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ORIGINAL ARTICLE
Year : 2015  |  Volume : 11  |  Issue : 4  |  Page : 684-689

Is thyroid gland an organ at risk in breast cancer patients treated with locoregional radiotherapy? Results of a pilot study


1 Department of Radiation Oncology, King Fahad Medical City, Riyadh 59046, Saudi Arabia
2 Department of Medical Physics, King Fahad Medical City, Riyadh 59046, Saudi Arabia
3 Department of Endocrinology, King Fahad Medical City, Riyadh 59046, Saudi Arabia
4 Department of Radiation Oncology, King Saud University, Riyadh 59046, Saudi Arabia

Date of Web Publication15-Feb-2016

Correspondence Address:
Mutahir Ali Tunio
Department of Radiation Oncology, Comprehensive Cancer Center, King Fahad Medical City, Riyadh 59046
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.167613

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 > Abstract 

Background: Aim was to evaluate the dose distribution within the thyroid gland its association with hypothyroidism in breast cancer (BC) patients receiving supraclavicular (SC) radiation therapy (RT).
Materials and Methods: Consecutive 40 BC patients with baseline normal thyroid function tests (TFTs), were randomized into two groups: (a) Adjuvant chest wall/breast with SC-RT (20 patients) and (b) control group (adjuvant chest wall/breast RT only); 20 patients. The thyroid gland was contoured for each patient. Each patient's dose volume histogram (DVH), mean thyroid volume, the volume percentages of the thyroid absorbing respectively 5, 10, 20, 30, 40, and 50 Gy (V5, V10, V20, V30, V40, and V50), and D mean (average dose in whole volume of thyroid) were then estimated. TFTs were performed at the time of the last follow-up and compared.
Results: Mean thyroid volume of cohort was 19.6 cm 3 (4.02-93.52) and D mean of thyroid gland in SC-RT and control group was 25.8 Gy (16.4-52.2) and 5.6 Gy (0.7-12.8), respectively. Median values of V5, V10, V20, V30, V40, and V50 were 54%, 51%, 42.8%, 30.8%, 27.8%, and 7.64%, respectively, in SC-RT as compared to control group (V5;4.9%, V10;2.4%, V20;1.75%, V301%, V40;0%, and V50;0%, respectively) with P < 0.0001. At 52 months, a majority of patients (90%) had a normal thyroid function whereas four patients (10%) had hypothyroidism; 3/20 (15%) patients in SC-RT and 1/20 (5%) in control group with P < 0.001. Significant prognostic factors were; SC-RT (P = 0.001), V30 above 50% (P = 0.001), and smaller thyroid volume (P = 0.03).
Conclusion: The risk of hypothyroidism in BC patients after SC-RT depends on the thyroid gland volume and V30 >50% and the risk can be minimized by thyroid gland shielding during RT.

Keywords: Breast cancer, hypothyroidism, supraclavicular radiotherapy, thyroid gland


How to cite this article:
Tunio MA, Al Asiri M, Bayoumi Y, Stanciu LG, Al Johani N, Al Saeed EF. Is thyroid gland an organ at risk in breast cancer patients treated with locoregional radiotherapy? Results of a pilot study. J Can Res Ther 2015;11:684-9

How to cite this URL:
Tunio MA, Al Asiri M, Bayoumi Y, Stanciu LG, Al Johani N, Al Saeed EF. Is thyroid gland an organ at risk in breast cancer patients treated with locoregional radiotherapy? Results of a pilot study. J Can Res Ther [serial online] 2015 [cited 2020 Jul 3];11:684-9. Available from: http://www.cancerjournal.net/text.asp?2015/11/4/684/167613


