By Dr. Jasim Muzaffar
Abstract:
INTRODUCTION:
Breast cancer is the most commonly diagnosed malignancy
among women in Western countries and accounts for over 25%
of cancers diagnosed in women worldwide¹. Approximately
one in eight women has a lifetime risk of developing this
malignancy. It accounts for 7% of all cancer-related deaths and
15% of female cancerrelated deaths². The majority of cases are
sporadic, with only about 5% attributable to known genetic
mutations³,. Breast cancer remains a major cause of morbidity
and mortality across numerous developing nations, including
Pakistan. An analysis of six major Pakistani cancer registries
revealed that breast cancer was the most common malignancy,
accounting for 21.4% of all cancer cases and 38.8% of female
cases5. Breast cancer typically presents as a palpable lump.
With early screening and mammography subclinical disease
can be detected earlier. Earlier diagnosis has led to better
outcomes and more treatment choices for breast cancer. In
recent years, management has changed significantly, with
treatment options such as surgery, chemotherapy, radiotherapy,
and hormonal therapy selected according to the Tumour, Node,
Metastasis (TNM) stage6. Historically, radical mastectomy
with axillary lymph node dissection was the standard
treatment, but it has been largely replaced by breast-conserving
strategies like wide local excision with sentinel lymph node
biopsy and adjuvant radiotherapy, which provide equivalent
survival and minimize morbidity7,8.
The thyroid gland is highly sensitive to ionising radiation,
which can cause a range of dysfunctions, with risk increasing
with dose. Radiation-induced thyroid disorders include
hypothyroidism, thyroiditis, Graves’ disease, adenomas,
multinodular goitre, and malignant transformation9. High-dose
irradiation, whether external or internal, is strongly linked to
hypothyroidism and, less commonly, Graves’
hyperthyroidism10. Adjacent organs such as the heart, lungs,
contralateral breast, brachial plexus, thyroid, spinal cord, skin,
and oesophagus are frequently exposed to ionizing radiation
during breast cancer radiation therapy11. Previous
meta-analyses have identified the prevalence of
hypothyroidism in patients receiving breast radiotherapy A systematic review of five studies involving 478 patients
reported a significant post-treatment rise in TSH,
hypothyroidism being the most common dysfunction,
highlighting the need to recognise the thyroid as an OAR in
breast cancer radiotherapy12. Another meta-analysis of 20
cohort studies found that breast cancer survivors had a
significantly higher risk of hypothyroidism than those without
breast cancer13. These findings highlight the importance of
including the thyroid as an OAR in radiotherapy planning and
post-treatment monitoring to minimise long-term
complications.
Modern radiotherapy techniques reduce risks with more
individualised and less toxic treatments. Threedimensional
conformal radiotherapy (3DCRT) is widely used, offering
improved dose conformity and better sparing of normal tissues
compared to earlier methods. It remains standard for
hypofractionated whole breast irradiation and post-mastectomy
chest wall treatment14.
Pakistan’s radiotherapy infrastructure is limited despite a high
patient load. Most centres rely on 3DCRT. National dosimetric
data are lacking, and no formal thyroid protection guidelines
exist for breast radiotherapy. This study aimed to quantify the
mean thyroid dose during 3DCRT in non-metastatic breast
cancer patients, with the goal of reducing radiation-induced
thyroid dysfunction and contributing baseline national data to
international literature.
METHODS
This study was conducted over a six-month period (July 2024
to January 2025) at the Department of Radiotherapy, Institute
of Nuclear Medicine and Oncology (INMOL) Hospital,
Lahore, following approval of the study synopsis by the
institutional review board. A descriptive cross-sectional design
was used, and participants were recruited via non-probability
consecutive sampling. Patients were eligible to be enrolled if
they had non-metastatic breast cancer defined as disease
confined to the breast and/or axillary lymph nodes without
evidence of distant metastasis; histopathological confirmation
of invasive ductal carcinoma (IDC), invasive lobular
carcinoma (ILC), or ductal carcinoma in situ (DCIS); and an
Eastern Cooperative Oncology Group (ECOG) performance
status of 1 or 2. Exclusion criteria included previous
radiotherapy to the head or neck, known thyroid disorders, age
over 70 years, history of other malignancies, or refusal to
participate.
