
==== Front
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Radiother Oncol
Radiother Oncol
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology
0167-8140
1879-0887

38467343
10.1016/j.radonc.2024.110220
nihpa2016221
Article
Longitudinal changes in the carotid arteries of head and neck cancer patients following radiation therapy: Results from a prospective serial imaging biomarker characterization study
Koutroumpakis Efstratios a
Mohamed Abdallah Sherif Radwan b
Chaftari Peter a
Rosenthal David I. b
Gujral Dorothy c
Nutting Christopher c
Kamel Serageldin b
Naser Mohamed A. b
Kim Peter a
Bassett Roland d
Fuller Clifton D. b*1
Mouhayar Elie a*1
MD Anderson Head Neck Radiation Oncology Cardiovascular Working Group
a Department of Cardiology, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
b Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
c The Royal Marsden NHS Foundation, London, United Kingdom
d Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
1 The 2 senior authors contributed equally.

* Corresponding authors at: Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA (C.D. Fuller). Department of Cardiology, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd # 1451, Houston, TX 77030, USA (E. Mouhayar). cdfuller@mdanderson.org (C.D. Fuller), emouhayar@mdanderson.org (E. Mouhayar).
23 8 2024
6 2024
11 3 2024
07 9 2024
195 110220110220
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (https://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction:

We prospectively evaluated morphologic and functional changes in the carotid arteries of patients treated with unilateral neck radiation therapy (RT) for head and neck cancer.

Methods:

Bilateral carotid artery duplex studies were performed at 0, 3, 6, 12, 18 months and 2, 3, 4, and 5 years following RT. Intima media thickness (IMT); global and regional circumferential, as well as radial strain, arterial elasticity, stiffness, and distensibility were calculated.

Results:

Thirty-eight patients were included. A significant difference in the IMT from baseline between irradiated and unirradiated carotid arteries was detected at 18 months (median, 0.073 mm vs −0.003 mm; P = 0.014) which increased at 3 and 4 years (0.128 mm vs 0.013 mm, P = 0.016, and 0.177 mm vs 0.023 mm, P = 0.0002 respectively). A significant transient change was noted in global circumferential strain between the irradiated and unirradiated arteries at 6 months (median difference, −0.89, P = 0.023), which did not persist. No significant differences were detected in the other measures of elasticity, stiffness, and distensibility.

Conclusions:

Functional and morphologic changes of the carotid arteries detected by carotid ultrasound, such as changes in global circumferential strain at 6 months and carotid IMT at 18 months, may be useful for the early detection of radiation-induced carotid artery injury, can guide future research aiming to mitigate carotid artery stenosis, and should be considered for clinical surveillance survivorship recommendations after head and neck RT.

Intima media thickness
Radiation induced carotid artery disease
Head and neck cancer
Radiation therapy
Vascular strain
==== Body
pmcIntroduction

Radiation therapy (RT) is an integral part of the treatment of head and neck cancer [1]. Most patients require treatment to the cervical lymph nodes adjacent to the carotid arteries, which most often cannot be excluded from the RT volume. This increases the risk for accelerated atherosclerosis, carotid artery stenosis and subsequent transient ischemic attack (TIA) and cerebrovascular accident (CVA) [2,3]. The long latent interval of several years from RT to the development of carotid artery stenosis makes it difficult to identify patients who will develop adverse outcomes [4,5].

In patients exposed to head and neck RT, increased common carotid artery (CCA) intimal medial thickness (IMT) correlates well with the degree of subsequent carotid artery stenosis [6–10]. The earliest timepoint that significant changes in IMT can be identified after RT has not been well studied. Furthermore, RT has also been associated with early vascular physiologic changes, including altered arterial elasticity. However, altered vascular elasticity is difficult to assess clinically. Imaging of vascular deformation with speckle tracking software, also known as strain, has been suggested as a good surrogate for the assessment of carotid artery elasticity [11–13].

