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    -  Das A
    -  Manikantan K
    -  Sharan R
    -  Mallick I
    -  Chatterjee S
    -  Arun P

 
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ORIGINAL ARTICLE
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Radiation-induced hypothyroidism in patients of oral squamous cell carcinoma: A retrospective analysis of 195 patients


1 Department of Head and Neck Surgery, Tata Medical Center, Kolkata, West Bengal, India
2 Department of Radiation Oncology, Tata Medical Center, Kolkata, West Bengal, India

Date of Submission30-Oct-2019
Date of Decision23-Jan-2020
Date of Acceptance23-Mar-2020
Date of Web Publication27-Jan-2021

Correspondence Address:
Prateek V Jain,
Department of Head and Neck Surgery, Tata Medical Center, Kolkata, West Bengal
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_946_19

PMID: 33753621

  Abstract 


Background: Radiation-induced hypothyroidism (RIH) is common after neck irradiation, and biochemical evaluation of thyroid function is recommended periodically for early diagnosis and treatment. This study aimed to evaluate the predictors of RIH after completion of adjuvant radiotherapy (RT) for primary oral squamous cell carcinoma (OSCC).
Methods: This is a retrospective study involving 195 patients who received RT after surgery for OSCC between August 2011 and December 2016. Thyroid function tests were obtained every 6 months and patients were considered to be hypothyroid if thyroid-stimulating hormone level was >5 mIU/mL.
Results: The study cohort comprised 130 men with a median age of 52 years (range 21–77 years). About 107 (54.87%) patients developed hypothyroidism, with a median of 21 months (range 2–67 months) for the development of RIH. Women [41 (63.1%) versus 66 (50.8%), p=0.035], addition of chemotherapy [36 (63.2%) versus 71 (51.4%), p= 0.019], and higher cumulative dose to the thyroid gland (median dose 4690 cGy versus 2981 cGy, P < 0.001) resulted in higher incidence of RIH on univariate analysis. On multivariate Cox regression analysis, female sex (P = 0.042), bilateral irradiation (P = 0.046), and cumulative dose to the thyroid (P = 0.001) were factors associated with increased risk of developing RIH.
Conclusion: The addition of chemotherapy, high dose of radiation to the thyroid gland, bilateral irradiation, and female sex were at higher risk of developing RIH. However, more studies are required to identify the dose-volume constraints of the thyroid gland.


Keywords: Adjuvant irradiation, oral squamous cell carcinoma, radiation.induced hypothyroidism
Key Message Radiation-induced hypothyroidism usually develops 2 to 3 years after completion of neck irradiation, especially in women receiving bilateral neck irradiation or a higher dose to the thyroid gland.



How to cite this URL:
Jain PV, Das A, Manikantan K, Sharan R, Mallick I, Chatterjee S, Arun P. Radiation-induced hypothyroidism in patients of oral squamous cell carcinoma: A retrospective analysis of 195 patients. Indian J Cancer [Epub ahead of print] [cited 2021 Oct 24]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=308064





  Introduction Top


Radiotherapy (RT) with or without chemotherapy is used as adjuvant treatment in locally advanced oral squamous cell carcinoma (OSCC). Radiation-related late side effects are known to adversely affect the quality of life of cancer survivors and thus have become increasingly important in head and neck (HN) cancer .[1]

As an organ situated at the anterior neck, the thyroid gland is often entirely or partially included in the high-dose region during planning for RT. Many related studies on HN cancers have reported that high-dose radiation to the thyroid resulted in an increased incidence of thyroiditis, hypothyroidism, Graves' disease, and thyroid nodules after irradiation.[2],[3],[4],[5]

It is generally believed that radiation causes damage to parenchymal cells and small blood vessels of the thyroid gland, leading to a reduction in the total mass of thyroid hormone-producing cells.[6],[7] Approximately 10–50% of patients develop hypothyroidism after irradiation to all or part of the thyroid gland. [4,8-10] Although the time for the development of hypothyroidism after RT has not been conclusively defined, most cases of hypothyroidism occur within the first three post-treatment years, with the peak incidence occurring between 1–3 years after RT.[1]

Thus, the present study evaluated the predictors of radiation-induced hypothyroidism (RIH) after the completion of treatment for primary OSCC.


  Materials and Methods Top


This study received a waiver from the institutional review board. This was a retrospective cohort study comprising patients who underwent surgery for OSCC followed by adjuvant irradiation, with or without chemotherapy from August 2011 to December 2016. Patients were excluded from the study if their primary lesion did not originate in the oral cavity, had a history of prior treatment, or if the patient did not follow-up for at least 4 months after completion of radiation or had disease progression or recurrence within this period. They were also excluded if they did not receive neck irradiation or if the dose to the neck was less than 50 Gy. They were also excluded from the study if they had diagnosed hypothyroidism or hyperthyroidism before initiation of irradiation or if records did not document at least one thyroid function test after irradiation.