All participants provided written informed consent and
underwent a comprehensive baseline evaluation, which
included a detailed clinical history, physical examination,
complete blood count, liver and renal function tests,
histological tumour biopsy, and radiological staging with
contrast-enhanced computed tomography (CT) of the chest,
abdomen, and pelvis, as well as whole-body bone scintigraphy.
For the purposes of this study, non-metastatic breast cancer was
consistently defined as malignancy limited to the breast and/or
axillary lymph nodes, with no evidence of distant spread.
3DCRT planning for breast cancer was conducted using a
systematic and standardised approach. Patients were positioned
supine on a breast board with both arms raised above the head.
A planning CT scan was done, extending from the lower jaw to
below the diaphragm, to visualise target areas and adjacent
organs including the thyroid gland. These images were then
imported into the treatment planning system (TPS). Clinical
target volumes (CTVs) were calculated for the breast, chest
wall, and regional lymph nodes by the TPS. Planning target
volumes (PTV) were created by adding a margin to
accommodate potential setup uncertainties. OARs, including
the thyroid gland, were carefully contoured to monitor and
limit radiation exposure. Treatment plans were developed
using 3DCRT techniques with tangential and oblique photon
beams of 6 MV arranged to adequately cover the PTV while
minimising dose to the thyroid, heart, lungs, and contralateral
breast. Dose homogeneity was improved by advanced
techniques such as field-in-field modulation. The minimum,
maximum, and mean thyroid doses were derived from the
dose-volume histograms (DVHs) generated by the TPS. The
primary dosimetric endpoint was the mean thyroid dose,
defined as the mean radiation dose absorbed by the entire
thyroid gland. Secondary endpoints included minimum and
maximum thyroid doses and referred to the extremes of
radiation dose received by any part of the thyroid gland during
treatment. These were also derived from the DVH. All
treatment plans were reviewed by a multidisciplinary team, and
quality assurance checks were conducted prior to the initiation
of radiotherapy.
Data were analysed using SPSS version 23.0. Normally
distributed quantitative variables such as age and thyroid doses
were reported as means with standard deviations, while
categorical variables including TNM stage and histological
subtype were summarised as frequencies and percentages.
To test for significant association between the mean thyroid
dose and normally distributed continuous variables, Pearson’s
correlation coefficient was used. To test for significant
association between the mean thyroid dose and categorical
variables, independent samples t-test or ANOVA were
employed, as appropriate. A p-value of <0.05 was considered
statistically significant.
RESULTS
A total of 32 breast cancer patients were included in the study.
The mean age was 55.75 ± 7.48 years. More patients had
left-sided (n=17, 53.1%) tumour. The most common histology
was invasive ductal carcinoma (n=21, 65.6%) and the most
frequently noted TNM stage was IIIA (n=12, 37.5%). 17
(53.1%) patients had ECOG status 1. Mean thyroid volume was
10.01 ± 1.66 cc, suggesting a relatively narrow distribution in
anatomical variation across patients. Mean thyroid dose was
not found to be significantly associated with age (p=0.31) or
thyroid volume (p=0.47). Similarly, significant associations
were not found between mean thyroid dose and tumour
laterality, TNM stage, histology or ECOG status. Baseline
characteristics of the study population are presented in Table I.
The analysis of thyroid dose distribution demonstrated that the
mean thyroid dose ranged from 22.57 to 29.02 Gy with an
average of 25.62 ± 1.62 Gy. The minimum thyroid dose ranged
from 2.10 to 9.87 Gy while the maximum thyroid dose
exhibited a broader distribution, ranging from 43.05 to 61.11
Gy. Thyroid dose distribution data are presented in Table II.
