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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 8 3657-3663
Copyright © 2003 by The Endocrine Society

No Damaging Effect of Chemotherapy in Addition to Radiotherapy on the Thyroid Axis in Young Adult Survivors of Childhood Cancer

Hanneke M. van Santen, Thomas Vulsma, Marcel G. Dijkgraaf, Regje M. E. Blumer, Richard Heinen, Monique W. M. Jaspers, Maud M. Geenen, Martin O. Offringa, Jan J. M. De Vijlder and Cor van den Bos

Departments of Pediatric Endocrinology, Clinical Epidemiology, and Biostatistics, Late Effects Study Group, Medical Informatics, Medical Oncology, Pediatrics and Pediatric Oncology, Emma Children’s Hospital, Academic Medical Center, University of Amsterdam, 1100 DE Amsterdam, The Netherlands

Address all correspondence and requests for reprints to: H. M. van Santen, M.D., Department of Pediatric Endocrinology, Emma Children’s Hospital, Academic Medical Center, G8-205, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands. E-mail: h.m.vansanten{at}amc.uva.nl.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Late effects of treatment for childhood cancer on the thyroid axis are ascribed predominantly to radiotherapy. Whether chemotherapy has an additional detrimental effect is still unclear. Our aim was to evaluate this effect in young adult survivors of a broad spectrum of childhood cancers. The thyroid axis in 205 childhood cancer survivors was evaluated in relation to former use of chemotherapy and radiotherapy (cranial, cranio-spinal, cervical, mediastinal, or thoracic). The mean follow-up time was 17.5 yr. Damage to the thyroid axis was found in 55 patients (26.8%). Thirty-seven patients (18%) had thyroidal disease. Diagnoses varied from TSH elevation to papillary carcinoma. After multivariate analysis, high risk radiation field, irradiation dose, and the diagnosis of non-Hodgkin lymphoma/Hodgkin’s disease were found to be significant risk factors for developing thyroid disease. Treatment with chemotherapy did not have an additional negative effect on the thyroid axis. For the development of central (pituitary or hypothalamic) thyroid dysfunction, patients with a brain tumor were at increased risk. Chemotherapy for childhood cancer does not contribute to the damage on the thyroid axis inflicted by radiotherapy during young adulthood.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
AS THE NUMBER of survivors of childhood cancer increases due to the improving treatment modalities for pediatric malignancies (1, 2, 3), follow-up studies into adulthood are increasingly important to give insight into the expected and unexpected late adverse events of the malignancy and its treatment (4).

External cervical radiotherapy has been used for the treatment of pediatric tumors, such as Hodgkin’s disease (HD), nasopharyngeal carcinoma, and rhabdomyosarcoma. This type of treatment has been demonstrated to be deleterious for the thyroid’s integrity, resulting in thyroid dysfunction and degeneration (5, 6, 7, 8), which has implications for almost all other tissues (9), especially during growth and development.

Overt hypothyroidism, subclinical (compensated) hypothyroidism, benign nodules, radiation thyroiditis, Graves’ hyperthyroidism followed by hypothyroidism, and secondary thyroid malignancies have been described after (peri-) cervical radiotherapy (9, 10, 11, 12). Thyroid damage has also been described as a consequence of stray irradiation during cranial radiotherapy, as used in prophylactic schemes for acute lymphoblastic leukemia (ALL) (13). Adjuvant risk factors for developing thyroid damage after external irradiation are higher radiation dose (14), diagnostic lymphangiography preceding radiotherapy (15), young age (16), female sex (17), and (preexistent) elevated TSH level (18).

It is still an issue of debate whether chemotherapy has an additional detrimental effect on the thyroid gland. This has never been studied in childhood cancer survivors treated for a broad spectrum of cancers and followed into adulthood. The enormous variety in toxicity of the drugs used during cancer treatment in childhood might explain why some patients remain free of thyroid problems, while others, exposed to the same radiation dose, develop thyroid dysfunction or even thyroid carcinoma. Several studies have shown negative effects of antineoplastic drugs on thyroid function, e.g. vincristine in combination with cisplatin (19, 20) and alkylating agents in combination with vinca-alkaloids, steroids, and radiotherapy (21). In children with brain tumors, the occurrence of hypothyroidism seems to be higher after the administration of alkylating agents and vinca-alkaloids with or without antimetabolites, cisplatin, or steroids in combination with irradiation than after radiotherapy alone (22, 23, 24).

