|Year : 2011 | Volume
| Issue : 2 | Page : 194-198
Thyroid diseases as a sequelae following treatment of head and neck cancer
RPS Banipal1, MK Mahajan1, B Uppal2, M John3
1 Department of Radiation Oncology, Christian Medical College, Ludhiana, Punjab, India
2 Department of Biochemistry, Christian Medical College, Ludhiana, Punjab, India
3 Department of Medicine, Christian Medical College, Ludhiana, Punjab, India
|Date of Web Publication||11-Jul-2011|
Department of Radiation Oncology, Christian Medical College, Ludhiana, Punjab
Source of Support: None, Conflict of Interest: None
Aims: To evaluate the radiation-induced sequelae on thyroid gland and influence of concomitant chemotherapy. Materials and Methods: This prospective study was carried out on 53 patients of head and neck carcinoma in the age group of 30-75 years (55.9 years). Patients were treated with external beam radiotherapy (52.8%) or concurrent chemo-radiotherapy with 5-flourouracil and cisplatinum (47.1%). The target volume included the thyroid gland, which received an average dose of 60 Gy in 30 fractions. Thyroid function tests were done at the start of radiotherapy. Follow up thyroid function tests were done on completion of radiotherapy treatment, at 3 months, at 6 months after treatment, and then every 6 months. Follow up ranges from 3-51 months (median: 27 months). Results: Subclinical hypothyroidism was seen in 4 (7.5%) of the 53 patients. In three patients, the incidence was seen after a gap of 12 months and in one patient after a gap of 35 months. Of the four patients, three were of age ≤41 years and 1 was of age 66 years. In younger age group (30-39 years) patients, TSH shows statistically significant (P < 0.05) increase in TSH values. No significant difference was observed in radiation and chemo-radiation treatment groups (P > 0.10). Conclusions: Subclinical hypothyroidism is an important sequelae seen in the treated patients of head and neck when thyroid is in the radiation field. The patients with age less than 45 years are more prone to develop hypothyroidism. Chemotherapy has not affected the incidence of hypothyroidism significantly. Also, the dose of radiation has not shown any statistically significant difference.
Keywords: Head and neck cancer, irradiation, thyroid dysfunction
|How to cite this article:|
Banipal R, Mahajan M K, Uppal B, John M. Thyroid diseases as a sequelae following treatment of head and neck cancer. Indian J Cancer 2011;48:194-8
| » Introduction|| |
Radiotherapy is an integral part of management of head and neck malignancies, used either alone or in combination with chemotherapy. Thyroid gland is invariably included in the target volume. Although it is considered to be relatively radio-resistant, the events of Hiroshima and Nagasaki bombings and the Chernobyl accident, has shown hypothyroidism and various other sequelae including thyroid malignancies. This indicates the existence of dose-effect relationship.  The dysfunctions ranged from thyroiditis, autoimmune thyroiditis, hypothyroidism, and thyroid tumors. Chemo-radiotherapy has now evolved as a standard of care in the treatment of head and neck malignancies. Radiation-induced hypothyroidism and the additional factors including chemotherapy when used in conjunction to radiation therapy needs to be explored.
| » Materials and Methods|| |
From 1st August 2004 to 31st July 2005, 53 patients with a histological diagnosis of carcinoma of head and neck were enrolled in the study, who were planned to receive therapeutic levels of radiation therapy to the head and neck region in which thyroid gland was included in the field of treatment. Patients with a prior history of thyroid disease or thyroid surgery, any neck surgery, abnormal pretreatment thyroid function tests and any previous history of radiation therapy to thyroid were excluded from the study.
Before initiation of the treatment, all patients underwent complete physical examination and biochemical investigations. A baseline thyroid function tests was done on day 1 at the start of therapy. Then the follow up thyroid function tests were done on completion of radiotherapy, at 3 months, 6 months, and then every 6 months. Twenty-five patients received chemo-radiotherapy, 22 (41.5%) with cisplatinum and 5-fluorouracil, and 3 (5.6%) with cisplatinum only. Twenty-eight patients (52.8%) had received radiotherapy only. Cisplatinum was given in a dose of 50 mg/m 2 on day 1, 22 and 42, and 5 Fluorouracil was given in a dose of 500 mg infusion over 6 h, twice a week, for 6 weeks. Radiotherapy was delivered with two lateral parallel opposed fields with Co-60 teletherapy machine. One patient with parotid gland tumor was also treated including ipsilateral lymphatic drainage of the neck. Target volume includes whole neck with spinal cord sparing after 4000 cGy. Target dose delivered varied from minimum of 4000 cGy in 20 fractions to maximum of 7000 cGy in 35 fractions over a period of 25-45 days (median dose 6000 cGy). Mean radiation dose received by the thyroid gland is 60.04 ± 3.91 Gy. The follow up ranges from 3 to 51 months (median: 27 months). Patient characteristics are shown in [Table 1].