DISCUSSION
In radiation therapy, OARs refer to healthy tissues and critical
structures located near a tumour target that may receive
significant radiation exposure during treatment. These organs
can develop acute or chronic complications if the dose of the
radiation exceeds to levels beyond their tolerance limits. The
primary goal of treatment planning is to deliver a therapeutic
dose to the tumour while minimizing radiation to OARs,
thereby reducing the risk of side effects. Radiation therapy for
breast cancer, the thyroid gland is increasingly recognized as an
OAR. During breast cancer radiotherapy, the thyroid gland
frequently receives substantial scatter radiation due to its
anatomical proximity to treatment fields. While 3DCRT has
significantly enhanced dose optimisation by allowing more
precise targeting of tumour volumes while sparing surrounding
normal tissues, specific dose constraints for the thyroid gland
remain less well defined, unlike the heart or lungs, for which
evidence-based dose thresholds are well established and
routinely integrated into treatment planning protocols to
minimise toxicity. This gap reflects both a historical
under-recognition of the thyroid as a radiosensitive organ in
breast cancer radiotherapy and a lack of robust clinical data
correlating dose-response relationships with long-term thyroid
dysfunction. Consequently, there is a pressing need to
standardise thyroid dose constraints in radiotherapy planning to
reduce the incidence of radiation-induced hypothyroidism and
related sequelae. Estimates from clinical and epidemiological
studies indicate that the threshold mean dose of thyroid for
radiation-induced hypothyroidism in adults is approximately
26 Gy when delivered in a fractionated schedule. Given the
high radiosensitivity of the thyroid and the established
threshold for radiation-induced dysfunction, commonly cited
in the range of 26–30 Gy, there is increasing recognition of the
gland’s vulnerability during breast cancer treatment. This
estimate arises primarily from head and neck cancer
radiotherapy cohorts, where hypothyroidism is a common
sequel and it is based on dose–response analyses derived from
cohorts undergoing external beam radiotherapy for head and
neck malignancies15,16. This value reflects the mean radiation
dose to the thyroid associated with a significant increase in the
incidence of clinical hypothyroidism.
The present study investigated thyroid radiation exposure in
breast cancer patients receiving 3DCRT and demonstrated that
the thyroid gland is subject to significant incidental irradiation.
This observation reinforces growing concerns regarding the
thyroid as an under-recognised OAR during regional
irradiation. In our study, the mean thyroid dose was 25.62 (±
1.62 Gy). These levels approach the established 26 Gy
threshold known to be associated with radiation-induced
hypothyroidism in adults making these levels clinically
significant. Our findings are in alignment with various
previous studies. In a retrospective analysis Johansen et al.
examined thyroid dose distributions in breast cancer patients
receiving CT-planned loco-regional radiotherapy at the
Norwegian Radium Hospital¹7. Although their reported median
thyroid dose (approximately 30 Gy) exceeded the mean dose
observed in our study, both studies highlight the substantial
unintentional thyroid exposure with standard 3DCRT.
Interestingly, Johansen et al. found no significant differences in
dose-volume parameters between patients who did and did not
develop hypothyroidism; however, they did identify smaller
thyroid volume as a risk factor for post-treatment thyroid
dysfunction. In contrast, we did not observe a statistically
significant association between thyroid volume and mean
thyroid dose. This discrepancy may be due to differences in
www.jcop.com.pk
51
patient demographics, contouring practices, or sample size. It is
also notable that in the Norwegian study, the thyroid was not
routinely contoured during initial treatment planning,
potentially introducing inaccuracies in retrospective dose
estimation.
