Acute Thyroid Profile Changes During External Beam Irradiation of Neck

Abstract

Thyroid gland is irradiated to a considerable dose in conventional radiotherapy of head neck cancer and significant proportion of patients later develop hypothyroidism. This study is an effort to shed light on acute changes in thyroid function after irradiation those are less clearly defined. Values were recorded before radiation treatment, after 4 week of irradiation, after completion of treatment, 1 month after completion of treatment and after 4 months of completion of treatment. A repeated measures ANOVA with a Greenhouse–Geisser correction determined that mean T3, T4 and TSH levels differed statistically significantly between time points. Post hoc test using the Bonferroni correction revealed statistical significance difference in values of T3, T4 and TSH done at specific intervals. External irradiation in cancer therapeutic doses affects thyroid function and sets at a new point with increased TSH, but in reference ranges, to maintain required thyroxin level.

Introduction

Radiotherapy in head and neck malignancies is the treatment of choice. Tolerance dose (TD) 5/5 and TD 50/5 (normal tissue complication probability at 5 and 50%, respectively within 5 years after radiotherapy) for thyroid gland are 45 and 80 Gy respectively [1]. In conventional head neck radiotherapy planning, thyroid gland is almost always irradiated and receives dose more than or equal to its tolerance. Hypothyroidism after lower neck irradiation is well documented and occurs in 12–53% of patients but typically between 15 and 30% in 4 weeks to 10 years [2–7]. There are very few and old studies about the acute effects of radiation on thyroid function. This study is a preliminary effort to find acute changes in thyroid function during and soon after irradiation.

Methods

This prospective study was conducted at M P Shah Medical College and associated hospital, Jamnagar. Study was approved by M P Shah Medical College ethics committee. Thirty patients who gave consent for the study and who were treatment naïve non thyroid head neck cancer with proposed conventional (2 Gy/fraction) radiation treatment by lateral opposed portals as sole modality or combination were selected. Other eligibility criteria were age between 25 and 70 years, an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or less, and adequate hematologic, renal, and hepatic function. Patients with history of thyroid and autoimmune diseases were excluded. Thyroid function tests were done before treatment, after 4 weeks of irradiation, on completion of treatment, 1 month after completion of treatment and after 4 months of completion of treatment. Thyroid profile was done in a national accreditation board for testing and calibration laboratories (NABL) certified laboratory in Jamnagar. Tests were done on fully automated immunoassay system “COBAS e-411” by electrochemiluminescence method. Normal laboratory reference values of triiodothyronine (T3), thyroxin (T4) and Thyroid stimulating hormone (TSH) were 0.84–2.02 ng/ml, 5.13–14.06 mcg/dl and 0.27–4.2 µIU/ml respectively. Initial evaluations beside thyroid profile included history taking, physical examination, dental evaluation, hematologic and biochemical analysis, electrocardiography, magnetic resonance imaging or computed tomography (CT) of the head and neck, and chest radiography. Other investigations were performed where indicated and required.

External beam radiotherapy (EBRT) was a 2-D plan based on clinical findings and CT scan correlation as well as lymphatic extension of tumor spread. Based on these clinical findings and risk assessment for involvement of draining lymph nodes according to tumor site and size, rectangular field was marked on patients with marker pen which had covered whole thyroid or part of it in the field. EBRT was delivered by cobalt 60 theratron 780E in 2 Gy per fraction, 5 fractions per week with minimum of 60 Gy/30 fractions for post operative patients and 70 Gy/35 fractions in inoperable tumor site by shrinking field technique according to tumor stage and risk of involvement. In all these patients, posterior border of field was shifted anterior to spinal cord after 46–50 Gy to prevent long term toxicity of spinal cord irradiation. Along with EBRT weekly Inj. Cisplatin 50 mg or Inj. Carboplatin 150 mg was administered where indicated.

Results

Out of 30 patients studied, twenty-seven were male and only three were female. Head neck cancer is more prevalent in male population due to characteristic habit of tobacco chewing and smoking. Median age of study population was 50 years with range of 33–70 years. Distribution of patient population according to T stage, N stage and group stage is shown in Table 1. Mean dose delivered to thyroid gland during treatment was 54.4 Gy with standard deviation of 8.52 (range 44–70 Gy). No correlation was found between age and thyroid profile at different level. Relation between T stage, nodal status and group stage with thyroid hormone level could not be established due to less number of patients.

Table 1.