The prespecified, primary aim of this prospective study was to evaluate IMT changes at 12 months after unilateral neck RT for head and neck cancer, between irradiated and unirradiated carotid arteries. Secondary endpoints included IMT changes at 3,6, 18 months and 2,3,4 and 5 years, as well as changes in vascular strain, elasticity, stiffness, and distensibility.

Methods

Patient population

Adult patients (age ≥ 18 years) with histologically confirmed head and neck cancer, scheduled to undergo ≥ 50 Gy unilateral neck RT at The University of Texas MD Anderson Cancer Center between February 2015 and February 2017 were enrolled. One patient had a history of prior carotid endarterectomy upon screening and was excluded. The study was approved by the Institutional Research Board of MD Anderson (ClinicalTrials.gov Identifier: NCT02069964). Demographic and clinical characteristics were prospectively collected prior to patients’ first RT. RT doses reported in this manuscript represent prescribed doses. Prescribed dose was defined as the prescription isodose for the involved neck. Tumor, nodes and carotid arteries were segmented regions of interest on the radiation planning CT scan and dose to tumor, nodes and carotid arteries was extracted from the treatment planning system (Pinnacle).

Carotid duplex

2D ultrasound and Doppler images of bilateral carotid arteries were captured at baseline and at predefined follow-up timepoints: 3, 6, 12, 18 months and 2, 3, 4, and 5 years following the initial RT and interpreted following the Society of Radiologists in Ultrasound consensus conference guidelines [14]. All images were captured using Philips ultrasound machines.

IMT was determined offline using a semi-automated technique, with far wall measurements taken at a B-mode longitudinal view of the posterior wall of the CCA, 2 cm proximal from the carotid bifurcation and away from any atherosclerotic plaques; the results were averaged over 3 readings on a magnified image (Fig. 1). Two-dimensional long- and short-axis gray-scale cine loops of the CCA were acquired for speckle tracking and strain analysis. An offline strain analysis was performed using a workstation equipped with 2-D strain software (EchoPac 7.0, GE Vingmed Ultrasound). Global and peak circumferential as well as radial peak systolic strain were measured in both carotid arteries for each patient (Fig. 2). Additional information on carotid duplex methodology and measurements as well as formulas assessing arterial elasticity, stiffness, and distensibility are outlined in the Supplementary Material. All studies were interpreted by a cardiologist expert in carotid duplex interpretation who was blinded to the patient’s medical history and treatment.

Endpoints

The primary endpoint of the study was the change in carotid IMT 12 months after RT between irradiated and unirradiated carotid arteries. Secondary endpoints included i. the change in carotid IMT at 3, 6, 18 months and 2, 3, 4, and 5 years ii. The change in carotid arterial wall strain (global and regional peak systolic circumferential and radial strain) and other measures of arterial elasticity, stiffness, and distensibility following RT between irradiated and unirradiated carotid arteries at the predefined follow up-timepoints; and iii. The incidence of atherosclerotic plaques, ≥ 50 % carotid artery stenosis, TIA/CVA, or need for revascularization in irradiated vs. unirradiated carotid arteries.

Statistical analysis

The sample size was originally estimated to be 45 patients based on the results of a study by Dorresteijn et al (using a paired t test with mean difference of 0.3, standard deviation of 0.7, significance level (α) of 0.05 and 80 % power) [9]. Although we had aimed to recruit a total of 60 patients to account for dropouts, relapses, and requirement for treatment to the unirradiated side, unexpected issues related to COVID-19 pandemic allowed us to enroll only 46 patients, out of which 38 had at least one follow up assessment and were included in the analysis. Continuous variables were summarized as mean values +/− standard deviation (SD) or median values and interquartile ranges. Categorical variables are presented as frequencies and percentages. Categorical variables were compared between groups using Fisher’s exact test, and continuous variables were compared using the Wilcoxon rank-sum test.

