Predictors of carotid artery stenosis after radiotherapy for head and neck cancers

Article Outline

• Abstract
• Methods
  • Study subjects
  • Radiotherapy treatment
  • Ultrasound technique
  • Data analysis
• Results
• Discussion
• Author contributions
• Acknowledgment
• References
• Copyright

Objective

To study the prevalence of and risk factors associated with carotid artery stenosis (CAS) after radiotherapy (RT) for head and neck cancer.

Methods

Design of study: Prospective, cross-sectional study. Setting: Patients recruited from a hospital Radiation-Oncology department. Subjects: From March 2002 to August 2006, 290 consecutive head and neck cancer patients were enrolled in this study. One hundred ninety-two of these patients had previously undergone RT (RT group) and 98 had no RT (control group). Intervention: After detecting CAS by carotid duplex sonography, the severity of CAS was evaluated by a bilateral plaque scoring system. Main outcome measure: CAS score.

Results

There were no differences in age or gender between the two groups. The RT group had a significantly higher plaque score than the non-irradiated group (P < .05). Multiple regression analysis of the 290 head and neck cancer patients revealed that bilateral plaque score was significantly correlated with age, hyperlipidemia, and RT. Multiple regression analysis was performed in the RT group alone with patients 41-50 years old serving as the reference group. This analysis showed that in RT patients > 50 years old, age was inversely correlated with plaque score; however, in RT patients ≤ 41 years old, age was positively correlated with plaque score.

Conclusion

In head and neck cancer, the high post-treatment incidence of radiation-induced CAS indicates the importance of regular examination of the carotid duplex and early antiplatelet prophylaxis. Different age groups may require different irradiation strategies to prevent radiation-induced CAS.

Radiotherapy (RT) is a common treatment for non-metastatic head and neck cancers, and long-term survival after such therapy is relatively favorable compared with survival for other cancers,¹ especially if the head and neck cancer is nasopharyngeal. However, after irradiation, late complications such as carotid atherosclerosis, endocrine dysfunction, and temporal lobe injury can occur in such patients.², ³

Carotid artery stenosis (CAS) is one late complication reported after RT for head and neck carcinomas.⁴, ⁵ Although the extracranial carotid arteries are always included in the radiation port for this type of cancer, the factors responsible for the late effect of radiation on these large vessels have not been adequately defined.⁶, ⁷, ⁸, ⁹, ¹⁰, ¹¹, ¹²

Carotid endarterectomy has been shown in several recent large-scale studies to be efficacious for stroke prevention.¹³, ¹⁴ Although the natural history of radiation-induced CAS remains uncertain, the recent guideline for carotid endarterectomy to prevent stroke is based on the severity of carotid stenosis and not the etiology. The more severe the carotid stenosis, the higher the risk of stroke development. In view of the potential risk of thromboembolic stroke caused by significant stenosis, this study assessed the extracranial carotid arteries by color-coded duplex ultrasound and performed a cross-sectional study of the prevalence of radiation-induced CAS and its related risk factors.

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Methods 

Study subjects 

A total of 293 consecutive head and neck cancer patients were included in this prospective, cross-sectional study from the department of Radiation Oncology in Linkou Chang Gung Memorial Hospital from March 2002 to August 2006. Three patients who had a history of stroke were excluded. One hundred ninety-two patients had a history of remission of head and neck cancer after a complete course of RT (RT group). The control group was comprised of 98 head and neck cancer patients who had ultrasound examination of their carotids prior to undergoing RT. The clinical features and stroke risk factors were obtained by detailed review of medical records and were classified as follows: hypertension, taking antihypertensive medication or having blood pressure (BP) ≥ 140/90 mmHg on at least two BP determinations made on three separate days; diabetes mellitus, taking insulin or oral hypoglycemic agents, or having a plasma glucose level of ≥ 140 mg/dL after an overnight fast on two occasions; heart disease, ischemic heart disease, at least one asymptomatic coronary artery stenosis ≥ 50%, valvular heart disease, atrial fibrillation, or heart failure; smoking, mean cigarette smoking ≥ 10 cigarettes/day for at least six months prior to the examination; and alcohol consumption, mean ethyl alcohol consumption ≥ 30 gm /day for at least six months prior to the examination.

