Abstract
Background/Aim: This study aimed to identify the progression of carotid artery stenosis (CAS) in patients with head and neck cancer following radiation therapy (RT) by characterizing associated risk factors. Patients and Methods: Panoramic radiographs (OPG), computed tomography (CT) scans, cone-beam CT (CBCT) scans, and ultrasonography (US) of 69 patients with head and neck tumors were selected and analyzed to identify the presence of CAS. Data on tumor location, smoking status, hypertension (HTN), hyperlipidemia (HLD), diabetes mellitus (DM), and treatment were collected from the patients’ medical records. Patients who received chemotherapy or no treatment were excluded from the study. The differential diagnosis of other radiopacities and anatomical landmarks were excluded. Patients were divided into two groups: those with CAS (group1) and those without CAS (group 2) and their clinical information was compared. Results: The overall prevalence of CAS on the panoramic radiographs was 16%. Of the 69 patients, 44 underwent radiography before and after radiotherapy, only seven had mild CAS on radiographs after radiotherapy, and no significant difference in CAS was identified before and after radiotherapy. There were also no differences between the groups regarding age, sex, smoking, hypertension, diabetes mellitus, hyperlipidemia, tumor location, and RT dose before and after radiation (p>0.05). Conclusion: Radiotherapy does not seem to affect the prevalence of CAS, although it has been identified in some patients after radiotherapy completion.
The pathological remodeling of the arterial wall known as atherosclerosis, is initiated by lipid build-up in the subendothelial layer of the arteries. Lipid retention initiates an inflammatory response that causes the invasion of numerous types of leukocytes. This inflammatory state promotes additional endothelial dysfunction, which in turn results in the creation of calcified, fragile plaques that are prone to rupture or full arterial obstruction (1). Several factors are associated with the development of atherosclerosis, including diabetes mellitus, obesity, hypertension, smoking, alcohol consumption, and chronic renal diseases. As a result of atherosclerosis, strokes can occur when the carotid arteries that supply the brain are affected, and myocardial infarctions can occur if the coronary arteries that supply the heart are affected, leading to the death of many people worldwide (2). Patients with head and neck tumors often benefit from radiotherapy (RT) as a definitive or adjuvant treatment. In contrast, the ionizing effect of radiation has been reported to alter microvascular endothelial cells and accelerate atherosclerotic changes in large vessels (3). Radiation therapy is particularly the treatment of choice for non-metastatic head and neck tumors, as it is believed that survival rates following this therapy are higher than those for other cancers. However, these patients may experience late side effects including carotid artery atherosclerosis following irradiation (4). Patients who received radiotherapy showed a thicker carotid artery wall, and a greater prevalence of carotid plaques compared with patients who did not receive radiotherapy (5). Nevertheless, the carotid stenosis induced by radiation mimics spontaneous atherosclerosis in terms of arterial wall and plaque changes (5). According to the American Cancer Society, standard external beam radiation therapy (EBRT) for the oral cavity or oropharynx is usually delivered in daily fractions (doses) five days per week for a period of approximately seven weeks.
Radiation-induced carotid artery stenosis (CAS) develops rapidly, and often affects the common carotid artery, and these patients are more susceptible to ischemic strokes (6). There is still lack of knowledge on the precise mechanisms underlying radiotherapy-induced carotid artery disease and less data on the occurrence and morphology of plaques (7). Atherosclerotic disease near the carotid bifurcation is thought to be the cause of 50% of all strokes (8). Panoramic radiographs are used to detect carotid artery atheroma, which manifests as a round radiopaque mass or two radiopaque vertical lines 1.5-4.0 cm inferior to the mandibular angle or between the posterior mandibular border and the third and fourth cervical vertebrae (9). It is possible to misinterpret anatomical structures and pathological radiopacities in the carotid region for carotid stenosis, including the hyoid bone, epiglottis, stylohyoid and stylomandibular ligaments, thyroid and triticeous cartilages, calcified lymph nodes, tonsilloliths, phleboliths, and sialoliths (10). The effect of radiotherapy varies with artery size; thus, sclerotic changes in all endothelial layers are more prominent in small- and medium-sized vessels compared to large ones. However, according to current research, radiation exposure is characterized by damage to the vessel wall and increased inflammation (11). This study aimed to verify whether head and neck RT can induce CAS in patients with head and neck tumors, and to compare the clinical findings of patients with and without CAS depending on their panoramic radiographs, computed tomography (CT) scans, and ultrasonography (US) screening after radiotherapy.