The IMT change of the irradiated carotid artery was compared with the IMT change of the unirradiated carotid artery using a Wilcoxon rank-sum test. This test was also used to compare changes in strain and other measures of elasticity, stiffness, and distensibility from baseline, between irradiated and unirradiated arteries. All statistical analyses were performed using R version 4.2.2 at a significance level of 5 %. No adjustments for multiple testing of the secondary endpoints were made because they are highly correlated within patient for two reasons: 1) multiple testing of the change from baseline for a single parameter and 2) the derivation of strain evaluation from the IMT changes.

Results

A total of 46 patients were enrolled, 38 of whom were included in the analysis (Supplement Fig. 1). The median patient age was 60 years (IQR 52.5,65.8); 40 % of patients were female, and all were white. The median BMI was 30.1 (25.5,34.9) kg/m2. Former or current tobacco use was reported in 43 % of patients, while 34 % were treated for hypertension, 11 % for diabetes mellitus; statins were used by 37 % and aspirin by 29 %. Twenty one percent of patients did not have lymph node involvement and were treated with 50–56 Gy of RT at a median of 30 fractions, while 79 % had lymph node involvement requiring a higher RT dose (66–70 Gy at a median of 33 fractions). RT was delivered to the left side of the neck in 70 % and the right side in 30 % of patients. The median total radiation dose was 60 Gy (60,66), delivered at a median of 30 fractions (IQR 30,30). The maximum dose delivered to the carotid artery was 60 Gy (IQR 60,66), and the mean dose was 58.1 Gy (57, 59.6). Eight percent of patients received induction and 39 % concurrent chemotherapy. Additional demographic and clinical characteristics are presented in Table 1. Serial ultrasonographic evaluations were performed, with 95 % of patients completing the 3- and 6-month follow up evaluation, 87 % the 12-month, 89 % the 18-month, 84 % the 2-year, 76 % the 3-year, 55 % the 4-year, and 18 % the 5-year (the 4- and 5-year follow-up were mostly impacted by COVID-19 restrictions; Supplement Fig. 1).

The 12-month IMT change from baseline between irradiated and unirradiated carotid arteries was not significantly different (median change, 0.007 vs 0.003 mm; P = 0.88). A significant IMT change was detected at 18 months (median change, 0.073 vs −0.003 mm; P = 0.014). The difference remained significant and increased at 3 and 4 years (0.128 vs 0.013 mm, P = 0.016, and 1.777 vs 0.023 mm, P = 0.0002, respectively; Table 2, Fig. 3).

Changes from baseline in the peak radial, as well as peak and global circumferential strains for the irradiated and unirradiated carotid arteries over time are presented in Table 3. A significant difference was noted in the change in the global circumferential strain from baseline between the irradiated and unirradiated carotid arteries at 6 months (median difference = −0.89, P = 0.023), which did not persist in follow-up studies (Supplementary Fig. 2). The rest of the measurements were not different between the 2 groups.

No significant changes in other measures of elasticity, stiffness, and distensibility between the irradiated and unirradiated arteries over time were detected (Supplementary Table 2).

Seven patients developed evidence of new atherosclerotic plaques on the irradiated side at a median of 12 months, compared to 5 on the unirradiated side at a median of 18 months (P = 0.74; 3 of these patients developed new atherosclerotic plaques on both the irradiated and unirradiated sides). All 7 patients had developed evidence of new atherosclerotic plaque by the second year of follow up (7/32 patients, 22 %). Of these, 2 patients developed ≥ 50 % carotid stenosis on the irradiated side at 1 year follow up (2/33, 6 %) vs 1 patient on the unirradiated side at 4 years. The patients who developed ≥ 50 % stenosis had no atherosclerotic plaques at baseline. One patient (3 %) out of those with ≥ 50 % stenosis, experienced a CVA on the side of the irradiated carotid artery, and was treated with revascularization and medical therapy. No patients experienced a TIA or CVA on the side of the unirradiated carotid artery. All patients who developed new atherosclerotic plaques, with or without ≥ 50 % stenosis on the irradiated side were males compared to the patients who did not develop new atherosclerotic plaques on the same side (100 % vs 51.6 %; P = 0.03). Otherwise, no significant differences in the demographic and clinical characteristics were noted between the 2 groups (Table 1).