Radiotherapy treatment 

All the patients were treated by 6 megavoltage (MV) photons for large field and 10-15 MV photons for boost by conventional opposing techniques. The fraction schedule was 1800-2000 cGy per daily fraction with five fractions per week. Generally, the initial elective fields included gross tumor areas with 1.5-2 cm margins on T1 contrasted magnetic resonance imaging (MRI). The initial fields included the whole pharynx, skull base, and whole neck lymphatics by bilateral opposing portals with an anterior lower neck portal. After 4600-4680 cGy, the field was reduced to 1400 cGY, and then the field was boosted to deliver a total median value of 7060 cGy (95% range, 6840-7200 cGy) to the initial area of gross disease. All upper neck areas received at least 6000 cGy of radiation dose in those patients who completed the radiotherapy treatment.

Ultrasound technique 

The study employed a color-coded duplex ultrasonograph with ATL HDI 3000 (Bothell, Wash), which combines a 5-10 MHz real-time B-mode image and a 3.0 MHz pulsed-wave color Doppler flowmetry. The B-mode imaging system was used to acquire sagittal (anterior-posterior, posterior-anterior, lateral) and transverse views of the extracranial carotid system. The severity of carotid atherosclerosis was evaluated by two indices: maximal stenosis and plaque score.

At the site of maximal stenosis of each carotid artery, the image was magnified two-fold to measure the severity of CAS. Duplex sonographic criteria for examining carotid arteries have been described in a previous report by this research team.¹⁵ The percentage of maximum stenosis in longitudinal views was determined by computer-assisted measurement of the 1-residual lumen diameter/vessel diameter × 100. In the Doppler study, a peak systolic velocity ≥ 120 cm/sec and ≥ 250 cm/sec were considered to indicate ≥ 50% and ≥ 70% stenosis. Overall accuracy in diagnosing occlusive carotid artery disease is above 90% in this neurosonology laboratory.¹⁵, ¹⁶ Significant stenosis was defined as maximum stenosis ≥ 50%.

The plaque scoring system was adapted from the method of Sutton et al¹⁷ as follows. The right and left carotid artery systems were each was divided into five segments: proximal common carotid (≥ 20 mm proximal to bulb bifurcation), distal common carotid (< 20 mm proximal to bulb bifurcation), carotid bulb and bifurcation, internal carotid, and external carotid. Each segment was then given a grade as follows: Grade 0, normal or no detectable plaque; Grade 1, all plaques occupy < 30% of the vessel diameter; Grade 2, at least one plaque occupies 30-49% of the vessel diameter; Grade 3, at least one plaque occupies 50-69% of the vessel diameter; Grade 4, at least one plaque occupies 70-99% of the vessel diameter; Grade 5, 100% occlusion of the vessel diameter by plaque. The bilateral carotid plaque score for each patient was taken as the summation of the scores obtained from the five arterial segments in both carotids.

All duplex scanning was performed by an experienced ultrasonographer and the results were read and classified by one neurologist (CYJ) who was blinded to each subject's clinical data. Carotid duplex scanning was performed only once, before radiotherapy in the control group and after radiotherapy in the RT group.

Data analysis 

For normally-distributed continuous variables, the mean ± standard deviation were shown and the two-sample test was used to test differences between two groups. When the continuous variable was not normally distributed, the median (range) and Mann-Whitney U test were used instead. For categorical variables, the number (percentage) was presented and the Chi-square test was used to examine the association between a variable and the variable group; the Chi-square test was replaced with the Fisher exact test, when more than 20% of the data cells had an expected count of less than 5. Univariate regression analysis was used to find factors related statistically to the outcome variable – that is, the bilateral plaque score. A multiple regression model that included all factors found significant in the univariate regression analysis was then used to find independently related factors. Because all data on time interval after RT and RT dose were only available in the RT group, additional multiple logistic models were established to test the effects of age, time interval after RT, and the RT dose. The multivariate model included age, gender, hyperlipidemia, smoking, time interval after RT, and RT dose. All statistics were two-sided and calculated by SPSS software (version 15.0, SPSS Inc, Chicago, Illinois, USA). Statistical significance was defined as P < .05.