Demographic data, adjuvant treatment details, and clinical outcomes were abstracted directly from patient charts. Other study variables obtained from patient charts included age, gender, primary tumor site (tongue or gingiva-buccal complex), the addition of chemotherapy to irradiation, laterality of irradiation (unilateral or bilateral), and dose received by the thyroid gland.

Patients were treated using conformal radiotherapy (CRT) planning. For patients who had unilateral volumes or relatively simple bilateral volumes, treatment was planned with 3D-CRT using multiple portals with 6 MV photon beams. Those who required bilateral treatment were treated with intensity-modulated radiation therapy (IMRT) using volumetric arc techniques on Novalis Tx® and Hi-Art Tomotherapy®. Planning with IMRT involved a dose constraint of 40 Gy mean dose to the thyroid gland, which had less priority than planning target volume (PTV) coverage.

Clinical outcomes were also obtained from the patient charts. The institutional practice of repeating thyroid-stimulating hormone (TSH) levels every 6 months; starting 6 months after completion of RT was followed. Days to develop hypothyroidism were defined as the time between the day of completion of irradiation and the date of the first report showing biochemical hypothyroidism. Patients were considered to have biochemical hypothyroidism if their TSH levels were >5 mIU/mL.

Data were abstracted from the patients' medical records. Data analysis was done using SPSS 17 (SPSS, Inc, Chicago, IL). Kaplan-Meier survival curves were used to estimate days taken for the development of hypothyroidism. Comparisons between groups developing and not developing hypothyroidism were performed using log-rank test. Multivariate Cox proportional hazards models were used to assess the prognostic impact of demographic and adjuvant treatment on the development of RIH. All variables were included in the multivariate models. Variable selection using both forward selection (P = 0.05 to enter) and backward elimination (P > 0.05 to remove) was performed to obtain final models. The level of statistical significance for all tests was <0.05.


  Results Top


Between August 2011 and December 2016, 412 patients underwent surgery followed by irradiation for OSCC. A total of 195 patients satisfied the eligibility criteria for this study.

Among the 195 patients in the study population, 130 (66.7%) were men and the median age was 52 years (range, 21–77). The primary OSCC site was tongue for 107 (54.9%) patients and gingivo-buccal complex for 88 (45.1%) patients. Around 119 (61%) patients received unilateral irradiation whereas 57 (29.1%) patients received chemotherapy in addition to RT [Table 1]. Weekly cisplatin 40 mg/m2 was used as the chemotherapeutic agent for concurrent chemoradiation, while RT was delivered in a conventional dose of 2 Gy/fraction, 5 days per week. All patients received 30–35 fractions (60–70 Gy). The median cumulative dose given to the thyroid was 3766 cGy (range 58 cGy–6399 cGy, N = 100). One hundred and six (54.1%) of our patients received the thyroid dose within the dose constraints of 40 Gy. IMRT was used in 100 (51%) patients while the remaining 95 (49%) patients were irradiated using the 3D CRT technique.
Table 1: Demographic data (n=165)

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The median period of follow-up was 33 (4–75) months. In this cohort, 107 (54.87%) patients developed hypothyroidism, with a median of 31 (2–67) months for the development of RIH. Women had a significantly more predisposed to the development of RIH [41 (63.1%) versus 66 (50.8%), p=0.035]. Other factors associated with a higher risk of development of RIH were the addition of chemotherapy [36 (63.2%) versus 71 (51.4%), p= 0.019] and higher cumulative dose to the thyroid gland (median dose 4690 cGy versus 2981 cGy, P < 0.001) on univariate analysis [Table 1].

On multivariate Cox regression analysis, the female gender (P = 0.042), bilateral irradiation (P = 0.046), and cumulative dose to the thyroid (P = 0.001) were factors that were associated with increased risk of development of RIH.


  Discussion Top


RIH is a common complication that affects the quality of life of cancer survivors. Due to its heightened prevalence, the National Comprehensive Cancer Network (NCCN) recommends that thyroid function tests should be repeated every 6–12 months after RT to the neck.[1] In this study, we found the incidence of RIH to be 54.87%, which is higher than reports from other studies.[1],[11] This probably reflects the fact that almost half of the patients were treated with 3D CRT technique, where the thyroid dose constraints were not met.