Discussion

This prospective study evaluated longitudinal changes in carotid artery morphology and functional characteristics using traditional and novel techniques (carotid IMT, carotid arterial wall stain, and other measures of elasticity, stiffness, and distensibility) at baseline and following unilateral neck irradiation for head and neck cancer. Even though, the prespecified, primary endpoint was not statistically significant, we did find significant changes in carotid IMT after the 18-month timepoint. Furthermore, significant changes in global circumferential strain were detected 6 months after RT. One in 5 patients developed new atherosclerotic plaques in the irradiated carotid artery at a median of 2 years.

The traditionally expected latent period separating initial radiation-induced vascular injury and subsequent development of clinical cardiovascular complications makes the investigation of radiation-induced vascular diseases challenging. In our study, 7 patients (22 %) had already developed evidence of new atherosclerotic plaque by the second year of follow up, out of which 2 (6 %) had developed ≥ 50 % carotid stenosis on the irradiated side by 1 year, and one of those two experienced a CVA. This finding suggests that a portion of patients exposed to neck RT develop carotid artery disease much earlier than what we traditionally believed, highlighting the need for earlier screening.

RT has been shown to be associated with early morphologic vascular changes, such as increased IMT [15]. A recent systematic review by Randolph et al. identified a total of 8 studies published after 2010, 4 of which were prospective, that evaluated carotid IMT change after RT [16]. All 8 studies showed significant increases in carotid IMT after neck irradiation [16]. Three of the 4 prospective studies, included patients who underwent bilateral neck irradiation and reported a significant IMT increase from baseline as early as 6 weeks after RT (sample size, 19–50 patients) [17–19]. The fourth prospective study by Wilbers et al. compared IMT changes between irradiated and unirradiated carotid arteries among 48 patients and reported a 5 times larger increase in IMT in the irradiated carotid artery at a median follow-up of 6.7 years [20]. Compared to the above-mentioned prospective studies, ours is the first that longitudinally compared IMT changes in the irradiated versus the unirradiated carotid arteries at multiple, frequent time points in patients who underwent unilateral neck RT. Compared to previous studies that used patients without cancer as control, our study used the contralateral, unirradiated carotid artery to control for baseline comorbidities and confounders that might have biased the results when patients with cancer were compared to patients without cancer. Furthermore, compared to previous studies with a single follow-up or a few short-term follow-up time points, our study included multiple serial assessments (from 3 months to 5 years after RT). We found a significant IMT increase in the irradiated compared to the unirradiated carotid artery as early as 18 months after RT, which persisted at 2, 3 and 4 years. At 5 years, the IMT change from baseline was 7.5 times higher in the irradiated carotid artery than in the unirradiated artery, which is in line with the results of the study by Wilbers et al. [20].

Other than the early morphologic vascular changes, RT has also been associated with vascular physiologic changes, including altered arterial elasticity [15]. In our prospective study, a significant difference was noted in the global circumferential strain between the irradiated and unirradiated carotid arteries at 6 months, which did not persist in follow-up studies. This difference might be related to subacute transient inflammatory changes that affect vascular tissue deformation and subsequently resolve or stabilize. This finding needs to be further tested in larger studies.

Traditional measures of elasticity, stiffness, and distensibility, although laborious to obtain and reproduce, have been used in previous studies to assess functional changes after RT. A retrospective study by Gujral et al. assessed elasticity (elastic modulus) and stiffness (beta stiffness index [β]) in 50 patients with head and neck cancer, ≥ 2 years after unilateral neck RT. The authors reported significant changes in elastic modulus but no significant changes in the beta stiffness index [21]. In our study, no significant differences were detected in the carotid artery elasticity, stiffness, and distensibility, between the irradiated and unirradiated arteries over time, suggesting that these measures are not sensitive enough to detect early changes in radiation-related carotid artery disease.