Population characteristics

Characteristics	Values
Age (years)
Mean ± SD	52.9 ± 10.93
Median (range)	50 (33–70)
Sex
Male (%)	27 (90)
Female (%)	03 (10)
Stage
T1 (%)	4 (13.33)
T2 (%)	8 (26.67)
T3 (%)	12 (40)
T4 (%)	6 (20)
Nodal status
N0 (%)	12 (40)
N1 (%)	03 (10)
N2 (%)	15 (50)
N3 (%)	0 (0)
Group stage
I (%)	2 (6.67)
II (%)	4 (13.33)
III (%)	7 (23.33)
IV (%)	17 (56.67)
Dose to thyroid gland (Gy)
Mean dose ± SD	54.40 ± 8.52
Range	44–70

Both T3 and T4 level increased after 4 week of treatment and gradually showed falling trend over different time points (Figs. 1, 2). TSH level decreased after 4 weeks of treatment and then gradually increased (Fig. 3). A repeated measures analysis of variance (ANOVA) with a Greenhouse–Geisser correction determined that mean T3, T4 and TSH levels differed statistically significantly between time points [F(3.134, 90.888) = 13.29, p < 0.001, F(2.653, 76.927) = 28.32, p < 0.001, F(2.327, 67.491) = 13.27, p < 0.001 respectively]. Post hoc test using the Bonferroni correction revealed that initial rise of T3 after 4 weeks of treatment was statistically significant when compared with the pre-treatment value (p = 0.0003). Fall in T3 value after 1 and 4 month is also statistically significant with the raised value after 4 weeks of treatment (p = 0.0001, p ≤ 0.0001 respectively). But falling T3 level (after 1 and 4 months) were not statistically significantly different from initial pre-treatment value (p = 0.2458–1.000). Decrease in T3 level after 4 month of treatment completion was statistically significantly different when compared to T3 level on treatment completion (Table 2). Similar trend was with T4 level but fall after initial rise was statistically significant at every time point. Initial falling trend in TSH in response to increased thyroid hormone was not statistically significant (p = 0.2948) but TSH raised after 4 month was statistically significant when compared with pre-treatment value (p = 0.0385). Rising TSH values are statistically significant from previous values starting from nadir except between on treatment completion and nadir (p = 0.8106). None of the patient developed subclinical or clinical hypo or hyperthyroidism in this study period.

Fig. 1.

Change in T3 level during and after irradiation

Fig. 2.

Change in T4 level during and after irradiation

Fig. 3.

Change in TSH level during and after irradiation

Table 2.

Thyroid profile on repeated measurement at different time points

Thyroid profile	Before treatment	After four weeks of treatment	On treatment completion	One month after treatment completion	Four months after treatment completion	p value
T3	1.074 ± 0.24	1.35 ± 0.32	1.24 ± 0.37	1.073 ± 0.24	1.01 ± 0.18	<0.001
T4	6.83 ± 1.38	8.83 ± 1.99	7.91 ± 2.05	6.62 ± 1.52	6.07 ± 1.33	<0.001
TSH	1.56 ± 0.18	1.18 ± 0.1	1.40 ± 0.16	1.83 ± 0.17	2.44 ± 0.22	<0.001

Discussion

Thyroid gland respond to radiation by acute rise in T3 and T4 level and decrease in TSH level. Though values didn’t cross normal range of perticular hormone but show statistically significant change in level. Sharp rise and sharp fall in level of T3 and T4 hormone within limit signifies acute inflammatory changes. Normalization of T3 and T4 values towards the completion of treatment while increasing TSH value could not be explained by acute thyroiditis. But it explains hypofunction of thyroid post irradiation that results in higher level of TSH in comparison to TSH before irradiation to maintain T3 and T4 level. With best of our knowledge there are only a few studies illustrating acute functional changes in thyroid gland. Pre clinical studied done in sixth decade of last century on radiation induced thyroid function changes are worth discussing in this regards.

J. R. Philp mentioned in his review article in 1966 about work done by Aubin, Kniseley and Andrews who studied the effect of external radiation in the thyroid histology and ¹³¹I (in tracer dose) metabolism in the dog. With a dose of 21,000 rads they found accelerated release of ¹³¹I (tracer dose) from the fourth day onwards accompanied by gross central necrosis with the same surviving rim of follicles at the periphery of the gland. Almost identical results were obtained by Levene and others. Biological explanation (e.g. blood vessel necrosis) was suggested for these phenomena. Although changes similar to these were observed with 10,000 rads they were surprisingly of minimal degree [8–10]. This small histological and functional response to a massive dose (10,000 rads) of X-rays is borne out by the electron microscope studies of McQuade et al. [11] in which no changes were found within 6 h of a 17,200 rad dose or within 5 days of a 6800 rad dose. These findings were with very high doses but provide mechanism of cell damage.