The median duration of the development of RIH was 31 months from the completion of irradiation. Although the time for the development of hypothyroidism after RT has not been conclusively defined, most cases of hypothyroidism occur within the first three posttreatment years.[1]

On univariate analysis, women receiving chemotherapy and higher dose to the thyroid were associated with an increased incidence of RIH in this study. Multivariate analysis revealed that women receiving bilateral irradiation and those receiving higher doses to the thyroid were at a higher risk of developing RIH. These findings are in concordance with the published data.

Previously identified risk factors for developing hypothyroidism were younger age, female gender, the addition of chemotherapy, and neck surgery.[4],[8],[12] It has been reported that the risk of RIH has increased by higher radiation volumes, bilateral neck irradiation, and higher radiation doses to the thyroid gland.[9],[10],[13],[14]

Alteiro observed that women have a higher level of RIH as compared to men, as they show higher levels of relative TSH (patient's TSH value/maximum value of the laboratory range) (P = 0.0005) and smaller thyroid volume (P = 0.0012) as compared with men.[4]

Norris et al. reported a rate of 31% at 5 years for the development of RIH with patients receiving chemoradiation and/or planned neck dissection being associated with a higher risk of developing RIH. They concluded that including the thyroid in the low-radiation field of <50 Gy can limit the incidence of RIH to 30–50%.[8] In patients treated for laryngeal malignancy, Kumpulainen et al. reported RIH in 24% of patients. The risk of development of RIH was higher in patients when the height of the irradiated field was more than 6.9 cm or more than half of thyroid bed was irradiated or the patient had undergone surgical management before irradiation.[9]

Tell et al. reported an actuarial rate of RIH at 5 and 10 years to be 20% and 27%, respectively, suggesting that the incidence of RIH increases over time. The hazard of developing RIH was higher in patients receiving bilateral irradiation and those who were operated before irradiation. The hazard ratio for developing RIH was 4.74 if the surgical procedure involved the thyroid gland.[10] On similar lines, Grande reported that the possibility of developing thyroid insufficiency was higher with higher radiation dose, cervical surgery, time after completion of treatment, and absence of midline shielding.[13]

We observed that patients developing RIH received more dose to thyroid gland compared to those who did not. This indicates that it is important to find out the dose-volumetric threshold of the thyroid gland and minimize the dose to the thyroid gland. Despite the introduction of IMRT, which spares normal surrounding tissue from high radiation doses while delivering a highly conformal dose to the tumor, a significant radiation dose is still unavoidably delivered to the thyroid gland.[15] The appropriate thyroid dose constraints must be used even when IMRT is used for delivering radiation.[16] It is difficult to strike a balance between maximum tolerable dose to the thyroid gland and delivering optimum dose to the areas which are at high-risk of recurrence, without compromising oncologic safety. The relationship between the radiation dose delivered to the thyroid and the development of RIH has been a matter of debate. Although previous studies have suggested that higher radiation doses to the thyroid gland are associated with higher rates of RIH, a clear threshold radiation dose has not been defined yet.[4],[11] Recent studies have used different dose-volumetric parameters for the prediction of RIH development, mostly including the proportion of thyroid volume receiving some X dose (VX). Various studies have used VX parameters from V30 to V55. [1,17-19] Even when a large meta-analysis that examined dose-response data in four studies including a total of 1027 patients showed that there was a radiation dose-response relation with a 50% risk of RIH at a dose of 45 Gy, the variation in the studies considered for meta-analysis (the dose of 50% RIH probability varied from 33 Gy to 65 Gy) caused difficulty in concluding dose-volumetric constraints.[20] The difference in the parameters used by different studies and the variable patient cohort makes it difficult to draw strong conclusions from these studies. The consensus is that, although the threshold dose at which most patients will develop RIH is still not defined, even low radiation doses have the potential to induce thyroid dysfunction.[18]

With the caveat of the lack of baseline thyroid function test before treatment, the strengths of our study include the use of standardized consistent radiochemotherapy protocols and a homogenous patient cohort who have received adjuvant chemoradiation in OSCC. The other shortcomings of this study are its retrospective design, lack of dose-volumetric analysis, and small cohort.