Several studies have shown that patients treated with neck RT are at increased risk of developing carotid artery stenosis. In a recent meta-analysis of 19 studies, carotid stenosis of ≥ 50 % was reported in 4 % (95 % CI: 2 %-5%) of patients after 1 year, 12 % (95 % CI: 9 %-15 %) after 2 years, and 21 % (95 % CI: 9 %-36 %) after 3 years from RT. In our cohort, 22 % of patients developed evidence of new atherosclerotic plaques at 2 years and 6 % developed ≥ 50 % carotid stenosis at 1 year follow up, with no additional patients developing stenosis in the years 2–4. All patients who developed ≥ 50 % stenosis had no atherosclerotic plaques at baseline. The differences in the reported incidence rates between our study and the meta-analysis could be attributed to several reasons. First, most studies included in the meta-analysis are retrospective and inherent to selection bias that might have led to falsely high reported rates of carotid stenosis. Additionally, many patients included in the meta-analysis were treated with bilateral RT and were not screened to rule out the presence of atherosclerotic plaques at baseline, which might have accounted for the higher reported incidence rates. Finally, the small sample size of our study and the relatively high dropout rate related to the COVID19 pandemic might have contributed.

Importantly, all patients who developed ≥ 50 % carotid stenosis in our cohort had the stenosis developed at 1 year follow up, with no additional patients developing stenosis in the years 2–4.This might indicate that there are two categories of patients who develop carotid artery disease following RT; the first category includes those with hyper-acute accelerated atherosclerosis with development of ≥ 50 % stenosis within 1 year of follow up; and the second category includes patients with slower progression of atherosclerosis following RT. Additionally, we noted that 1 patient developed > 50 % carotid stenosis on the unirradiated side at 4 years. This indicates that the contralateral carotid artery of patients with head and neck cancer treated with RT can still be injured and develop atherosclerosis, though at a lower incidence rate and a slower pace. This is in line with a recent paper by Carpenter et al., which reported that even though the contralateral carotid artery is outside the target volumes designated to receive the full prescribed radiation dose, it may still receive a nonnegligible radiation dose of 10 Gy or greater, which was significantly associated with development of carotid artery stenosis [22].

This study has several limitations, the main one being the small sample size. Follow up was affected by the restrictions that the COVID-19 pandemic posed during the 4th and 5th year. Despite the small sample size, we were still able to obtain multiple serial ultrasonographic measurements and detect the findings reported above. All patients in our study were white, which did not allow for an assessment of racial differences, and patients were not followed up past 5 years after RT. This relatively brief follow-up period and the subsequent small number of clinical outcomes in our cohort (carotid stenosis, TIA/CVA, or need for revascularization) did not allow us to make correlations between the increased IMT noted at 18 months and the subsequent development of clinically significant stenosis. Despite the above limitations, our study is one of the few prospective studies with serial carotid imaging at frequent time intervals which strengthens the value of our findings. Larger prospective studies are needed to confirm our results.

In conclusion, alterations in the functional and morphologic characteristics of the carotid arteries following exposure to RT include significant early changes in global circumferential strain at 6 months and carotid IMT at 18 months.

Supplementary Material

Supplementary data 1

Supplementary figure 1

Supplementary data 2

pplementary figure 2

Acknowledgements

The authors would like to acknowledge the team of Editing Services, Research Medical Library at MD Anderson Cancer Center for their help with editing the manuscript.

Fig. 1. Intima Media Thickness measurements at the longitudinal view of the posterior wall of the CCA, 2 cm proximal from the carotid bifurcation and away from any atherosclerotic plaques; the results were averaged over 3 readings on a magnified image.

Fig. 2. Measurement of circumferential global (dotted line) and regional (solid line) peak systolic strain (top) as well as radial peak systolic strain (bottom) using the speckle-tracking based strain analysis of the EchoPac 7.0, GE Vingmed Ultrasound.