 > Introduction Top


Despite their specific functional consequences, radiotherapy (RT) induced thyroid disorders remain underestimated and underreported. Primary hypothyroidism, the most common RT-induced thyroid dysfunction, affects 20-30% of patients with lymphomas, and head and neck cancers (HNCs) following curative radiotherapy to the neck region and with approximately half of these events occurring within the first 5 years after treatment. [1],[2],[3] The RT to head and neck region results in significant doses of radiation to the thyroid gland (10-80 Gy) as the whole or large part of the thyroid gland is located within or near to the target which leads to biochemical hypothyroidism, thyroid neoplasms, Graves' disease, and hyperparathyroidism. [4] However, a possible association between primary hypothyroidism and RT in breast cancer (BC) patients especially those receiving RT to the ipsilateral supraclavicular (SC) area has been debated. [5],[6],[7],[8],[9]

To date, the tolerance dose (TD) of the thyroid gland has not been definitively established. [10] The minimal thyroid TD defined as TD 5/5 (incidence of clinical hypothyroidism in 5% at 5 years after treatment) is considered 20 Gy when all or part of the gland is irradiated with conventional fractionation. [2],[11] This value is accepted for individuals with a normal baseline organ function (excluding children and elderly) and an absence of previous surgery or chemotherapy. Emami et al. reported different tolerance values of 8/5, 13/5, and 35/5 (incidence of clinical hypothyroidism in 8%, 13%, and 35% of patients at 5 years) at the level of 45, 60, and 70 Gy, respectively. [11] However, quantitative analysis of normal tissue effects in the clinic has not suggested any thyroid gland TD-volume. Few studies have reported the occurrence of RT-induced hypothyroidism at high radiation doses of ≥30 Gy. [5],[12]

In the present study, we performed a prospective analysis on 40 consecutive BC patients treated with and without SC-RT in which evaluation of thyroid dose distribution and its correlation with thyroid function tests (TFTs) was performed.


 > Materials and Methods Top


Eligibility

After getting the approval from Institutional Ethical Review Committee and taking informed consents from patients for participation in the study in March 2008, 40 among 156 with BC patients between July 2008 and April 2009 were selected when they met the following eligibility criteria: (1) Histologically proven BC with; (2) clinical or pathological stages IIA-IIIC with no other evidence of distant metastasis; (3) who underwent modified radical mastectomy or lumpectomy (breast-conserving surgery [BCS]) and axillary lymph dissection; (4) received adjuvant chemotherapy and/or hormonal therapy; (5) no comorbidities (diabetes or hypertension, hyperlipidemia), and (6) who were euthyroid (with normal TFTs) prior to commencement of adjuvant radiotherapy to chest wall/breast/SC-RT. Patients with a previous history of any thyroid disorders, hypothyroidism or on thyroxin replacement therapy were excluded. Normal TFT were defined as; thyroid stimulating hormone (TSH) (mIU/L) ≤4.2; FT4 (pmol/L) 12.5-22 and T3 (pmol/L) between 3.1 and 5.5.

Radiation therapy

Simulation

All patients had computed tomography (CT) simulation. During simulation, the patients were positioned supine on breast board adjusted to have flat chest wall with head turned away from the side of treatment with both arms placed above the head. For patients receiving SC-RT; a single isocenter was chosen at the level of match line between the ipsilateral SC areas and chest wall below the medial end of the clavicle. During simulation, a reference transverse plane was identified by laser alignment at the level of the breast areola. CT images were obtained with a high-speed 16-slice helical scanner at CT slice thickness and pitch of 5 mm through the region of interest.