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Results 

From March 2002 to August 2006, 290 consecutive head and neck cancer patients, mean age 49.9 ± 12.0 years (range, 15.1-82 years), were enrolled in this study. As shown in Table I, the baseline characteristics of the two groups did not differ significantly, except for operation history (all P >.05). The male/female ratio and age were similar between the two groups. The RT group included 139 males and 53 females with a mean age of 49.9 years (standard deviation [SD], 11.7 years), whereas the control group included 71 males and 27 females with a mean age of 49.8 years (SD, 12.5 years). However, a higher percentage of subjects in the RT group had prior surgical treatment of their cancer (22.4% vs 8.2%, P = .003).

Table I. Characteristics of 290 head and neck cancer patients

		Radiotherapy
	Total (n = 290)	Yes (n = 192)	No (n = 98)	P
Age(years)	49.9±12.0	49.9±11.7	49.8±12.5	.917
<41	75(25.9)	50(26.0)	25(25.5)	.063
41-50	76(26.2)	43(22.4)	33(33.7)
51-60	88(30.3)	67(34.9)	21(21.4)
≥61	51(17.9)	32(16.7)	19(19.4)
Time interval after RT(years)	2.0(0.0,19.1)	2.0(0.3,19.1)	0	—
RT dose(cGY)	5600(0,7750)	6000(3600,7750)	0	—
Gender				.99
Male	210(72.4)	139(72.4)	71(72.4)
Female	80(27.6)	53(27.6)	27(27.6)
Hypertension	28(9.7)	18(9.4)	10(10.2)	.821
Diabetes mellitus	28(9.7)	17(8.9)	11(11.2)	.518
Heart disease	10(3.4)	8(4.2)	2(2.0)	.348
Hyperlipidemia	103(35.5)	73(38.0)	30(30.6)	.212
Operation history	51(17.6)	43(22.4)	8(8.2)	.003⁎
Smoking habit	82(28.3)	52(27.1)	30(30.6)	.528
Alcohol consumption	57(19.7)	38(19.8)	19(19.4)	.935
Right carotid plaque score	2(0,12)	2(0,12)	1(0,8)	<.001⁎
Left carotid plaque score	2(0,16)	2(0,16)	1(0,6)	<.001⁎
Bilateral carotid plaque score	4(0,25)	5(0,25)	1(0,12)	<.001⁎
Carotid artery stenosis (CAS)
CAS ≥ 50%	38(13.1)	38(19.8)	0(0.0)	<.001⁎
CAS ≥ 70	17(5.9)	17(8.9)	0(0.0)	.002⁎
CAS = 100%	4(1.4)	4(2.1)	0(0.0)	.150

Continuous data are presented as mean ± standard deviation or median (range); categorical data are presented as number (percentage).

RT, Radiotherapy.

The plaque score measured the extent of carotid atherosclerosis. The most severe stenosis in these carotid segments was located in the carotid bulbs and bifurcations, and plaque scores decreased rostrally and caudally to these segments (Fig 1). Plaque scores of individual patients varied widely. However, the bilateral carotid plaque score of the RT group was significantly higher than that of the control group (Table I; P < .001). A higher percentage of irradiated than non-irradiated patients was observed in each stenosis category, and significant stenosis (CAS ≥ 50%) was observed in 38 irradiated but none of the non-irradiated patients (P < .001; Table I).

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• Fig 1. 

  Distribution of plaque scores between radiotherapy (RT) and control groups (R, right; L, left; D, distal; CCA, common carotid artery; BIF, carotid bifurcation; ICA, internal carotid artery; ECA, external carotid artery).

When a univariate linear regression analysis was applied to all patients (Table II), the bilateral plaque score (an index of atherosclerosis) was significantly correlated with RT use, RT dose, length of time after RT, hyperlipidemia, and age. All parameters except age were positively associated with plaque score (P = .018 for hyperlipidemia, P < .01 for the others). In contrast, comparing to the patients aged 41-50 years old, higher plaque score as observed in patients ≤ 41 years old, but similar score was found in patients > 50 years old. When multiple linear regression analysis was applied to all patients (n = 290), plaque score remained positively correlated with RT use; furthermore, in patients > 50 years old, the positive correlation between age and plaque score was revealed (all P < .05; Table III). However, the interaction term consisting of age and RT was also significantly correlated with plaque score (P < .001), it was apparent the effect of age on plaque score was not the same in subjects with and without RT. The interaction between plaque score and age is shown in Fig 2. The bilateral plaque score increased with age in the non-RT group but decreased with age in the RT group.