Fig. 3. Median change in intima-media thickness (IMT) from baseline over time between irradiated and unirradiated carotid arteries.

Table 1 Demographic and clinical characteristics of patients based on whether they developed the composite outcome of development of atherosclerotic plaques, ≥ 50 % stenosis, TIA/CVA, or need for revascularization in the irradiated carotid artery.

	Total (n = 38)	Development of new plaques on the irradiated side (n = 7)	No new plaques on the irradiated side (n = 31)	P value	
	
Age, mean (SD), yrs	59.1 (12.5)	63.0 (6.3)	58.2 (13.4)	0.31	
Female sex, n (%)	15 (39.5)	0 (0)	15 (48.4)	0.03	
White race, n (%)	38 (100)	7 (100)	31 (100)	1.00	
BMI, mean (SD), kg/m2	30.4 (6.1)	31.1 (7.0)	30.2 (6.0)	0.73	
Smoking pack- years, mean (SD)	25.0 (28.3)	21.5 (18.5)	26.0 (31.1)	0.94	
ACE inhibitors, n (%)	6 (16.7)	0 (0)	6 (19.4)	0.56	
Other anti-hypertensive	13 (34.2)	2 (28.6)	11 (35.5)	1.00	
therapy used, n (%)					
Anti-diabetic therapy used, n (%)	4 (10.8)	1 (14.3)	3 (10.0)	1.00	
Statins, n (%)	14 (36.8)	3 (42.9)	11 (35.5)	1.00	
Aspirin, n (%)	11 (28.9)	3 (42.9)	8 (25.8)	0.39	
Diuretics, n (%)	7 (18.4)	1 (14.3)	6 (19.4)	1.00	
Hemoglobin, mean (SD), g/dL	13.0 (2.2)	14.1 (1.5)	12.7 (2.3)	0.11	
Creatinine, mean (SD), mg/dL	0.8 (0.2)	0.9 (0.2)	0.8 (0.2)	0.24	
Albumin, mean (SD), g/dL	4.9 (4.3)	4.2 (0.5)	5.1 (4.8)	0.86	
Glucose, mean (SD), mg/dL	105.8 (25.4)	104.4 (31.1)	106.1 (24.5)	0.84	
Cholesterol, mean (SD), mg/dL	183.3 (49.4)	186.4 (45.4)	182.6 (50.9)	0.65	
LDL, mean (SD), mg/dL	99.8 (43.4)	106.4 (38.1)	98.3 (44.9)	0.60	
HDL, mean (SD), mg/dL	50.9 (14.7)	48.1 (16.3)	51.5 (14.5)	0.36	
Grade of tumor differentiation, n (%)*					
 Well	3 (13.0)	2 (40.0)	1 (5.6)		
 Moderate	11 (47.8)	1 (20.0)	10 (55.6)		
 Poorly	9 (39.1)	2 (40.0)	7 (38.9)		
Nodal sites, n (%)*					
 I	3 (13.0)	0 (0)	3 (17.6)		
 II	11 (47.8)	3 (50)	8 (47.1)		
 III	2 (8.7)	0 (0)	2 (11.8)		
 IV	1 (4.3)	1 (16.7)	0 (0)		
 None	6 (26.1)	2 (33.3)	4 (23.5)		
Side treated, n (%)					
 Left	26 (68.4)	6 (85.7)	20 (64.5)		
 Right	12 (31.5)	1 (14.3)	11 (35.4)		
Dose to tumor, mean (SD), Gy	62.8 (3.7)	60.9 (2.3)	63.3 (3.8)		
Number of fractions to tumor, mean (SD)	30.7 (1.4)	30.0 (0)	30.9 (1.5)		
Dose to neck nodes, mean (SD), Gy	61.2 (4.1)	59.1 (1.5)	61.7 (4.5)		
Number of fractions to nodes, mean (SD)	30.7 (1.4)	30 (0)	30.9 (1.5)		
Mean carotid artery dose, mean (SD), Gy	58.1 (4.2)	55.6 (6.2)	58.8 (3.3)		
Max carotid artery dose, mean (SD), Gy	63.4 (5.6)	62.6 (5.3)	63.6 (5.8)		
Chemotherapy, n (%)					
 Induction	3 (8.1 %)	0 (0)	3 (10)		
 Concurrent	14 (38.9)	3 (42.9)	11 (37.9)		
* Available data in 23 patients.

