|Ahead of print publication
Functional and biochemical changes in the thyroid gland following exposure to therapeutic doses of external beam radiotherapy in the head-and-neck cancer patients
Amritjot Singh Randhawa1, Hanuman Prasad Yadav1, Raja Paramjeet Singh Banipal1, Gitanjali Goyal2, Pardeep Garg1, Sapna Marcus1
1 Department of Radiotherapy, GGSMCH, Faridkot, Punjab, India
2 Department of Biochemistry, GGSMCH, Faridkot, Punjab, India
|Date of Submission||04-Mar-2019|
|Date of Decision||16-May-2019|
|Date of Acceptance||14-Oct-2019|
|Date of Web Publication||09-Jun-2020|
Amritjot Singh Randhawa,
Randhawa, H. No. 4978/A Amarkot, Lane No. 3, P/O Box Khalsa College, Amritsar - 143 001, Punjab
Source of Support: None, Conflict of Interest: None
Context: Majority of the head-and-neck cancers are locoregionally advanced at the time of diagnosis. Hence, radiotherapy (RT) portals will invariably cover the whole neck and thus, the thyroid gland which may lead to its dysfunction.
Aims: The purpose of this study is to identify the functional and biochemical changes in the thyroid gland following RT to the neck using single-photon emission computed tomography-computed tomography (SPECT-CT) and thyroid function tests (TFTs).
Subjects and Methods: In this prospective study, 45 patients of the head-and-neck cancer, receiving RT with or without chemotherapy were investigated. Baseline TFTs and thyroid scans (on SPECT-CT) were done, and the same were repeated at the completion of RT, at 3 and 6 months.
Results: All patients received a minimum of 30 Gy to the whole neck. Baseline TFTs and thyroid scans were normal. None of them developed hypothyroidism clinical or subclinical (C/S) at the completion of RT. Six patients developed hypothyroidism (four subclinical, two clinical) at 3 months of the completion of treatment. At 6 months of follow-up 14 patients (31.1%) developed hypothyroidism (ten subclinical, four clinical) with P≤ 0.01. All patients having clinical or subclinical hypothyroidism had decreased uptake on thyroid scan. Patients having decreased uptake on thyroid scan only, with normal TFTs and no symptoms of hypothyroidism were zero at the completion of RT, 1 at 3 months follow-up, and seven at 6 months follow-up.
Conclusions: Hypothyroidism (C/S) is an under-recognized but significant complication of therapeutic doses of RT to the neck. In our study, we recognized hypothyroidism as early as 3 months following the completion of RT. Hence, tests to evaluate functional and biochemical changes in the thyroid gland should be instituted as early as 3 months following RT.
Keywords: Head-and-neck cancers, hypothyroidism, radiotherapy, thyroid function tests, thyroid scans
|How to cite this URL:|
Randhawa AS, Yadav HP, Banipal RP, Goyal G, Garg P, Marcus S. Functional and biochemical changes in the thyroid gland following exposure to therapeutic doses of external beam radiotherapy in the head-and-neck cancer patients. J Can Res Ther [Epub ahead of print] [cited 2020 Sep 27]. Available from: http://www.cancerjournal.net/preprintarticle.asp?id=286247
| > Introduction|| |
Majority of the head-and-neck cancers are locoregionally advanced at the time of diagnosis. Hence, radiotherapy (RT) portals will invariably cover the whole neck and thus, thyroid gland which may lead to its dysfunction. Hypothyroidism can be clinical (low free T4 and high thyroid-stimulating hormone [TSH]) or subclinical (normal free T4 and high TSH).
Hence, the purpose of this study is to identify functional and biochemical changes in thyroid gland following RT to the neck using single-photon emission computed tomography-computed tomography and thyroid function tests (TFTs), to stress on the necessity of including TFTs as early part of follow-up.
| > Subjects and Methods|| |
A total of 45 patients were enrolled in this prospective nonrandomized study. Patients with histologically proven head-and-neck cancer who received RT in our institution's RT department were enrolled from November 2012 to November 2014.
All patients with normal thyroid function at the time of enrolment were selected to receive a minimum of 30 Gy to the whole neck. Patients were excluded if they had undergone surgery for thyroid disease, those who had preexisting thyroid disease, and patients having received any RT earlier.
A single baseline TSH, free T4, and thyroid scan test were performed before the start of RT. All patients received external beam RT to the neck using Cobalt 60 teletherapy. TSH, free T4 values, and thyroid scan were repeated at the completion of RT, at 3 months, and at 6 months following the completion of RT.
