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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 12  |  Issue : 3  |  Page : 111-118

To compare the effect of conventional radiotherapy versus concurrent chemoradiotherapy on the thyroid gland after external beam radiotherapy in head-and-neck carcinoma


1 Department Radiation Oncology, SNMC, Agra, Uttar Pradesh, India
2 Department of Radiation Oncology, District hospital, Varanasi, Uttar Pradesh, India
3 Department Biochemistry, SNMC, Agra, Uttar Pradesh, India
4 Department Radiodiagnosis, SNMC, Agra, Uttar Pradesh, India

Date of Submission13-Jun-2021
Date of Acceptance10-Jul-2021
Date of Web Publication23-Sep-2021

Correspondence Address:
Surabhi Gupta
Department Radiation Oncology, SNMC, Agra, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jrcr.jrcr_13_21

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  Abstract 


Introduction: Radiotherapy-induced hypothyroidism has remained underestimated and under reported ailment, because of noninclusion of routine assessment of thyroid function test in baseline workup and during follow-up protocol, which results in failure to detect and treat a reversible cause of morbidity in significant proportion of surviving patients. Greater magnitude and duration of thyroid-stimulating hormone elevation increase the probability of progression to clinical hypothyroidism and therefore increase the potential benefit of treatment of subclinical hypothyroidism. Hence, recognizing subclinical hypothyroidism at an early stage can prevent clinical hypothyroidism and its associated morbidities. Aims and Objectives: The aim of the present prospective study was to evaluate the functional and anatomical changes in thyroid glands in patients with head-and-neck cancer treated with conventional radiotherapy (external beam radiotherapy) and concurrent chemoradiotherapy and to assess the necessity of inclusion of routine thyroid function test in the workup and follow-up protocol of these patients. Materials and Methods: A total of 98 patients were randomly allocated in two arms. In arm I, 50 patients received concurrent chemoradiotherapy and in arm II, 48 patients underwent radical conventional radiotherapy alone. Baseline thyroid function test and ultrasonography of neck along with thoroughly clinical evaluation were done for every patient and these investigations were repeated in the middle of radiotherapy treatment (after 17 #), at the end of radiotherapy treatment, 3 months after completion of radiotherapy, and after that, at every 3rd-month follow-up to determine late changes in thyroid function test and echotexture. Results: In arm I, total 60% patients developed acute hyperthyroidism while in arm II, 68.75% patients developed acute hyperthyroidism. A total of 18.36% patients were found to have subclinical hypothyroidism. At the 9th month of follow-up, 55 out of 98 patients (56.12%) developed hypothyroidism. Among 55 patients, 37 were having clinical hypothyroidism while 18 patients were having subclinical hypothyroidism (P ≤ 0.0001). Maximum number of patients, i.e. 26/98 (47.27%) developing hypothyroidism were between 51 and 60 years of age group. Addition of surgery and chemotherapy had shown no difference in thyroid dysfunction. Patients with clinical hypothyroidism required medical management while patients with subclinical hypothyroidism were kept on close monitoring. Conclusion: Recognizing hypothyroidism (clinical or subclinical) early and treating it timely can prevent associated complications which are often ignored. Hence, thyroid function tests should be done routinely that is before starting of radiotherapy, on completion of radiotherapy, and during follow-up as well.

Keywords: Clinical hypothyroidism, concurrent chemoradiotherapy, hyperthyroidism, radiotherapy, subclinical hypothyroidism


How to cite this article:
Gupta S, Upadhyay SB, Yadav S, Singh H, Tyagi AK. To compare the effect of conventional radiotherapy versus concurrent chemoradiotherapy on the thyroid gland after external beam radiotherapy in head-and-neck carcinoma. J Radiat Cancer Res 2021;12:111-8

How to cite this URL:
Gupta S, Upadhyay SB, Yadav S, Singh H, Tyagi AK. To compare the effect of conventional radiotherapy versus concurrent chemoradiotherapy on the thyroid gland after external beam radiotherapy in head-and-neck carcinoma. J Radiat Cancer Res [serial online] 2021 [cited 2021 Nov 30];12:111-8. Available from: https://www.journalrcr.org/text.asp?2021/12/3/111/326434