Target delineation and treatment planning

For purpose of study, the thyroid gland was delineated in each patient along with breast or chest wall clinical target volume (CTV), ipsilateral SC area CTV, spinal cord, heart (for left BC), liver (for right BCs), esophagus, and both lungs by two experienced radiation oncologists. Treatment planning and dose calculation were performed using the Eclipse ARIA ® treatment planning system (Varian Medical Systems, Palo Alto, California, USA) applying a pencil beam algorithm. The voxel size in the dose calculation matrix was 0.5 cm 3 × 0.5 cm 3 × 0.5 cm 3 . Parallel opposed tangential for chest wall/breast was used along with, anteroposterior field (12-15°) for ipsilateral SCV and one occasionally one posteroanterior field for SC to achieve adequate dose distribution [Figure 1]. The total radiation dose delivered to chest wall/breast was 50 Gy in 25 fractions (2 Gy/fraction) followed by ± additional scar boost/tumor bed boost of 10-16 Gy/5-8 fractions using photons or 9-12 MeV electrons. Total prescribed radiation dose to the ipsilateral SCV was kept 46-50 Gy. Shielding blocks were used primarily for spinal cord; no attempt was made to shield thyroid gland itself to prevent any under dosage in SC fields.
Figure 1: Radiation therapy technique using four half-beams; parallel opposed tangential for chest wall/breast, anteroposterior field (0°) for ipsilateral supraclavicular area and one oblique field, typically 110-115°, covering the cranial part of breast/chest wall and ipsilateral supraclavicular area

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Dose volume histograms data

Based on each patient's dose volume histogram (DVH), the total thyroid glandular volume, mean dose to whole thyroid (D mean ), and the volume percentages of the thyroid absorbing, respectively, 5, 10, 20, 30, 40, and 50 Gy were then calculated (V5, V10, V20, V30, V40, and V50) and were then estimated. The continuous variables were dichotomized at their median values. Association between the cut point of 50% of the thyroid receiving 30 Gy with hypothyroidism was also analyzed.

Follow-up

After the completion of treatment, all patients were seen at 6 weeks then every 4-6 months for first 5 years and then annually. Each follow-up included a detailed history and physical examination. Annual mammograms, ultrasonography breast, and gynecologic assessment for patients on tamoxifen were performed. For the purpose of the study, TFTs including FT3 (free triiodothyronine), FT4 (free thyroxin), TSH, TG (thyroglobulin), and thyroid antibodies (anti-TG, antimicrosomal, and antiperoxidase) were performed annually after the completion of radiation therapy. Based on TFTs at the last follow-up, patients were then grouped in both (a) euthyroidism (normal TFTs) and (b) hypothyroidism (high level of TSH and/or low FT3/FT4 or receiving thyroid replacement therapy).

Statistical analysis

The study design was planned using Simon's optimal two-stage design. According to this, in the first stage of document ≥2 events, 19 patients were required in each group; otherwise to close study prematurely. [13] Associations between TFTs with relevant clinical data (age, clinical stage, surgery, chemotherapy, and hormonal therapy) or dosimetric data (total glandular volume, D median , V5, V0, V20, V20, V30, V40, and V50) were tested by Fisher's exact test. Pretreatment TFTs were compared with the corresponding posttreatment TFTs using Wilcoxon test. The Student's t-test unpaired t-test was used to determine the significance of the difference between two groups. A P = 0.05 was considered statistically significant. All analysis was done using, SPSS version 17.0 (IBM, New York, USA) and Mathematica 9 (Wolfram, Champaign, IL, USA) software systems.


 > Results Top


Clinicopathological, treatment, and dosimetric characteristics of the 25 patients are summarized in [Table 1]. Median follow-up was 52 months (range: 12-60).
Table 1: Patient's characteristics


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Dosimetric analysis

The mean thyroid gland volume was 19.6 cm 3 (4.02-63.52) in SC-RT and 18.7 cm 3 ( 4.02-61.49) ±17.30 in the control group. The thyroid gland was found to be localized within SCV fields were as: (a) The part of thyroid within the SC-RT field without any shielding block in 4/20 cases (20%); (b) the part of thyroid within the SC-RT field with shielding block over partial volume in 11/20 cases (55%); (c) the part of thyroid within the SC-RT field but with complete shielding block in 3/20 cases (15%); and (d) the part of thyroid adjacent to SC-RT field in 2/20 cases (10%) [Figure 2]a-d]. The main purpose of shielding block was only to achieve a maximum total dose of <45 Gy to the spinal cord. No under dosage in SC fields was observed secondary to these shielding blocks.
Figure 2: The thyroid gland was found to be localized within supraclavicular fields were as; (a) the part of thyroid within the radiation therapy field without any shielding block; (b) the part of thyroid within the radiation therapy field with shielding block over partial volume; (c) the part of thyroid within the field but with complete shielding block; and (d) the part of thyroid adjacent to radiation therapy field