Our institution is government hospital situated in the periphery and is not equipped with LINAC so the patients are treated with Cobalt teletherapy.
Detailed history, complete physical examination, and basic laboratory investigation necessary for starting RT were done. Pre-RT dental evaluation was performed for all patients. Treatment details were explained to the patient and their relatives and informed consent was obtained before the start of the treatment. Treatment included simulation using X-ray fluoroscopy when indicated. The whole neck was included in the field of irradiation in all the patients.
All patients were treated with Cobalt 60 teletherapy unit with conventional fractionation of 1.8–2 Gy/Fraction/day for 5 days a week. Weekly assessment of reactions was made during treatment. The patients were asked to come for regular follow-up after treatment. The first follow-up was 15 days after RT, and subsequent follow-up was monthly for 6 months.
The treatment portals included the primary tumor with margin and the whole neck. After 4000–4500 cGy, the field was reduced to spare the spinal cord. The field was further reduced after 6000 cGy to boost only the primary tumor up to 6600–7000 cGy.
The treatment intent was either radical RT or postoperative adjuvant RT. In some patients concurrent chemoradiation was followed with the weekly infusion of 50 mg cisplatin. All patients eligible for the final analysis received ≥30 Gy to the whole neck.
Blood sample analysis
Five milliliters of blood was collected in a vacutainer and the serum and plasma were separated by centrifugation.
TSH and free T4 estimation were done using the chemiluminescence method. The normal values used for the study were:
TSH – 0.35–5.50 mIU/L.
Free T4 – 0.61–1.12 ng/dl.
The patient was injected on bed with 5 μ curie of pertechnetate and blood flow study was done. After 20 min, static images were acquired in anterior view. The blood flow to the thyroid was measured in blood flow phase. Moreover, uptake studies were performed for the static image.
Normal thyroid uptake: 0.4%–4%.
The normal time for blood to reach thyroid from the aorta was 5 to 10 s.
| > Results|| |
In our study the age group of patients varied from 34 yrs to 80 yrs with a mean of 57.60±10.15 yrs [Figure 1]. Of the 45 patients, 37 (82.2%) were male and 8 (17.8%) were female [Figure 2]. The sites of primary cancer were hypopharynx, larynx, buccal mucosa, lower alveolus, maxilla, anterior tongue, the base of tongue, tonsil, nasopharynx, and oropharynx and neck nodal metastases of unknown origin. Majority of the patients were carcinoma hypopharynx-nine (20%). In all the patients, the whole neck was included in the field of irradiation. All patients received a minimum of 30 Gy to the whole neck [Figure 3]. About 88.89% received concurrent chemotherapy and 11.11% received RT alone [Figure 4]. Of the 45 patients, only two patients underwent prior surgery in the form of neck dissection before RT [Figure 5].
Fourteen patients (31.1%) were found to have hypothyroidism (clinical + subclinical). This was strongly significant, with a P ≤ 0.01. Of this, 10 (71.4%) patients were found to have subclinical hypothyroidism and four (28.6%) were found to have clinical hypothyroidism [Figure 6]. Among the 14 patients who developed hypothyroidism, nine were in the age group of 41–50 years (P = 0.0522) which had a suggestive significance [Figure 7]. Ten out of 37 among males and four out of eight among females developed radiation-induced hypothyroidism [Figure 8]. 12/40 patients who received chemotherapy were diagnosed with having hypothyroidism, whereas two out of five who received RT alone developed the condition [Figure 9]. Only two patients underwent surgery before RT, and out of that, one developed overt hypothyroidism [Figure 10].
|Figure 7: Occurrence of hypothyroidism (clinical + subclinical) according to age in years|
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|Figure 8: Occurrence of hypothyroidism (clinical + subclinical) according to gender|
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|Figure 9: Occurrence of hypothyroidism (clinical + subclinical) according to chemotherapy|
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|Figure 10: Occurrence of hypothyroidism (clinical + subclinical) according to surgery|
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All patients having clinical or subclinical hypothyroidism had decreased uptake on thyroid scan. Patients having decreased uptake on thyroid scan only, with normal TFTs and no symptoms of hypothyroidism were zero at the completion of RT, one at 3 months follow-up and seven at 6 months follow-up.
| > Discussion|| |
In this prospective study, the age group of patients varied from 34 years to 80 years with a mean of 57.60 ± 10.15 years. Mean age of men was higher (58.78 ± 975 years) as compared to that of women (52.13 ± 10.84 years). In our study, 37 (82.2%) were male and eight (17.8%) were female. These patient characteristics were similar to other studies published. Tell et al., in their study of 391 patients, had a median age of 65 years, 76% were males and 24% females. Aich et al.'s study of 187 patients had an age range of 32–78 years, 85% of males and 15% of females. This is in concordance with our study.