| » Results|| |
Majority of the patients (62.2%) were in 6th-7th decade of their life [Table 2]. At 1-month follow-up 1 patient was lost to follow-up, at 3 months 40 patients reported to the outpatient department with 13 patients lost to follow-up and at 6 months 31 patients reported with 22 patients lost to follow-up. Three (5.6%) patients were less than 41 years of age. At 12-month follow-up, three patients had subclinical hypothyroidism. At 35-month follow up, one more patient presented with subclinical hypothyroidism. Of the three patients in the younger age group, all three had developed subclinical hypothyroidism. Two (3.7%) patients had received only radiotherapy, while one (1.88%) had received concomitant chemo-radiotherapy [Table 3]. The study showed a statistically significant (P < 0.05) decreasing trend in the mean FT3 and mean FT4 values over time [Figure 1]. Mean TSH value showed an increasing trend from the baseline values till 180 days and this was found to be statistically significant (P < 0.05) [Figure 2]. The study showed no statistically significant difference between radiotherapy and chemo-radiotherapy groups (P > 0.10)[Figure 3]. None of the patients received thyroid replacement therapy. Complete data of four patients with subclinical hypothyroidism is given in.
|Figure 2: Thyroid stimulating hormone levels at different times of measurement in diffrent age groups|
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|Figure 3: Thyroid stimutating hormone levels at different times of measurement according to mode of treatment|
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| » Discussion|| |
Thyroid gland has an important role in keeping the metabolic activity in organized performing way. Radiotherapy plays an important role in the management of head and neck cancers. The majority of new cases of invasive head and neck cancer need radiotherapy as a primary treatment, as an adjunct to surgery alone or in combination with chemotherapy or as palliation.
Thyroiditis, autoimmune thyroiditis, hypothyroidism, and thyroid tumors have been reported as sequelae to therapeutic radiation. These effects occur with latency periods ranging from 6 months to 40 years. Bird and Bryce  report hypothyroidism as a sequel to external radiation administered to the neck. In 1961, Felix et al., first reported a case of hypothyroidism 6 years after treatment with external radiotherapy for laryngeal carcinoma.  Green et al.,  reported hypothyroidism in 37% (subclinical + clinical) of patients treated for Hodgkin's disease, and 24% incidence of hypothyroidism was reported in patients treated for childhood brain tumors in a study done by Palmer et al.  Einhorn and Wikholm  followed 41 patients for more than 10 years after treatment for carcinoma of larynx and hypopharynx, the incidence of established hypothyroidism was 7.3%.
A depressed serum T 4 level accompanying an elevated TSH level is recognized as a diagnostic of primary hypothyroidism. Patients with normal T 4 levels and elevated TSH levels are considered to be in a "latent" or "compensated" hypothyroid state. This state is also known as subclinical hypothyroidism. Although plasma TSH and T 4 levels change inversely, it is recognized that there is not good correlation between degree of reduction in serum T 4 levels and the degree of elevation of TSH.  It is, however, unequivocal that in primary hypothyroidism the TSH is always elevated before the development of T 4 depression. During this period of subclinical hypothyroidism the T 4 levels are maintained by TSH levels.
Leining et al.,  reported hypothyroidism after radiotherapy in 26% of patients; the majority of the patients had subclinical hypothyroidism manifested by an elevated TSH. Weissler and Berry  reported that 57% of the patients developed elevated TSH levels. Most TSH elevations occur within 1 year of treatment. In a study by Mercado et al., , with a median follow up of 4.4 years, reported Kaplan-Meier projected incidence of hypothyroidism at 5 and 8 years was 48% and 67%, respectively. The documented incidence varies between 3% and 44%.
The incidence of hypothyroidism in the present study is 7.54%. Four cases demonstrated subclinical hypothyroidism in this study. Out of these four cases, three cases presented with subclinical hypothyroidism at 12 months follow up and one presented at 35 months follow up. The time for development of subclinical hypothyroidism in three patients is 12 months after minimal dose of 6000 cGy. The study has not shown statistically significant change in the values of FT3, FT4, and TSH with the escalation of radiation dose [Figure 4].
|Figure 4: Thyroid stimutating hormone levels at different times of measurement according to radiotherapy dose|
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Hancock et al.,  had reported that children irradiated to the thyroid gland during spinal axis treatment for central nervous system tumors had incidence of hypothyroidism that ranged from 20% to 66%. In other studies, 7 of the 15 patients (47%) younger than 20 years of age  and 6 of 9 patients (67%) younger than 16 years of age had abnormal thyroid functions.  Subclinical hypothyroidism occurs in 3%-8% of general population. It is more common in women and its incidence increases with age.  In the present study, all the three patients less than 41 years developed subclinical hypothyroidism. Majority of the patients were in the 5th to 7th decades of life. The reason for low incidence in study may be because follow up in patients after 18 months falls to as low as 24% and also old age of patients at the time of treatment. Continuing this study for longer follow up period to observe the various late effects on thyroid gland may lead us to more findings.
It is expected that chemotherapy, particularly concurrent chemotherapy would sensitize the thyroid gland to radiation and will increase the incidence of hypothyroidism. But Posner et al., Sinrad et al., and Kanti et al., found no effect of combination chemotherapy on thyroid gland function in patients with head and neck malignancies. In the present study, we used chemotherapy in concomitant settings only and the difference observed in the radiotherapy and chemo-radiotherapy group is also not statistically significant.
Although there is no question as to the propriety of replacement thyroid therapy in the patient with overt clinical hypothyroidism, the question of replacement therapy in the patient with subclinical hypothyroidism raises a controversy.  Our policy is to closely observe the patients of subclinical hypothyroidism with serial T 4 levels and to start thyroid replacement therapy for patients with clinical hypothyroidism only. The study is planned to be continued to follow the changes in the thyroid functions with time.
The importance of making the diagnosis of hypothyroidism in these patients lies in the fact that treatment with thyroid hormone replacement is simple, inexpensive, and effective and usually without major side effects  especially in <45 years age group.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3]