  Introduction Top


Head-and-neck cancer (HNC) is the most common cancer in developing countries. It is the most common cancer of males in India and the fifth most common in females.[1]

Nearly 60% of all head-and-neck carcinoma are diagnosed in locally advanced stage, and usually all the three modalities, i.e. surgery, radiotherapy, and chemotherapy are combined together for the treatment of these tumors.[2] External beam radiotherapy (EBRT) treatment is an integral part of curative management of head-and-neck malignancies and is used either alone in early-staged tumors or in combination with surgery and/or chemotherapy in advance stages. In radiotherapy treatment for carcinoma of the head-and-neck region, radiotherapy portals, apart from including the primary site of the tumor, invariably cover the whole neck, thereby including the thyroid gland in the radiation field leading to its dysfunction.

Thyroid hypofunction is a common side effect after such irradiation and is reported in the literature for over 40 years, with figures reaching up to 50% of irradiated patients in some works.[3] Despite their specific functional consequences, radiotherapy-induced thyroid abnormalities remain underestimated and under reported.

EBRT to head-and-neck region where radiation portal invariably includes thyroid gland has acute and late effect on thyroid function. During the radiation period, hyperfunction of thyroid occurs, and levels of thyroid-stimulating hormone (TSH) exhibit two phases: a significant decrease during radiotherapy (thyroxic phase) and an increase after radiotherapy (hypothyroid phase). At higher dose levels, functional changes and thyroiditis become more prevalent during radiotherapy and this is usually transient. Increases in thyroid hormones are subtle during radiotherapy. Symptomatic hyperfunction of thyroid requires symptomatic treatment in some patients.[4] The most common clinical late effect of thyroid gland irradiation in patients exposed to therapeutic doses to the neck is hypothyroidism. This effect may be clinically overt (clinical hypothyroidism) characterized by low free T4 and high TSH or subclinical (biochemical or compensated hypothyroidism) with normal free T4 and high TSH. In the majority of cases, subclinical hypothyroidism evolves to clinical hypothyroidism. Progression to clinical hypothyroidism occurs at a rate of about 5%–20% per year.[5]

Greater magnitude and duration of TSH elevation increase the probability of progression to clinical hypothyroidism and therefore increase the potential benefit of treatment of subclinical hypothyroidism. Recognizing subclinical hypothyroidism at an early stage can hence prevent clinical hypothyroidism and its associated morbidity.[6]

Radiotherapy-induced hypothyroidism has remained underestimated and under reported, because routine assessment of thyroid function is not included in investigation protocol and not done routinely during follow-up, resulting in failure to detect and treat a reversible cause of morbidity for a significant proportion of surviving patients.

Hence, the purpose of this study was to identify the acute and late effects of radiotherapy on thyroid gland with or without concurrent chemotherapy, the magnitude of hypothyroidism following radiotherapy with assessment of the mean time period for the development of hypothyroidism.

Aims and objective

The aims of this study were to evaluate the changes in the thyroid function and echotexture in patient with HNC treated with conventional radiotherapy (EBRT) and concurrent chemoradiotherapy and to find the necessity of inclusion of routine thyroid function test in the workup protocol and during follow-up of these patients.

The objective of this study was to study:

  1. The acute and late effects of radiation and chemoradiation on thyroid gland
  2. To assess the mean time period for the development of thyroid dysfunction
  3. To assess the anatomical change in thyroid gland in patients treated with radiotherapy and with concurrent chemoradiotherapy
  4. To find the necessity of including thyroid function tests as part of workup and follow-up protocol and need of treating the symptomatic patients as well as patients having subclinical hypothyroidism.



  Materials and Methods Top


Study Population: The study was conducted on patients of squamous cell carcinoma of head-and-neck region, attending the radiotherapy OPD and referred patients from the department of ENT, department of surgery, and from nearby districts.