The aim of this study was to analyze whether the use of chemotherapy during childhood is an additional risk factor for developing lasting thyroid axis damage in young adult survivors of childhood cancer treated with (peri-) cervical irradiation. Also, we investigated whether the type and combination of cytostatic drugs were related to the type and severity of thyroid axis damage.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Survivors of childhood cancer who had been in complete remission for at least 5 yr after finishing their treatment were investigated for thyroid axis damage. Informed consent was obtained from all survivors for the use of clinical data.

Of 498 survivors, 207 were irradiated with cranial, cranio-spinal, cervical, mediastinal, thoracic, or total body irradiation. Two patients (1%) were excluded due to missing data. Of 205 survivors, a history of thyroid disease was taken, and physical examination for thyroid disease was performed. Blood was drawn to determine concentrations of plasma TSH, total T4, and, for some, free T4. Data concerning oncological diagnosis, staging, treatment, and earlier measured thyroid functions were collected. These data were extracted from the PLEKsys database of the Late Effects Study Group of our hospital (Jaspers, M. W. M., C. van den Bos, H. Behrendt, R. C. Heinen, P. J. M. Bakker, M. M. Geenen, F. van Leeuwen, H. N. Caron, manuscript in preparation).

Radiotherapy date, field, dose, and number of fractions were determined. Radiation fields were grouped into three categories according to the expected risk for developing thyroid damage; high risk cervical irradiation [neck, mantle field, spinal (C2-Th2), medulla oblongata (P-A), Waldeyer’s ring and neck, mediastinum, supraclavicular region, and nasopharynx], intermediate risk cervical irradiation [Waldeyer’s ring, cerebrum to C2, medulla oblongata (lateral), and pulmones], and low risk irradiation (cranial, orbital, frontal lobe, and parietal lobe). Patients were grouped according to the exposed radiation field with the highest risk category. Hence, the patient could also have been irradiated in a low risk field when included in the high-risk group.

Chemotherapy treatment date, drugs, and doses were determined. For the current analysis, all administered drugs were divided into eight groups according to mode of action (Table 1Go). The use of any drug and the use of chemotherapy during radiotherapy were recorded. The drugs administered during radiotherapy consisted mainly of intrathecal steroids, methotrexate, and cytarabin as part of central nervous system prophylaxis in ALL and non-Hodgkin lymphoma (NHL).


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  		TABLE 1. Groups of chemotherapy used for our patients and their generic names

 
Thyroid damage was scored as present when one of the following criteria was met: elevated plasma TSH concentration (>4.5 mU/liter), decreased plasma T4 or free T4 concentration (compared with the age-related normal value), enlarged thyroid by physical examination, or diagnosis of thyroid disorder or use of thyrostatics or thyromimetics. Of the 291 survivors who had not been irradiated in the (peri-) cervical region, the use of thyromimetics, thyrostatics, and history of thyroid disease were evaluated. Four of these patients had to be excluded, as their primary tumor was a thyroid carcinoma. The incidence of thyroid disease in this group was compared with the incidence of thyroid disease in the same age group in The Netherlands.

Statistical analysis

Descriptive statistics were performed using the independent samples t test and Pearson {chi}2 test for parametric data and the Mann-Whitney test for nonparametric data using Excel 97 and SPSS 10.0.7 (SPSS Statistics UK, SPSS Inc., Chicago, IL). For analysis of relative risks, separate analyses were made for the group of survivors with and without thyroid and central thyroid axis damage (see Tables 6Go and 8Go). To correct for overlap of use of the group without thyroid damage, in these univariate analyses significance was noted at P < 0.025. If an increased risk to develop thyroid damage was expected for the variable, the test was performed one-tailed with the confidence interval set at 94.94%; for two-tailed tests (no increased risk expected) the confidence interval was set at 97.47%. In these analyses the subgroup of carboplatin and cisplatin was excluded because the number of patients was too small.