Patients and Methods
This retrospective study included 69 patients with head and neck tumors and was conducted at the Stomatology Department of the University Hospital in Pilsen, Czech Republic, between March 2015 and November 2021. The diagnoses of the patients in the study were based on their panoramic radiographs, CT scans, cone-beam (CBCT) scans, and US performed before and after completion of head and neck radiotherapy.
The inclusion criteria were: malignancies of the oral cavity, tonsils, oropharynx, nasopharynx, pharynx, mandible, floor of the mouth, and larynx. Tumor location, smoking status, and the presence of chronic diseases including hypertension (HTN), hyperlipidemia (HLD), and diabetes mellitus (DM). Treatment information was collected from the patients’ medical records. Patients who received chemotherapy or no treatment were excluded from this study. Digital images were carefully examined by an experienced oral radiologist for the presence of nodular, and linear radiopacities in the soft tissues of the neck posteroinferior to the mandibular angle at the lower margins of the third and fourth cervical vertebrae. The differential diagnosis of other radiopacities and anatomical landmarks were excluded.
Patients were divided into two groups: without CAS (group 1) and those with CAS (group 2), and their medical and clinical data were compared.
Demographic characteristics were analysed using frequencies, and percentages. The presence of CAS was considered the outcome variable (response variable), and the predictor variables included sex, smoking, DM, hypertension, hyperlipidemia, radiotherapy dose, and tumor location (floor of the mouth, tongue, tonsils, mandible, retromolar region, and others). Categorical variables were compared using chi-square or Fisher’s exact tests. Statistical analyses were performed using SAS® (Statistical Analysis System). p-Values <0.05 were considered statistically significant.
The Ethics Committee of the University Hospital and the Faculty of Medicine, Charles University in Pilsen with reference number 392/23, approved the study protocol.
Results
The study population consisted of 69 patients and the majority were male (61%); most of them (75%) were between 50 and 70 years of age. Most of the patients were non-smokers. The tongue (28%), tonsils (24%), and mandible (22%) were the most common tumor sites. Most patients (76.67%) received a total dose of 50-70 Gy as either exclusive or adjuvant treatment (range=40-70 Gy). A review of their medical histories showed that 15 patients (42%) had arterial hypertension, eight (18%) had DM, and five (14%) had hyperlipidemia. Of the 69 patients enrolled, 44 patients had their radiographs before and after RT, only seven patients (16%) were identified with mild CAS (group 1) on both radiographs before and after RT and there was no significant change in the severity of CAS after finishing the RT. Representative images from patients are shown in Figure 1, Figure 2, and Figure 3. Furthermore, 37 patients (84%) presented without CAS (group 2) before RT, and they did not develop CAS after radiation treatment. Differences related to sex (p=0.2728), age (p=0.3629), smoking (p=0.081), tumor location (p=0.304), RT dose (p=0.1084), and chronic diseases such as arterial hypertension (p=0.9351), DM (p=0.437), and hyperlipidaemia (p=0.3332) were not significant between those with and those without CAS (p>0.05) (Table I).
Panoramic radiographs of a 64-year-old female with squamous cell carcinoma (SCC) in the tongue. Total dose of radiotherapy was 54+60 Gy. OPGs were obtained before radiotherapy and two years after radiotherapy. Mild unilateral carotid artery calcification is shown with no significant change before and after radiotherapy. A) Before radiotherapy. B) After radiotherapy.
Computed tomography (CT) scan of 80-year-old-female with a tumor in the mandible, total dose of radiotherapy was 54+45.9 Gy, CT scans were taken before radiotherapy and after three years of finishing radiotherapy. Calcified carotid plaque is shown before and after radiotherapy without significant change or increase in calcifications with time. The difference in pictures is due to the fact that other modalities of imaging methods with different timing of contrast administration were used for the controls. For the examination, PET/CT of the trunk was most often used as part of the staging examination, CT of the neck or CT of the neck and chest. On the left of the picture, a multiplanar reconstruction showing the examined area in a plane. On the right, VRT reconstruction (volume rendering technique) with 3D visualization of the area of interest. A) Before radiotherapy. B) After radiotherapy.