Table 2 Median intima-media thickness (IMT) change from baseline between unirradiated and irradiated carotid arteries; differences were significant at 18 months and later.

Time	No. of patients	Median change: unirradiated artery	Median change: irradiated artery	P value	
	
3 months	36	0.000	0.003	0.84	
6 months	36	0.005	0.008	0.72	
12 months	33	0.003	0.007	0.88	
18 months	34	−0.003	0.073	0.014	
2 years	32	0.023	0.048	0.013	
3 years	29	0.013	0.128	0.016	
4 years	21	0.023	0.177	0.0002	
5 years	7	0.020	0.17	0.078	

Table 3 Comparison of differences in peak radial, peak circumferential, and global circumferential strain between irradiated and unirradiated carotid arteries over time.

Time	Measurement	Median difference between irradiated and unirradiated carotid arteries	P value	
	
3 months	Peak Radial	−0.12	0.23	
	Peak Circumferential	1.34	0.61	
	Global Circumferential	−0.68	0.37	
6 months	Peak Radial	−4.05	0.062	
	Peak Circumferential	−3.10	0.32	
	Global Circumferential	−0.89	0.023	
12 months	Peak Radial	−4.53	0.09	
	Peak Circumferential	−4.37	0.35	
	Global Circumferential	−1.09	0.40	
18 months	Peak Radial	−1.60	0.43	
	Peak Circumferential	−1.01	0.75	
	Global Circumferential	−0.53	0.46	
2 years	Peak Radial	−2.99	0.065	
	Peak Circumferential	−0.16	0.92	
	Global Circumferential	−0.76	0.17	
3 years	Peak Radial	−3.16	0.41	
	Peak Circumferential	0.41	0.78	
	Global Circumferential	−0.66	0.29	
4 years	Peak Radial	−1.76	0.14	
	Peak Circumferential	−1.61	0.52	
	Global Circumferential	−0.12	0.89	
5 years	Peak Radial	3.58	0.47	
	Peak Circumferential	−6.22	0.16	
	Global Circumferential	0.93	0.38	

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The statistical analysis was supported in part by the NIH/NCI Cancer Center Support Grant (award number P30 CA016672) and used the Biostatistics Resource Group. EK is supported in part by NIH/NCI 1R01 HL157273 and CPRIT RP200381 both of which are not related to the current work. Dr. Fuller has received unrelated grants/honoraria from Elekta AB, has received travel support from Philips Medical Systems, and has served in an advisory capacity for Siemens Healthineers.

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.radonc.2024.110220.

CRediT authorship contribution statement

Efstratios Koutroumpakis: Data curation, Writing – original draft, Visualization. Abdallah Sherif Radwan Mohamed: Data curation, Writing – review & editing. Peter Chaftari: Data curation, Writing – review & editing. David I. Rosenthal: Writing – review & editing. Dorothy Gujral: Conceptualization, Methodology, Writing – review & editing. Christopher Nutting: Conceptualization, Methodology, Writing – review & editing. Serageldin Kamel: Data curation, Writing – review & editing. Mohamed A. Naser: Data curation, Writing – review & editing. Peter Kim: Data curation, Writing – review & editing. Roland Bassett: Formal analysis, Writing – review & editing. Clifton D. Fuller: Conceptualization, Methodology, Project administration, Writing – review & editing. Elie Mouhayar: Conceptualization, Methodology, Project administration, Supervision, Writing – review & editing.
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