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The D mean of the thyroid gland in SC-RT and control group was 25.8 Gy (16.4-52.2) and 5.6 Gy (0.7-12.8), respectively. The calculated mean values for the percentages of thyroid volume absorbing given doses (V5, V10, V20, V30, V40, and V50) are shown in [Table 2]. The cumulative thyroid DVH for all patients (SC-RT and control) is shown in [Figure 3]. It was found that the volume percentage of the thyroid absorbing ≥30 Gy was above 50% in 7/20 in patients receiving SC-RT (35%).
Figure 3: Cumulative dose-volume histograms of study population

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Table 2: Dosimetric characteristics


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Thyroid function tests analysis

Baseline TFTs and which were obtained during the annual follow-up period; are shown in [Table 3]. When comparing baseline TFTs values with the same values obtained RT, the mean for TSH, FT3/FT4 was not statistically different, however a slight statistically significant trend of rise in TSH and decline in FT3/FT4 was observed by using paired Wilcoxon test (P = 0.04). A majority of patients (90%) had a normal TFTs, whereas four patients (10%) had hypothyroidism; 3/20 (15%) patients in SC-RT and 1/20 (5%) in control group with P < 0.001. Among hypothyroid patients, one (5%) patient had subclinical hypothyroidism and was on follow-up without any thyroxin replacement therapy at the time of analysis. Initial time for onset of RT-induced hypothyroidism was 38 months (95% confidence intervals: 32-52) with a cumulative hazard ratio of 1.2 [Figure 4].
Figure 4: Kaplan-Meier curve of cumulative hazard ratio of radiation therapy-induced hypothyroidism

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Table 3: Mean baseline and follow - up values of thyroid function tests in our cohort


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Statistical associations

Using Fisher's exact test, three significant associated prognosticators for hypothyroidism were seen; (a) the patients with V30 >50% had high risk of hypothyroidism (P = 0.001); (b) presence of thyroid shielding blocks (primarily aimed for to decrease spinal cord dose) reduced the risk of hypothyroidism (P = 0.045); and (c) smaller thyroid volume increased the risk of hypothyroidism (P = 0.03). No association of age, menopausal status, laterality, chemotherapy, or hormonal therapy with RT-induced hypothyroidism was seen in our cohort.


 > Discussion Top


The true prevalence of RT-induced hypothyroidism in patients who receive SCV-RT for BC treatment is not known because TFTs are not routinely assessed after RT in clinical practice. Additionally, the radiation dose to the thyroid gland is not routinely evaluated during target delineation in such cases. [5] In Addition, the dose to the thyroid gland and the pre- and post-RT TFTs have not been assessed prospectively yet in clinical practice. In our study, the incidence of RT-induced hypothyroidism (15%) in BC patients receiving SC-RT is consisting of relevant literature (6-18%), which is much lesser than reported in lymphoma and HNC data. [7],[8],[9] However, RT-induced hypothyroidism of 15% is much higher than expected frequency of hypothyroidism in the population for women who do not receive SC-RT at all (≤5%); also shown in our study. [12]