Computed tomography (CT) scan of 70-year-old male with a tumor in the mandible; total dose of radiotherapy was 69.9+59.4 Gy. CT scans were obtained before radiotherapy and one year after finishing radiotherapy. Calcified carotid plaque is shown before and after radiotherapy without significant change or increase in calcifications with time. A) Before radiotherapy volume rendering technique reconstruction. B) After radiotherapy (multiplanar reconstruction).
Comparison of clinical findings of patients with and without carotid artery stenosis.
Discussion
This study evaluated the role of RT in causing CAS in patients with head and neck tumors, who were evaluated before and after RT using panoramic radiographs, CBCT, CT scans, and ultrasonography. It was estimated that the population in this study would have a high incidence of CAS since they received a high dose of RT. Although the prevalence was higher in these patients, it was not as high as that reported in other studies. Our data indicate that RT to the head and neck is not associated with a higher prevalence of CAS after completion of RT. In support of these findings, Markman et al. (2017) reported an overall prevalence of CAS (35%) on panoramic radiographs and there was no significant difference in CAS before and after RT (9). Similarly, a prospective study by Valentin et al. (2020) that included 156 patients who underwent duplex ultrasound examination after RT, showed that severe stenotic plaques were found in only 27.5% of patients and the prevalence of CAS in the population was very low (7). There was a difference between these results and those of other studies. In a study by Zhou et al. (2015) of 72 patients who received head and neck RT, CAS was present in 67 (93.1%) patients (12). Additionally, a study by Greco et al. (2012) showed that CAS worsened in 62% of patients in the RT group. In a systematic review by Texakalidis et al., which included 19 studies comprising 1,479 patients, the prevalence of CAS >50% was 25%, CAS >70% was 12%, and carotid occlusion was 4% following RT. According to this study, 16% of patients with head and neck tumors had mild CAS on radiographs following RT, most patients with CAS also had these changes prior to treatment, and there was no difference between the three groups regarding the presence of systemic diseases. Thus, these results indicate that RT did not alter the prevalence of CAS. However, it should also be noted that the scope of this study was limited by the lack of a long-term follow-up. In studies considering the possibility that RT causes CAS, risk factors, such as arterial hypertension, DM, smoking, and advanced age may be important influencing factors.
In this retrospective study, the association between head and neck cancer treatment modalities and CAS incidence was further investigated, and this could be used to develop standardized screening and management guidelines for patients after treatment. Patients with and without CAS did not differ significantly in terms of chronic disease or age. This finding is in accordance with that of a previous study (9).
The demographic findings of these patients were consistent with those of other studies, in which patients were usually men in their fifties or seventies and diagnosed at advanced clinical stages. Considering the small sample size and retrospective nature of this study, there were many limitations, and we were unable to detect a statistically significant difference between the groups. Because the patients who received radiotherapy may have had more advanced disease, selection bias may also be present.
Digital panoramic radiographs can detect calcified atheromatous plaques in the carotid artery. Calcifications that are not always indicative of significant stenosis, may suggest significant latent carotid artery disease (8). It is likely to be challenging to treat young patients with CAS over the long term and a deeper understanding of its pathogenesis will aid in guiding treatments to improve long-term outcomes and quality of life. Evidence suggests that CAS is common after treatment for head and neck tumors, and future studies are needed to clarify the role of CAS screening in this patient population.
Conclusion
RT did not change the prevalence of CAS on panoramic radiographs and CT scans of patients with head and neck tumors during this follow-up period, but patients with these calcifications were at greater risk of developing stroke. Dental professionals should be alert to the presence of CAS on panoramic radiographs when caring for patients who have received radiation to the head and neck.
Acknowledgements
Special thanks go to the supervisor, M.D. Omid Moztarzadeh, PhD, for his guidance.
Footnotes
Authors’ Contributions
Conceptualization, O.M. and W.S.; methodology, W.S. and J.P.; validation, L.H.; formal analysis, W.S., J.P. and N.B.; investigation, O.M., M.N.S., J.P., J.G and L.H.; resources, W.S and N.B.; data curation, W.S. and O.M.; writing – original draft preparation, W.S.; writing – review and editing, O.M., L.H., and W.S.; visualization, W.S.; supervision, L.H.; project administration, O.M. and L.H.; funding acquisition, L.H. All Authors have read and agreed to the published version of the manuscript.
Conflicts of Interest
The Authors declare that they have no conflicts of interest in relation to this study.
Funding
This study was funded by the Charles University Research Fund.
- Received October 14, 2023.
- Revision received November 5, 2023.
- Accepted November 6, 2023.
- Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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