In this study, majority (30%) of the cancers were seen to arise from the hypopharynx (pyriform sinus, postcricoid area, posterior pharyngeal wall). The primary site varied in literature. Aich et al. had a higher percentage of cancers arising from the larynx (49%). The primary site of the tumor was not a significant factor as all the patients received whole neck irradiation, and as a result, there is a uniformity in the volume of thyroid irradiated.
All patients in the study received a minimum of 30 Gy in conventional fractionation to the whole neck. About 86.67% received more than 60 Gy, which is the dose necessary for the radical treatment of the head-and-neck cancer. The mean dose to the neck was 64.54 ± 16.12 Gy. This is again in concordance with the literature where, except for studies on children treated for Hodgkin's, the minimum dose was 40 Gy to the neck and it went up to 70 Gy in patients with radical intent.,,,
Forty (88.89%) patients received chemotherapy in the form of concurrent chemoradiation or neoadjuvant and five (11.1%) received RT alone. The use of chemotherapy in the head-and-neck varies from center to center. Turner et al. had a very high number of patients receiving chemotherapy (77%). Mercado et al. had 50% of the patients receiving chemotherapy. These studies had a higher percentage of patients with locally advanced disease or were randomized to compare the effect of chemotherapy on tumor response as well as the incidence of hypothyroidism. In our study also, many of the patients were locally advanced and the majority of them received chemotherapy.
RT and surgery are the established curative modalities in the treatment of the head-and-neck cancers. Often the two modalities are combined to reduce local recurrence rates. In our study, we had only two out of 45 patients who underwent surgery before RT and where neck dissection was performed. The majority of patients were treated with radical RT. Studies in literature have a higher number of patients who have received both surgery and RT. Sinard et al. randomized patients into groups depending on whether they received RT alone, adjuvant RT or RT combined with thyroid surgery. Hence, the surgery arm had larger numbers. In our study, no randomization was done and all patients who received a radiation dose of ≥30 Gy have been included in the study.
Hypothyroidism can be clinical when there is the elevation of TSH and reduction of T4 and when thyroid uptake decreases on thyroid scan and the patient is symptomatic.
Hypothyroidism can be subclinical when there is the elevation of TSH but normal T4 and when thyroid uptake decreases on thyroid scan and the patient is not symptomatic.
In our study, all patients having clinical or subclinical hypothyroidism had decreased uptake on thyroid scan.
Asymptomatic patients with normal TSH and T4 but decreased uptake on thyroid scan are not labeled as having subclinical hypothyroidism. However, these patients need close follow-up as they can develop subclinical and later clinical hypothyroidism. In our study, patients having decreased uptake on thyroid scan only, with normal TFTs and no symptoms of hypothyroidism were zero at the completion of RT, one at 3 months follow-up, and seven at 6 months follow-up.
Because thyroid scans can reveal abnormalities in patients who are clinically and biochemically normal, we recommend pertechnetate scanning as a useful screening modality in the follow-up of irradiated patients.
. In our study, the follow-up period was 6 months post-RT, which is lower than the majority of studies. Tell et al. followed patients up to 3 years post-RT, Turner et al. had a mean follow-up of 21 months., In our study, 14/45 (31.1%) patients developed hypothyroidism (clinical + subclinical) at the end of 6 months of follow-up in our analysis, which is statistically strongly significant (P < 0.00027). In the study, we also evaluated the thyroid status at 3 months post-RT, and we noticed that six (14%) patients had developed hypothyroidism (two clinical, four subclinical) during this time.
The earliest follow-up was done by Aich et al. who evaluated the thyroid status at 6 weeks post-RT. They noticed a 4.2% incidence of clinical hypothyroidism at 12 months and not earlier.
The occurrence rate of clinical hypothyroidism is low in our study due to the shorter duration of follow-up. 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.
This is one of the few studies, which had a high incidence at 1st year. Most studies, however, have a lower rate even after the end of the 2nd year. Tell et al. found that the Kaplan–Meier predictive risk for hypothyroidism after 5 years and 10-year postirradiation was only 20% and 27%, respectively. Aich et al. had an incidence of 16.6% at the end of 2 years follow-up.