Duration: Duration of the study was from August 2017 to August 2019.

This study was approved by institutional local ethical committee. Informed consents were taken from all patients at the time of enrolment for this study.

Criteria of patient's inclusion

  1. Histopathologically confirmed squamous cell carcinoma of head-and-neck region
  2. Surgically resected confirmed case of squamous cell carcinoma of head-and-neck region
  3. Age <75 years
  4. Karnofsky performance scale ≥70
  5. Preradiation normal thyroid function test or patient having no previous thyroid dysfunction
  6. Patient not received any previous oncological treatment.


Plan and procedure of study

Total 98 patients were enrolled and randomized into two treatment arms.

  • Arm I: Total 50 patients received concurrent chemoradiation with injection cisplatin 35 mg/m2 intravenous weekly along with radiotherapy
  • Arm II: Total 48 patients received conventional radiotherapy alone.


In both the groups, all patients had received radiation dose of 60–70 Gy/30–35 fractions at the rate 2 Gy per fraction with 5 fractions per week in 6–7 weeks by Theratron Phoenix Cobalt-60 teletherapy machine.

In both arms, thyroid function test was done by radioimmune assay method; it included serum TSH, serum T4, and serum T3 levels.

First, baseline thyroid function test and ultrasonography of neck along with thoroughly clinical evaluation were done for every patient and these investigations were repeated in middle of radiotherapy treatment (after 17 #), at the end of radiotherapy treatment, 3 months after completion of radiotherapy, and after that, at every 3rd-month follow-up to determine the late changes in thyroid function and echotexture after radiotherapy and concurrent chemoradiotherapy. Individual patient's records were maintained.

For statistical analysis, data were collected and entered in Microsoft Excel spreadsheet. All care was taken to ensure that there is no data entry error. Categorical variables were described as frequency and proportion. Continuous variables were described as mean ± standard deviation. We compared proportions using Chi-square test and Fisher's exact test as and when required. The means in the two groups were compared using Student's t-test. P < 0.05 was considered statistically significant. The data were analyzed using SPSS version 20.0, manufactured by IBM, Armonk, New York, U.S.


  Results Top


This prospective randomized study of head-and-neck carcinoma was conducted to assess the various association and effects of concurrent chemoradiotherapy and radiotherapy alone on thyroid functions and anatomical change in thyroid gland during and after the radiotherapy. In our study, total 98 eligible patients of head-and-neck carcinoma were randomized in two arms.

In arm I, total 50 patients out of 98 (51%) patients received concurrent chemotherapy and in arm II, total 48 patients out of 98 (48.97%) received radiotherapy alone.

In our prospective, randomized clinical study, following patients and tumor characteristics were observed.

Majority of patients were in the age group of 51–60 years, i.e. 36.73% (Chi-square = 9.25, P = 0.100). Out of 98 patients, 90 (91.83%) were males and 8 (8.16%) were females, and due to less number of female patients, statistically no conclusion could be drawn on the basis of gender (Chi-square = 0.971, P = 0.324) [Table 1].
Table 1: Age and gender-wise distribution of patients

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Oral cavity was the most common site of presentation, constituting, 56.12% (55/98) of all sites [Table 2].
Table 2: Site-wise distribution of malignancy

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Total 66/98 patients (67.34%) were found to have acute hyperthyroidism. It was found to be statistically significant (Chi-square = 92.8, P ≤ 0.0001). The status of hyperthyroidism was temporary and most of the patients developed either euthyroid or hypothyroid state in subsequent follow up. In arm I, total 30/50 (60%) patients developed acute hyperthyroidism and in arm II, total 33/48 (68.75%) patients developed acute hyperthyroidism. Although significant number of patients developed acute hyperthyroidism, there was no significant difference in two arms (Chi-square = 0.817, P = 0.366) [Figure 1]. Only 2 patients required medical management for theirsymptoms [Table 3]. Total 55 patients developed hypothyroidism. In this study, 16 patients were those who had underwent surgery before radiotherapy and 9 out of these 16 (56.25%) patients developed hypothyroidism. This was statistically nonsignificant (Chi-square = 0.0035, P = 0.995) [Table 4].
Figure 1: Radiation Induced Hyperthyroidism