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  		TABLE 6. Relative risks for developing thyroid damage (univariate analyses)

 

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  		TABLE 8. Relative risks for central hypothyroidism (univariate analyses)

 
Covariates were included in a multivariate analysis if they turned out to have P < 0.0506 in the univariate assessments. The multivariate analysis was performed using a logistic regression model, with thyroid or central thyroid axis damage as the dependent variable. Subsequent significance testing was performed with {alpha} = 0.05.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Of the 205 survivors who had been irradiated for their childhood tumor, 33 had not received any chemotherapy. The mean age during radiotherapy was 8.1 yr (range, 0.1–19.7 yr); the mean age at follow-up was 27.4 yr (range, 17.0–44.8 yr). Those treated with chemotherapy were significantly younger during radiotherapy than those not treated with chemotherapy; the mean durations of follow-up after radiotherapy, however, were similar (Table 2Go).


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  		TABLE 2. Clinical characteristics of 205 survivors of childhood cancer

 
The most frequent malignancy in the total group was ALL (38.2%), followed by NHL/HD (26.0%) and brain tumors (25.0%). Of the 172 survivors treated with radiotherapy and chemotherapy, 45.6% was diagnosed with ALL, and 28.5% with NHL/HD. Of 33 survivors not treated with chemotherapy, 78.8% had a brain tumor.

Radiotherapy in the high risk field for developing thyroid damage was given to 53.2% of all patients, in the intermediate risk field to 34.1%, and in the low risk field to 12.7%. Of those irradiated in the high risk field, 85.3% were also treated with chemotherapy. In contrast, more than 46% of survivors irradiated in the low risk field were not treated with chemotherapy (Table 3Go). Survivors not treated with chemotherapy received significantly higher radiation doses in the high and intermediate risk fields (Table 4Go).


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  		TABLE 3. Percentage of patients treated with chemotherapy in each field of radiation treatment

 

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  		TABLE 4. Mean dose of radiotherapy in each radiation field

 
The most used drugs were the vinca-alkaloids, followed by corticosteroids and antimetabolites (used in 93%, 84.9%, and 72.7% of patients treated with chemotherapy, respectively). Fifty-seven percent of the patients treated with chemotherapy also received it during irradiation.

The occurrence of thyroid axis damage after treatment with radiotherapy, with or without chemotherapy, is shown in Table 5Go. Of 205 irradiated survivors, 55 (26.8%) developed thyroid axis damage, either thyroidal or central. Of the survivors who received both radiotherapy and chemotherapy (n = 172), 16.9% developed a variety of thyroid problems, and 5.8% developed central hypothyroidism. Of those who did not receive chemotherapy, 48.4% developed thyroid axis damage, of whom 24.2% developed thyroid disease and 24.2% developed central hypothyroidism. These differences were statistically significant, mainly caused by the higher prevalence of central damage in survivors with brain tumors not treated with chemotherapy (standard residual, 3.0).


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  		TABLE 5. Occurrence of thyroid axis damage after treatment with (peri-) cervical radiotherapy, with or without chemotherapy during childhood

 
Overall, 37 survivors developed thyroid disease. Their diagnoses were thyroidal hypothyroidism (n = 20), TSH elevation/subclinical hypothyroidism (n = 7), benign nodules (n = 2), thyroid cyst (n = 1), multinodular goiter (n = 2), thyroid carcinoma (n = 2), and hyperthyroidism (two transient and one Graves’ disease). The survivors diagnosed with thyroidal hypothyroidism had an average age of 10.4 yr during exposure to radiation; the average dose was 37.8 Gy (range, 19.5–66.0 Gy) in the high risk radiation field. Two survivors irradiated on the cervical area with 18 Gy during treatment for ALL at 2 and 4 yr of age developed papillary thyroid carcinoma 11 and 14 yr after being irradiated. One of them received another 24 Gy on the head.