In our study, 52.9% of the patients developing hypothyroidism (clinical + subclinical) were between the age groups of 41 and 50 years this had statistically suggestive significance (P = 0.0522). Colevas et al. stated that there was an increased incidence in patients with age >60. Hancock et al. stated that the relative risk of primary hypothyroidism decreased by a factor of 0.99 with each additional year of age.
In our study, there was a higher occurrence among females (50%, F:M:1.5: 1), but this was not statistically significant as the number of female patients was very less. Posner et al. stated that female sex has been associated with 20% increased hypothyroidism, and Hancock et al. observed an increased relative risk of 1.6:1 in females.,
The occurrence of hypothyroidism (clinical + subclinical) was 30% in patients who received chemotherapy and 40% in patients who did not. This was not statistically significant. Turner et al. and Mercado et al. had a higher number of patients receiving chemotherapy, but they too noticed no difference in the incidence of hypothyroidism with the addition of chemotherapy., Aich et al. on the contrary had a 21% incidence with the addition of chemotherapy as compared to 16.6% with RT alone.
In our study, we had only two patients who had undergone surgery before RT and one (50%) developed hypothyroidism (clinical). This was not statistically significant due to the very low number of patients who underwent surgery. Liening et al. divided their patients into 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%, 65% patients, respectively. This indicates that with the addition of RT to thyroid surgery the incidence increases.
In our study, we noticed that there were ten out of 45 (22.2%) patients, who developed subclinical hypothyroidism at 6 months following RT. This was statistically significant. Subclinical hypothyroidism is an unrecognized complication. Wickham's survey showed that people with subclinical hypothyroidism have 38 times more risk of progression to overt hypothyroidism. 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 as early as 6 months with RT alone with an incidence of 20.8% with RT alone at 2 years. We noticed four cases of subclinical hypothyroidism at 3 months follow-up. The reported incidence in the literature varies between 4% and 79%.
Our occurrence of 22.2% falls within this wide range. Cooper has stated that recognizing and treating subclinical hypothyroidism early have benefits such as prevention of clinical hypothyroidism and reduction in lipid levels, thereby reducing the cardiac complications.
| > Conclusions|| |
Hypothyroidism (clinical or subclinical) is an under-recognized but significant complication of radical external beam irradiation to the neck. It occurs more in young people. Addition of surgery particularly thyroid surgery has shown to increase the incidence, but the addition of chemotherapy has shown no difference.
In our study, we have recognized hypothyroidism as early as 3 months following RT. Recognizing hypothyroidism (clinical or subclinical) early and treating it has benefits as it improves the quality of life of patients. Hence, tests to evaluate structural, functional, and biochemical changes in the thyroid gland should be instituted as early as 3 months following RT.
The authors would like to thank the Department of Nuclear Medicine, GGSMCH, Faridkot.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Tunbridge WM, Evered DC, Hall R, Appleton D, Brewis M, Clark F, et al.
The spectrum of thyroid disease in a community: The Whickham survey. Clin Endocrinol (Oxf) 1977;7:481-93.
Tell R, Sjödin H, Lundell G, Lewin F, Lewensohn R. Hypothyroidism after external radiotherapy for head and neck cancer. Int J Radiat Oncol Biol Phys 1997;39:303-8.
Aich RK, Ranjan DA, Pal S, Naha BL, Amitabh R. Iatrogenc hypothyroidism: A consequence of external beam radiotherapy to the head and neck malignancies. J Cancer Res Ther 2005;1:142-6.
Bhatia S, Ramsay NK, Bantle JP, Mertens A, Robison LL. Thyroid abnormalities after therapy for Hodgkin's disease in childhood. Oncologist 1996;1:62-7.
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.
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.
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.
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.
Hancock SL, Cox RS, McDougall IR. Thyroid diseases after treatment of Hodgkin's disease. N
Engl J Med 1991;325:599-605.
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.
Liening DA, Duncan NO, Blakeslee DB, Smith DB. Hypothyroidism following radiotherapy for head and neck cancer. Otolaryngol Head Neck Surg 1990;103:10-3.
Nishiyama K, Tanaka E, Tarui Y, Miyauchi K, Okagawa K. A prospective analysis of subacute thyroid dysfunction after neck irradiation. Int J Radiat Oncol Biol Phys 1996;34:439-44.
Cooper DS. Clinical practice. Subclinical hypothyroidism. N
Engl J Med 2001;345:260-5.
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