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Table 3: Radiation-induced hypothyroidism (subacute and late effect of radiation)

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Table 4: Subclinical and clinical hypothyroidism at the 9th month of follow-up

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In this study, the occurrence of clinical and subclinical hypothyroidism was studied over a follow-up period of 9 months [Figure 2]. On age-wise distribution, maximum number of patients who developed hypothyroidism were between 51 and 60 years of age group, i.e. 26/55 (47.27%). This may be due to more number of patients enrolled in study also belonged to this age group. Patients of both the arms had approximately similar distribution in terms of developing hypothyroidism. Difference between two arms was statistically nonsignificant (Chi-square = 9.25, P = 0.100) [Figure 3].
Figure 2: Age Wise distribution of observed Hypothyroidism

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Figure 3: Hypothyroidism According To Gender

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Although 7 out 8 female in study group, developed hypothyroidism, as number of patient was less as compared to male patients so statistically definite conclusion could not be drawn on the basis of gender (Chi-square = 3.28, P = 0.070).

Out of 98 patients who received RT irrespective of concurrent chemotherapy, 55/98 (56.12%) patients developed radiation-induced hypothyroidism which was statistically significant (Chi-square = 55.1, P ≤ 0.0001). In arm I and arm I, total 56% and 56.25% patients developed hypothyroidism, respectively. On observation of our study, it seems that there was no significant impact of concurrent chemotherapy in the development of hypothyroidism in these patients. The difference is also statistically nonsignificant (Chi-square = 0.622, P = 0.98). In this study, it was observed that total 18 patients out of 98 patients found to have subclinical hypothyroidism, which was statistically significant (Chi-square = 19.8, P ≤ 0.0001). While at the 9th month after completion of radiotherapy, 37/98 patients (37.75%) who received radiotherapy irrespective of chemotherapy were found to have clinical hypothyroidism, which was also statistically significant (Chi-square = 45.61, P ≤ 0.0001) [Figure 4].
Figure 4: Hypothyroidisms at 9 Month Follow Up After Completion of RT

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Total 9 out of 98 patients developed anatomical changes at the 9th month of follow-up period. These postradiotherapy anatomical changes in thyroid gland were statistically significant (chi-squire = 9.433, P = 0.0021) [Figure 5].
Figure 5: Development of Hypothyroidism on Increasing Follow Up Period

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On analyzing, the result it appears that the development of hypothyroidism increases with increasing follow-up time period (Chi-square = 90.7 P ≤ 0.0001).


  Discussion Top


The radiation-induced thyroid injury includes vascular damage, parenchymal cell damage, and autoimmune reactions. Total radiotherapy dose, irradiated volume of thyroid gland, and the extent of prior thyroid resection are the important factors associated with the risk of hypothyroidism. Tolerance dose of thyroid (TD 5/5–TD 50/5) is 20–40 Gy. The mean dose and V35-V50 results are significantly associated with hypothyroidism.[7]

Because of both the nonspecific symptoms of hypothyroidism and the similar symptoms and morbidities associated with malignancies and their treatment, hypothyroidism can often go undiagnosed and untreated in patients with cancer. Failure to adequately manage both overt and subclinical hypothyroidism can have serious consequences; hence, the recognition of its presence is crucial for the successful treatment of cancer patients. Hypothyroidism is easily treated with thyroxin (T4) replacement. Subclinical thyroid dysfunction, which can be diagnosed by thyroid function test, is more frequent but is often missed because routine testing of thyroid hormones is not usually done during follow-up. Consequence of subclinical hypothyroidism is much less well established. Most of the literature refers to adverse consequences such as cardiac dysfunction, adverse cardiac endpoints, including atherosclerotic disease and cardiovascular mortality, elevation in total and low-density lipoprotein, systemic or neuropsychiatric symptoms, and progression to clinical hypothyroidism. T4 replacement improves cardiac function in subjects with subclinical hypothyroidism. The clinical manifestations of clinical hypothyroidism include slowed mentation, depression, chronic fatigue, skin dryness, pleural and pericardial effusions, decreased gastrointestinal motility, weight gain, cold intolerance, congestive heart failure, and acceleration of atherosclerosis.[8]