Table 6Go shows the relative risk for predictors of damage to the thyroid gland among survivors of childhood cancer (n = 187). Survivors with central hypothyroidism are not included in this analysis. Of survivors with thyroid problems, 83.8% had received high risk cervical irradiation. Risk for development of thyroid damage was increased in those who had survived NHL/HD (P = 0.000). The vinca-alkaloids were the drugs most used in the survivors with thyroid disease and in the survivors without thyroid disease (in 70.3% and 84.0%, respectively). Treatment with chemotherapy in general, with any type of drugs or with any previously described combinations of drugs, did not increase the risk for developing thyroid damage. The risk for developing thyroid damage was, however, lower after treatment with the combination of antimetabolites and steroids, with antimetabolites alone, and with administration of chemotherapy during irradiation (relative risk, 0.33, 0.41, and 0.32, respectively).

For the 37 survivors with thyroid damage, all administered drugs were analyzed separately. Due to low patient numbers, the relationship between a certain drug and the type of thyroid damage could not be assessed reliably.

The mean radiation dose for survivors who developed thyroid damage was 35.4 Gy (range, 18.0–70.0; Table 6Go). Radiation in the high risk field was given in a mean dose of 36.6 Gy (range, 18.0–70.0) to survivors who developed thyroid disease, which was significantly higher than the mean dose given to survivors who did not develop thyroid damage (Table 7Go). The numbers of survivors who developed thyroid damage in the intermediate and low risk fields were too small to allow for statistical analysis.


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  		TABLE 7. Mean radiation dose for developing thyroid damage in the different risk groups

 
The mean radiation dose of survivors developing central hypothyroidism was 34.7 Gy (range, 7.5–65.0; Table 8Go). Central hypothyroidism occurred most frequently in survivors with brain tumors (72.2%). Five patients given irradiation (three in the low and intermediate risk fields, one in the high and low risk fields, and one in the low risk field) with a mean total dose of 27.2 Gy in the treatment for ALL (n = 4) and HD (n = 1) also developed central hypothyroidism.

Survivors who were irradiated in the low risk field for developing thyroid damage were more at risk for developing central hypothyroidism than were those who were irradiated in the high and intermediate risk fields. The risk to develop central hypothyroidism was decreased for survivors who had been treated with any chemotherapy, with chemotherapy during RT, and with chemotherapy after the administration of vinca-alkaloids and steroids.

Multivariate analysis for the occurrence of thyroid damage showed significant associations of high risk irradiation field, dose of radiation, and history of NHL/HD (Table 9Go).


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  		TABLE 9. Significant risk factors for developing thyroid axis damage after chemotherapy and radiotherapy during childhood (multivariate analysis)

 
The use of vinca-alkaloids showed near-significance after correction for covariates (P = 0.067; eß = 0.311; 95% confidence interval, 0.89–1.084) for protection of hypothalamic/pituitary damage. A history of brain tumor was the only predictor for central hypothyroidism in the multivariate analysis.

In the group of 291 survivors who had not been irradiated in the pericervical region, a similar incidence of thyroid dysfunction was found (1.1%) compared with the registered incidence of thyroid problems in a similar age group in The Netherlands (0.9%) (25).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In this study we confirm the occurrence of thyroid dysfunction after pericervical irradiation as described by others (6, 9, 11); in 55 (26.8%) of 205 young adults who survived childhood cancer, thyroid axis disease was found, of which 67.2% was related to the thyroid itself. However, in contrast to some existing literature described in the introduction of this report, no lasting deleterious effect of any drug or scheme of chemotherapy in addition to radiotherapy on the thyroid axis was found. Also, in the 291 survivors treated only with chemotherapy, there was no evidence of increased incidence of thyroid problems.

