CT did not seem to add to the deleterious effect of radiotherapy in either the CSI or the CIR group. There have been conflicting reports on the contribution of CT to thyroid dysfunction (5, 9, 23). In the earlier study by Ogilvy-Stuart et al. (5) the data indicated that a combination of irradiation of the thyroid gland and CT had a deleterious impact on thyroid function. In contrast, in both the present study and that by Chin et al. (23) no additive risk of CT could be found.
As a consequence of central hypothyroidism in both the CSI and CIR groups we found exaggerated and prolonged TSH responses after TRH stimulation, indicating an HP origin of hypothyroidism resulting from alterations in TRH secretion or transport to the anterior pituitary (24). The fact that the response to TRH was clearly more pronounced in the CSI group compared with the CIR group and also compared with controls may reflect the higher basal TSH level in the CSI group.
In conclusion, we recommend prolonged surveillance of full pituitary thyroid function in long-term survivors of childhood brain tumor and the institution of thyroid hormone replacement if the levels of TSH and free T4 are above and below the normal range, respectively, to ensure normal growth and metabolism.
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Acknowledgments |
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Footnotes |
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Abbreviations: BED, Biological effective dose; CIR, cranial irradiation; CSI, craniospinal irradiation; CT, chemotherapy; HP, hypothalamus/pituitary.
Received March 11, 2002.
Accepted October 8, 2002.
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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; median, 3.65 mU/liter; range, 0.87–22.5 mU/liter) vs. CIR (
; median, 1.78 mU/liter; range, 0.56–7.99 mU/liter) vs. controls (
; median, 1.51 mU/liter; range, 0.53–2.61 mU/liter). The dashed line of 4 mU/liter indicates the upper normal limit of serum TSH levels.