In conventional radiotherapy treatment, an anterior cervical field is used to treat the whole neck down to the supra-sternal notch, these techniques may deliver substantial dose to the thyroid gland ranging from 54 to 66 Gy. Documented incidences of primary hypothyroidism after RT have varied from 3% to 47%. An incidence of 20%–30% has been reported by most investigators.[9]

The minimal thyroid tolerance dose defined as TD5/5 is considered 20 Gy when all or part of the gland is irradiated with conventional fractionations.[10] In our study, we used 60–70 Gy as per radical dose protocol.

In our study, the age group of patients varied from 20 years to 80 years with a mean of 52.8 years. Mean age of man was higher (52.93 years) as compared with woman (51.75 years). Out of total 98 patients, 91 (92.85%) were males and 7 (7.14%) were females. These patients' characteristics were similar to other published studies.[9],[10] In our study, maximum number of patients were from oral cavity 55 (56%), though the primary site of the tumor was not a significant factor as all the patients received whole-neck irradiation, and hence, uniformity in the volume of thyroid irradiated was maintained.

In our study, total 50 (51.02%) patients received concurrent chemotherapy along with radiotherapy and 48 (48.97%) patients received RT alone.

K Nishiyama et al. study observed that mean serum levels of TSH were 1.53, 0.55, 0.78, 2.14, and 7.57 μU/ml before radiotherapy, after 40 Gy irradiation, 2 weeks after the end of radiotherapy, 3 and 6 months after radiotherapy, respectively. Thus, levels of TSH exhibited two phases: a significant decrease during radiotherapy (thyroxic phase) and an increase after radiotherapy (hypothyroid phase) (baseline vs. 40 Gy: P < 0.0001, baseline vs. 6 months: P =0.003). Increases of thyroid hormones were subtle during radiotherapy.[11]

In our study, the average baseline (before radiotherapy) value of T3, T4, and TSH was 130.2 ng/dl, 8.05 μg/dl, and 2.50 μIU/ml. On mid radiotherapy (17#), average T3, T4, and TSH levels were 143.18 ng/dl, 10.20 μg/dl, and 1.14 μIU/ml, and at completion of radiotherapy, T3, T4, and TSH values were 164.1 ng/dl, 12.28 μg/dl, and 0.62 μIU/ml, respectively. During radiotherapy, total 63 out of 98 (61.53%) patients showed hyperthyroid state. In arm I, total 30 out of 50 (60%) patients developed hyperthyroidism, while in arm II, total 33 out of 48 (68.75%) patients developed hyperthyroidism. The changes in thyroid functions were subtle and subsequently changed into euthyroid state, subclinical, or hypothyroid state during follow-up period. Only two patients required active management for hyperthyroid state.

In our study, the minimum follow-up period after completion of radiotherapy was 9 months, which was lower than the majority of studies. Tell et al. followed up patients up to 3 years; Turner et al. had a mean follow-up of 21 months.[12],[13]

In our study, 55 of 98 (56.12%) patients developed clinical hypothyroidism at the 9th-month follow-up, which was statistically significant (P < 0.0001). we also evaluated the thyroid status at 3rd-month post-RT and we noticed that 27 out of 98 (27.51%) patients developed hypothyroidism; at 6th-month post-RT, 53 out of 98 (54.08%) patients developed hypothyroidism; and at 9th-month post-RT, 55 out of 98 (56.12%) patients had developed clinical hypothyroidism. The incidence of hypothyroidism was higher in our study when compared with other studies. The incidence in studies varies from 3% to 40%. Colevas et al. noted that 50% of the patients who developed hypothyroidism did so in the 1st year.[14]