The differences between the results of our analysis and those found in previous studies are most likely explained by the confounding effect of irradiation. To correct for this confounding effect, multivariate analysis was performed. In the univariate analyses, the administration of antimetabolites, the combination of antimetabolites with steroids, and chemotherapy during radiotherapy showed some effect on the thyroid gland, but instead of a negative effect, a protective effect was found (Table 6Go). Although one other study has described a possible radioprotective capability of chemotherapy for thyroid tissue of different drugs (26), the significance of chemo-protection disappeared after correction for radiation dose and field in our multivariate analysis (Table 9Go). After correction for the presence of other determinants, the risk factors identified for developing thyroid damage were field of irradiation, higher irradiation dose, and the history of NHL/HD.

The two survivors who had developed papillary thyroid carcinoma had both been irradiated with 18 Gy in the cervical region. These doses are low compared with the doses administered to the 17 survivors who developed (subclinical) hypothyroidism (mean, 39 Gy; range, 19.5–66 Gy). This observation is in line with those of many other studies, demonstrating that the risk to develop hypothyroidism increases with radiation dose (6, 11, 14), whereas the risk to develop thyroid malignancy peaks at relatively low doses and levels off with increasing radiation dose (27, 28).

Statistical analysis showed an increased risk for survivors with NHL/HD to develop thyroidal damage even after correction for radiation field and dose. Many studies evaluating thyroid function after treatment for lymphoma in childhood have been performed (6, 17, 21, 29), but the presence of an increased susceptibility for thyroid damage in these survivors has not been described. Although this could be a chance finding of the present study, this observation merits further research.

For patients with brain tumors, it is remarkable that after multivariate analysis the risk for central hypothyroidism is significantly increased without regard for radiation dose or field (Table 9Go). This implies the need for thyroid function monitoring in all patients with brain tumors. However, we also found central hypothyroidism in five patients treated with cranial irradiation for ALL and HD, supporting the previously described damaging effect of irradiation on the pituitary gland and hypothalamus (24, 30, 31).

Although we did not find any permanent additional adverse effects of chemotherapy on the thyroid axis, a few remarks seem justified. First, it is important to realize that the susceptibility of the thyroid gland for chemotherapy is apparently lower than that of other endocrine organs (e.g. the gonads) (19), and that those other endocrine functions should be monitored continuously in cancer survivors after treatment with chemotherapy.

Second, as was stated recently (31, 32), unrecognized thyroid problems may be present in survivors of childhood cancer. These subclinical thyroid problems could have been missed in this evaluation as we did not perform dynamic thyroid function tests (e.g. TRH tests, overnight surge of TSH) when the thyroid function determinants were normal at first evaluation. Also, transient dysfunction of the thyroid gland cannot be excluded, as we measured thyroid parameters several years after the chemotherapy and radiotherapy was given.

For these reasons we suggest that thyroid function should be monitored carefully during and shortly after treatment with chemotherapy, as low thyroid hormone concentrations in children can have severe consequences for growth and development. After treatment with (peri-) cervical radiotherapy, we advise always evaluating both thyroid structure and function using ultrasonography and sequential measurements of plasma TSH together with free T4 (for evaluation of thyroid and central hypothyroidism).

In conclusion, permanent radiation-associated thyroid axis damage is present in young adults who survived childhood cancer. However, permanent thyroid axis damage is not ascribable to treatment with chemotherapy.


   Acknowledgments
 
We thank Dr. L. J. A. Stalpers (Department of Radiotherapy, Academic Medical Center, Amsterdam, The Netherlands) for his support in determining the risk fields of irradiation.


   Footnotes
 
This work was supported by Emma Children’s Hospital, Academic Medical Center, Stichting Kindergeneeskundig Kankeronderzoek, Pharmacia BV.

Presented in part at the meeting of the European Society for Pediatric Endocrinology 2001 (abstract published in Pediatr Res 49(Suppl):161A, 2001) and at the meeting of the Société Internationale d’Oncologie Pédiatrique 2001 (abstract published in Med Pediatr Oncol 37:303, 2001).

Abbreviations: ALL, Acute lymphoblastic leukemia; HD, Hodgkin’s disease; NHL, non-Hodgkin lymphoma.

Received February 10, 2003.

Accepted April 22, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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