In our study, different factors were found to be associated with higher risk of RT-induced hypothyroidism such as; first the V30 >50% (the absolute thyroid volume receiving ≥30 Gy) significantly increased the risk RT-induced hypothyroidism as less tissue with radiation doses <30 Gy is available for sufficient thyroxine production. This was also confirmed by Johansen et al. in a retrospective study of 32 patients (16 patients received SC-RT). [5] Second, the smaller thyroid glands were found at high risk of RT-induced hypothyroidism. Small thyroid volume a risk for RT-induced hypothyroidism has been studied by Alterio et al. in a retrospective study of 73 patients with HNC post-RT; in which they concluded that females had inherently smaller thyroid glands compared to males and were at higher risk of RT-induced hypothyroidism during HNC RT. [2] In our cohort, the presence of thyroid shielding blocks, which were primarily aimed for to decrease spinal cord dose were associated with reduced the risk of hypothyroidism. Similarly, data have reported that thyroid shielding can significantly reduce the radiation dose of the thyroid gland neck without a remarkable noise increase while increasing CT attenuation. [14],[15],[16] Interestingly, we did not see any effect of adjuvant chemotherapy/hormonal therapy on TFTs, however Jereczek-Fossa et al. have mentioned that the impact of chemotherapy on the risk of hypothyroidism is still controversial. [1] Further, data have demonstrated a similar incidence of thyroid disturbances in patients with BC and controls. No relationship was found among estrogen receptor and progesterone receptor status, and the presence of serum thyroid autoantibodies. In addition, TSH and FT3/FT4 levels are unchanged in women taking tamoxifen. [17],[18]

Strengths of our study were; prospective study with the availability of pre- and post-RT TFTs for all patients. However, our study can be criticized mainly for two points. First, the delineation of the thyroid gland volume was performed on noncontrast CT images. However, thyroid gland sizes ranging from 2.5 to 4.7 cm in length, 2.1-4.3 cm in width in our cohort are more in agreement with literature. [19] Second, for its low sample size of our study.

We concluded that hypothyroidism after SCV-RT for BC still represent a clinically underestimated problem, and thyroid gland delineation is not yet performed routinely, probably owing to lack of literature data. We found that patients with V30 ≥50% and small glandular volumes are at high risk to develop RT-induced hypothyroidism. The presence of thyroid shielding blocks and mid-line position of the head during treatment may decrease the risk of hypothyroidism. However, further large prospective studies on dose-hypothyroidism in BC patients are therefore warranted, and thyroid gland should be considered as an OAR in all BC patients receiving SC-RT.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 > References Top

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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. 2
    
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Bruning P, Bonfrèr J, De Jong-Bakker M, Nooyen W, Burgers M. Primary hypothyroidism in breast cancer patients with irradiated supraclavicular lymph nodes. Br J Cancer 1985;51:659-63.  Back to cited text no. 9
    
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Emami B, Lyman J, Brown A, Coia L, Goitein M, Munzenrider JE, et al. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 1991;21:109-22.  Back to cited text no. 11
    
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Laway BA, Shafi KM, Majid S, Lone MM, Afroz F, Khan S, et al. Incidence of primary hypothyroidism in patients exposed to therapeutic external beam radiation, where radiation portals include a part or whole of the thyroid gland. Indian J Endocrinol Metab 2012;16 Suppl 2:S329-31.  Back to cited text no. 12
    
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Dijkema IM, Hofman P, Raaijmakers CP, Lagendijk JJ, Battermann JJ, Hillen B. Loco-regional conformal radiotherapy of the breast: Delineation of the regional lymph node clinical target volumes in treatment position. Radiother Oncol 2004;71:287-95.  Back to cited text no. 14
    
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Lee YH, Park ET, Cho PK, Seo HS, Je BK, Suh SI, et al. Comparative analysis of radiation dose and image quality between thyroid shielding and unshielding during CT examination of the neck. AJR Am J Roentgenol 2011;196:611-5.  Back to cited text no. 15
    
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Constine LS, Donaldson SS, McDougall IR, Cox RS, Link MP, Kaplan HS. Thyroid dysfunction after radiotherapy in children with Hodgkin's disease. Cancer 1984;53:878-83.  Back to cited text no. 16
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Prince JS, Stark P. Normal cross-sectional dimensions of the thyroid gland on routine chest CT scans. J Comput Assist Tomogr 2002;26:346-8.  Back to cited text no. 17
    
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Mamby CC, Love RR, Lee KE. Thyroid function test changes with adjuvant tamoxifen therapy in postmenopausal women with breast cancer. J Clin Oncol 1995;13:854-7.  Back to cited text no. 18
    
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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