In our study, 46.27% of the patients developing clinical hypothyroidism were between the age groups of 51–60 years, which was earlier as compared to western patients because of more number of patients belonged to this age group. Tobacco consumption and smoking are more prevalent in our country so early onset of malignancy is reported in our patients. Colevas et al. stated that there was an increased incidence (47.27%), in patients with age more than 60 years.[14] Hancock et al. stated that the relative risk of primary hypothyroidism decreased by a factor of 0.99 with each additional year of age.[15] In our study, the incidence was definitely higher in the elder age group as compared with the younger; however, the mean patient age groups analyzed were also in the range of 52 years.

In our study, there was a higher occurrence of hypothyroidism among female patients (F: M = 1.5: 1), but this was not statistically significant as the number of female patient was very less. Posner et al. stated that female sex has been associated with 20% increased hypothyroidism[16] and Hancock et al. observed an increased relative risk of 1.6:1 in females.[15]

In our study, the occurrence of hypothyroidism was 28 out of 50 (56%) in patients who received concurrent chemotherapy along with radiotherapy and 27 out of 48 (56.25%) in patients who received radiotherapy alone, thus in both the arms, the occurrence of hypothyroidism was approximately equal. Hence, chemotherapy did not show significant impact on the development of hypothyroidism in head-and-neck patients as compared to radiotherapy alone. This was again supported by studies of Turner et al. and Mercado et al.[13],[17]

Liening et al. divided their patients into the following three groups according to the therapy: RT alone, surgery in combination with RT, and thyroid-involving surgery and RT. They found an elevated TSH in 6%, 28%, and 65% patients, respectively.[18] In our study, we had only 16 patients who had underwent surgery before RT and 9 out of 16 (56.25%) patients developed hypothyroidism. This was not statistically significant (P value = 0.995), and hypothyroidism in these patients was same as compared to patients without surgery.

Sinard et al. study revealed that people with subclinical hypothyroidism have 38 times more risk of progression to clinical hypothyroidism.[19] Hence, there is a definite advantage in recognizing this complication and treating it early. Aich et al. noticed subclinical hypothyroidism as early as 6 weeks with the addition of chemotherapy and at 6 months with RT alone, with an incidence of 20.8% at 2 years.[19] In our study, we noticed 18 of 98 (18.36%) patients developing subclinical hypothyroidism at 9 months following RT. The result was statistically significant (P ≤ 0.0001).

Cooper et al. have stated that recognizing and treating subclinical hypothyroidism early has benefits such as prevention of clinical hypothyroidism and reduction in lipid levels, thereby reducing the cardiac complications.[10] Tell et al. recommended lifelong TSH testing, as the incidence of clinical hypothyroidism increases with time even after long-term follow-up.[12]


  Conclusion Top


Patients with clinical hypothyroidism require medical management while subclinical patient must be on close monitoring.

Addition of surgery and chemotherapy has shown no difference in thyroid dysfunction. Recognizing hypothyroidism (clinical or subclinical) early and treating it timely can prevent associated complications which are often ignored. Hence, thyroid function tests should be made routine before starting of radiotherapy, on completion of radiotherapy during follow-ups from as early as 3 months and should be carried out lifelong.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209-49.  Back to cited text no. 1
    
2.
Cognetti DM, Weber RS, Lai SY. Head and neck cancer: An evolving treatment paradigm. Cancer 2008;113:1911-32.  Back to cited text no. 2
    
3.
Bhandare N, Kennedy L, Malyapa RS, Morris CG, Mendenhall WM. Primary and central hypothyroidism after radiotherapy for head and neck tumours. Int J Radiat Oncol Biol Phys 2007;68:1131-9.  Back to cited text no. 3
    
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Jereczek-Fossa BA, Alterio D, Jassem J, Gibelli B, Tradati N, Orecchia R. Radiotherapy-induced thyroid disorders. Cancer Treat Rev 2004;30:369-84.  Back to cited text no. 4
    