Thyroid radiation doses in patients treated with 3DCRT versus
tomotherapy for breast cancer were compared using a
comparative dosimetric analysis ¹8. The average mean thyroid
dose seen with 3DCRT (28.83 Gy) was considerably greater
than the average mean thyroid dose seen with tomography
(19.59 Gy), demonstrating that thyroid exposure could be
reduced with the use tomogrpahy. Although the study’s limited
sample size and lack of long-term thyroid function follow-up
preclude drawing firm conclusions, their results imply that
modern radiation methods like tomotherapy may provide
greater thyroid sparing. In our study, we saw lower average
mean thyroid dose from 3DCRT (25.62 Gy) vs. this reference
study (28.83 Gy), however both trials showed radiation
exposure levels close to or beyond 26 Gy, the threshold for
hypothyroidism. Significant association between thyroid
volume and radiation exposure was not found in either study,
implying that factors beyond anatomical variation contribute to
thyroid dose heterogeneity.
Similarly, a larger prospective dosimetric study conducted at a
tertiary care centre in South India assessed thyroid radiation
doses in 131 breast cancer patients receiving 3DCRT following
mastectomy or breastconserving surgery¹. The median mean
thyroid dose in that cohort was 20.68 Gy, substantially lower
than the average mean thyroid dose seen in our population. In
addition, the estimated median thyroid volume in that cohort
was 7.4 cc while the mean thyroid volume in our patients was
10.01 cc. This could account for the higher average mean
thyroid dose observed in our study. The authors advocated that
in light of the higher background prevalence of hypothyroidism
in the Indian population, routine thyroid contouring and
long-term endocrine surveillance should be conducted in
patients undergoing 3DCRT for breast cancer. This
recommendation is important because subclinical thyroid
dysfunction may remain undetected in the absence of targeted
monitoring.
A study investigating thyroid radiation exposure in breast
cancer patients receiving post-operative 3DCRT involved
retrospective dosimetric analysis of 122 patients all of whom
received standard fractionation regimens. CT-based planning
with 2 – 5 mm slice thickness was utilised, and the thyroid
gland was contoured to assess volume and dose distribution.
The results indicated substantial incidental thyroid irradiation,
with an average mean dose of thyroid of 22.5 Gy. Importantly,
44% of patients exhibited mean thyroid doses exceeding 26 Gy,
a level associated with an elevated risk of hypothyroidism. By
contrast, our patients had a slightly higher average mean dose
of thyroid (25.62 Gy). In the two studies, mean maximum
thyroid doses were similar (54.54 Gy in our studygh and 46.5
Gy in this reference study). Additionally, thyroid volumes in
our cohort were lower (mean=10.01 cc) than those reported by
Akin et al. (mean=16.7 cc). Taken together, the converging
evidence from both studies reinforces the need for considering
the thyroid as an OAR for breast radiotherapy, and for
incorporating thyroid dose constraints into breast radiotherapy
planning protocols. Overall our study findings are consistent
with the data reported in the literature which strongly supports
inclusion of thyroid as an OAR for breast radiotherapy and
routine thyroid monitoring in clinical follow-up protocols.
The principal limitations of our study include its single-centre
nature and modest sample size, both of which may constrain
the generalizability of the findings. Furthermore, the analysis
focused exclusively on dosimetric endpoints, with no
prospective follow-up to assess the clinical consequences of
thyroid exposure. The lack of thyroid function testing
precludes any correlation between radiation dose and
biochemical or symptomatic hypothyroidism. These
limitations are consistent with challenges reported in similar
dosimetric studies, highlighting the need for longitudinal data
to better characterise the long-term endocrine impact of
regional radiotherapy in breast cancer.
CONCLUSION
Our study findings concur with the growing body of evidence
that the thyroid gland is subject to clinically relevant radiation
exposure during 3DCRT for breast cancer and should be
routinely contoured as an OAR. Additionally, our data supports
incorporation of thyroid dose constraints into breast
radiotherapy planning protocols. Further research integrating
both dosimetric and functional thyroid assessment are needed
to guide optimisation of radiotherapy protocols