  Conclusions Top


RIH is common after neck irradiation and hence, biochemical evaluation of thyroid function should be done periodically for early diagnosis and treatment. The addition of chemotherapy, high dose of radiation to the thyroid gland, bilateral irradiation, and female sex were at higher risk of developing RIH. More studies are required to identify the dose-volume constraints of the thyroid gland.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Kim MY, Yu T, Wu HG. Dose-volumetric parameters for predicting hypothyroidism after radiotherapy for head and neck cancer. Jpn J Clin Oncol 2014;44:331-7.  Back to cited text no. 1
    
2.
Ziora K, Bubala H, Glowacki J, Sonta-Jakimczyk D, Legaszewski T, Zajecki W. Thyroid function after external irradiation of the neck in patients with Hodgkin's disease--long-term observation. Endokrynol Diabetol Chor Przemiany Materii Wieku Rozw 2006;12:261-7.  Back to cited text no. 2
    
3.
Ding SH, Pledge SD, Harrison BJ, Peck RJ, Bull MJ, Holland P, et al. The incidence of thyroid abnormalities in adults irradiated for lymphoma. Int J Oncol 2002;20:1065-9.  Back to cited text no. 3
    
4.
Alterio D, Jereczek-Fossa BA, Franchi B, D'Onofrio A, Piazzi V, Rondi E, et al. Thyroid disorders in patients treated with radiotherapy for head-and-neck cancer: A retrospective analysis of seventy-three patients. Int J Radiat Oncol Biol Phys 2007;67:144-50.  Back to cited text no. 4
    
5.
Tami TA, Gomez P, Parker GS, Gupta MB, Frassica DA. Thyroid dysfunction after radiation therapy in head and neck cancer patients. Am J Otolaryngol 1992;13:357-62.  Back to cited text no. 5
    
6.
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.  Back to cited text no. 6
    
7.
Cannon CR. Hypothyroidism in head and neck cancer patients: Experimental and clinical observations. Laryngoscope 1994;104:1-21.  Back to cited text no. 7
    
8.
Norris AA, Amdur RJ, Morris CG, Mendenhall WM. Hypothyroidism when the thyroid is included only in the low neck field during head and neck radiotherapy. Am J Clin Oncol 2006;29:442-5.  Back to cited text no. 8
    
9.
Kumpulainen EJ, Hirvikoski PP, Virtaniemi JA, Johansson RT, Simonen PM, Terava MT, et al. Hypothyroidism after radiotherapy for laryngeal cancer. Radiother Oncol 2000;57:97-101.  Back to cited text no. 9
    
10.
Tell R, Lundell G, Nilsson B, Sjodin 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. 10
    
11.
Boomsma MJ, Bijl HP, Langendijk JA. Radiation-induced hypothyroidism in head and neck cancer patients: A systematic review. Radiother Oncol 2011;99:1-5.  Back to cited text no. 11
    
12.
Hancock SL, Cox RS, McDougall IR. Thyroid diseases after treatment of Hodgkin's disease. N Engl J Med 1991;325:599-605.  Back to cited text no. 12
    
13.
Grande C. Hypothyroidism following radiotherapy for head and neck cancer: Multivariate analysis of risk factors. Radiother Oncol 1992;25:31-6.  Back to cited text no. 13
    
14.
Bhandare N, Kennedy L, Malyapa RS, Morris CG, Mendenhall WM. Primary and central hypothyroidism after radiotherapy for head-and-neck tumors. Int J Radiat Oncol Biol Phys 2007;68:1131-9.  Back to cited text no. 14
    
15.
Sommat K, Ong WS, Hussain A, Soong YL, Tan T, Wee J, et al. Thyroid V40 predicts primary hypothyroidism after intensity modulated radiation therapy for nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2017;98:574-80.  Back to cited text no. 15
    
16.
Diaz R, Jaboin JJ, Morales-Paliza M, Koehler E, Phillips JG, Stinson S, et al. Hypothyroidism as a consequence of intensity-modulated radiotherapy with concurrent taxane-based chemotherapy for locally advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 2010;77:468-76.  Back to cited text no. 16
    
17.
Akgun Z, Atasoy BM, Ozen Z, Yavuz D, Gulluoglu B, Sengoz M, et al. V30 as a predictor for radiation-induced hypothyroidism: A dosimetric analysis in patients who received radiotherapy to the neck. Radiat Oncol 2014;9:104.  Back to cited text no. 17
    
18.
Prpic M, Kruljac I, Kust D, Suton P, Purgar N, Bilos LK, et al. Dose-volume derived nomogram as a reliable predictor of radiotherapy-induced hypothyroidism in head and neck cancer patients. Radiol Oncol 2019;53:488-96.  Back to cited text no. 18
    
19.
Ling S, Bhatt AD, Brown NV, Nguyen P, Sipos JA, Chakravarti A, et al. Correlative study of dose to thyroid and incidence of subsequent dysfunction after head and neck radiation. Head Neck 2017;39:548-54.  Back to cited text no. 19
    
20.
Vogelius IR, Bentzen SM, Maraldo MV, Petersen PM, Specht L. Risk factors for radiation – induced hypothyroidism: A literature based meta-analysis. Cancer 2011;117:5250-60.  Back to cited text no. 20
    



 
 
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