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Rodondi N, Newman AB, Vittinghoff E, de Rekeneire N, Satterfield S, Harris TB, et al. Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events, and death. Arch Intern Med 2005;165:2460-6.  Back to cited text no. 5
    
6.
Fatourechi V. Subclinical hypothyroidism: An update for primary care physicians. Mayo Clin Proc 2009;84:65-71.  Back to cited text no. 6
    
7.
Namdar AM, Sadeghi-Bazargani H, Mohammadzadeh M, Mesbahi A. Radiation-induced hypothyroidism in survivors of head-and-neck and breast cancers after 3-dimensional radiation therapy: Dose-response models and clinical-dosimetric predictors. Rep Radiother Oncol 2020;7:e102343.  Back to cited text no. 7
    
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Srikantia N, Rishi KS, Janaki MG, Bilimagga RS, Ponni A, Rajeev AG, et al. How common is hypothyroidism after external radiotherapy to neck in head and neck cancer patients? Indian J Med Paediatr Oncol 2011;32:143-8.  Back to cited text no. 8
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9.
Aich RK, Deb AR, Pal S, Naha BL, Ray A. Iatrogenic hypothyroidism: A consequence of external beam radiotherapy to the head neck malignancies. J Cancer Res Ther 2005;1:142-6.  Back to cited text no. 9
    
10.
Cooper DS. Clinical practice. Subclinical hypothyroidism. N Engl J Med 2001;345:260-5.  Back to cited text no. 10
    
11.
Nishiyama K, Kozuka T, Higashihara T, Miyauchi K, Okagawa K. Acute radiation thyroiditis. Int J Radiat Oncol Biol Phys 1996;36:1221-4.  Back to cited text no. 11
    
12.
Tell R, Lundell G, Nilsson B, Sjödin H, Lewin F, Lewensohn R. Long-term incidence of hypothyroidism after radiotherapy in patients with head-and-neck cancer. Int J Radiat Oncol Biol Phys 2004;60:395-400.  Back to cited text no. 12
    
13.
Turner SL, Tiver KW, Boyages SC. Thyroid dysfunction following radiotherapy for head and neck cancer. Int J Radiat Oncol Biol Phys 1995;31:279-83.  Back to cited text no. 13
    
14.
Colevas AD, Read R, Thornhill J, Adak S, Tishler R, Busse P, et al. Hypothyroidism incidence after multimodality treatment for stage III and IV squamous cell carcinomas of the head and neck. Int J Radiat Oncol Biol Phys 2001;51:599-604.  Back to cited text no. 14
    
15.
Hancock SL, McDougall IR, Constine LS. Thyroid abnormalities after therapeutic external radiation. Int J Radiat Oncol Biol Phys 1995;31:1165-70.  Back to cited text no. 15
    
16.
Posner MR, Ervin TJ, Miller D, Fabian RL, Norris CM Jr., Weichselbaum RR, et al. Incidence of hypothyroidism following multimodality treatment for advanced squamous cell cancer of the head and neck. Laryngoscope 1984;94:451-54.  Back to cited text no. 16
    
17.
Mercado G, Adelstein DJ, Saxton JP, Secic M, Larto MA, Lavertu P. Hypothyroidism: A frequent event after radiotherapy and after radiotherapy with chemotherapy for patients with head and neck carcinoma. Cancer 2001;92:2892-7.  Back to cited text no. 17
    
18.
Liening DA, Duncan NO, Blakeslee DB, Smith DB. Hypothyroidism following radiotherapy for head and neck cancer. Otolaryngol Head Neck Surg 1990;103:10-3.  Back to cited text no. 18
    
19.
Sinard RJ, Tobin EJ, Mazzaferri EL, Hodgson SE, Young DC, Kunz AL, et al. Hypothyroidism after treatment for nonthyroid head and neck cancer. Arch Otolaryngol Head Neck Surg 2000;126:652-7.  Back to cited text no. 19
    


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