Law and Thomlinson [12] demonstrated increase in vascular permeability, resulting in effusion of plasma protein and oedema. Some authors described vascular changes and fibrosis in thyroid post irradiation but couldn’t find relation with inconsistent level of T3, T4 and TSH [13, 14]. Holten [15] tried to find response to external irradiation and concluded that thyroid gland is influenced by external irradiation with cancer therapeutic doses. He interpreted thyroid hormone measurable changes shortly after radiotherapy as sign of dysfunction. He explained radiation induced mitotic death being the essential component of thyroid hypofunction and suggested possibility of contributory mechanism.

Nishiyama et al. published an article in International Journal of Radiation Oncology, Biology, Physics in 1996 on acute radiation thyroiditis and concluded that radiation promotes release of excessive amounts of thyroid hormones during radiotherapy owing to suppression of TSH secretion [16, 17]. In present study, we believe that due to radiation thyroiditis there was acute rise in T3 and T4 level causing fall in TSH level. Plasma concentration of T3 and T4 starts decreasing afterward causing compensatory increase in TSH level. Review by Jereczek-Fossa et al. [5] suggested including baseline thyroid function assays in all patients undergoing thyroid or parasellar irradiation for the diagnostic approach to thyroid radiation injury.

Lin et al., though not during radiation but following irradiation studied thyroid function in patients of nasopharyngeal cancer (NPC) who were treated by EBRT. Serum free triiodothyronine and fT4 levels showed mild changes of <2.5% at 6 months, started to drop by 8.8 and 11.3%, respectively, at 12 months, and became stable at 18 months. The mean serum TSH level increased mildly at 6 months after radiotherapy and more steeply after 18 months. At 18 months after radiotherapy, 12 out of 45 patients had primary hypothyroidism with an elevated serum TSH, in which 4 of them also presented with low serum fT4. There was a significant difference (p = 0.014) in the mean thyroid doses between patients with hypothyroidism and normal thyroid function [18].

Bakhshandeh et al. evaluated thyroid function and some other parameters in head neck cancer patients. There was a significant fall in TSH level (p < 0.0001) but an increase in free T4 (p < 0.0001) and T4 (p < 0.022) levels during the radiotherapy course. The threshold dose required to produce significant changes was 12 Gy. Study demonstrated that changes in thyroid vessels occur during radiotherapy delivered to patients and vessel changes also can be attributed to the late effect of radiation on the thyroid gland [19].

Similar study design with effect of scatter radiation on thyroid gland due to irradiation of nonthyroid cancer in children and adolescent was done by Bonato et al. recently. With median radiation dose of 296.6 cGy (IQR 16.7–1709.0) levels of T3, T4 and TSH were statistically similar before irradiation, on the last day and at 1 and 3 months after the end of radiotherapy [20]. Author suggested more sensitive method to ascertain whether acute damage to follicular epithelium occurs with low scattered irradiation.

In this study, patients were treated on cobalt source EBRT machine (Theratron 780E) that is only facility at the centre where study was conducted. Both gamma rays and X-rays have similar radiobiological properties except their origin. It is the integral dose to thyroid gland that leads to patho-physiological and biochemical effects. It is unlikely that modern radiation treatment facilities where X-rays are used for irradiation will have different effect. Study with large patient cohort and control population with determination of accurate doses to volume of thyroid gland can elucidate patho-physiology accurately. Confounding variables such as age and chemotherapy can also be explained by multivariate analysis with large sample size. Most of the T3 and T4 remains in protein bound state and it is free thyroid hormone level that is responsible for physiologic effect. Cancer itself and deprived nutrition during radiation treatment affect serum protein and hence free thyroid hormone level. Total as well as free T3 and T4 level and their relation with volume of thyroid receiving particular radiation dose may possibly give new insight in this subject.

Concluding, we can say that external irradiation in cancer therapeutic doses affects thyroid function and sets at a new point with increased TSH, but in reference ranges, to maintain required thyroxin level. Though, clinical or biochemical thyroid dysfunction is not evident during and shortly after external irradiation. What essentially happens at cellular level should be determined by modern functional imaging techniques by a larger study.

Compliance with Ethical Standards

Conflict of interest

None of the author has conflict of interest to disclose.

Human and Animal Right Statements

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed Consent

Informed consent was obtained from all individual participants included in the study.