Table II. Univariate regression analysis of bilateral plaque score for 290 subjects^†

Variables	Beta	95% confidence interval	P
Radiotherapy
No	Ref	—	—
Yes	3.625	(2.517,4.734)	<.001⁎
Age (years)
<41	2.046	(0.517,3.576)	.009⁎
41-50	Ref	—	—
51-60	−0.305	(−1.776,1.166)	.648
≥61	−0.016	(−1.717,1.684)	.985
Time interval after RT (years)	0.566	(0.439,0.693)	<.001⁎
RT dose (cGy)	0.001	(0.000,0.001)	<.001⁎
Gender
Male	Ref	—	—
Female	−0.985	(−2.245,0.254)	.118
Hypertension
No	Ref	—	—
Yes	1.748	(−0.140,3.636)	.069
Diabetes mellitus
No	Ref	—	—
Yes	1.392	(−0.500,3.285)	.149
Heart disease
No	Ref	—	—
Yes	1.429	(−1.641,4.549)	.360
Hyperlipdemia
No	Ref	—	—
Yes	1.403	(0.242,2.564)	.018⁎
Operation history
No	Ref	—	—
Yes	−0.736	(−2.207,0.734)	.325
Smoking habit4
No	Ref	—	—
Yes	−0.621	(−1.864,0.623)	.327
Alcohol consumption4
No	Ref	—	—
Yes	−1.211	(−2.616,0.193)	.091

RT, Radiotherapy.

Table III. Multiple regression analysis of bilateral carotid score for 290 subjects^†

Variables	Beta	95% confidence interval	P
Radiotherapy
No	Ref	—	—
Yes	10.120	(7.984,12.856)	<.001⁎
Age (years)
<41	5.962	(3.982,7.943)	<.001⁎
41-50	Ref		—
51-60	8.276	(4.918,11.633)	<.001⁎
≥61	13.424	(8.636,18.212)	<.001⁎
Age⁎radiotherapy	−2.894	(−3.837,−1.950)	<.001⁎
Gender
Male	Ref	—	—
Female	−1.101	(−2.250,0.048)	.060
Hyperlipdemia
No	Ref	—	—
Yes	0.942	(−0.072,1.957)	.068
Smoking
No	Ref	—	—
Yes	−0.778	(−1.927,0.371)	.183

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• Fig 2. 

  Bilateral plaque scores for different age groups of the radiotherapy (RT) and control groups.

Because of the interaction between age and RT therapy on plaque score, multiple linear regression analysis was performed separately for the RT and the non-RT groups. As shown in Table IV, the effect of age on the degree of carotid stenosis in the RT group was opposite to its effect in the non-RT group. When the subjects who were 41-50 years old were used as the reference group, the bilateral carotid plaque scores of subjects > 51 years decreased in the RT group but increased in the non-RT group (all P < .05). In other words, if no radiotherapy was performed, the amount of plaque increased with age relative to subjects in the 41-50 year age range; however, in patients who had radiotherapy, the amount of plaque decreased with age. This relationship was reversed in younger subjects; plaque score was positively correlated with age in subjects ≤ 41 years old in patients with RT.

Table IV. Multiple regression analysis of bilateral carotid score for patients with and without radiotherapy^†

Variables	Radiation
	Yes (n = 198)	No (n = 92)
	Beta(95% confidence interval)	Beta(95% confidence interval)
Age
<41	3.349(1.563,7.378)⁎	−0.535(−1.695,0.624)
41-50	Ref	Ref
51-60	−2.459(−4.134,−0.784)⁎	3.315(2.061,4.570)⁎
≥61	−2.080(−43.112,−0.049)⁎	3.862(2.579,5.145)⁎
Gender
Male	Ref	Ref
Female	−1.940(−3.380,−0.500)⁎	−0.315(−1.399,0.768)
Hyperlipdemia
No	Ref	Ref
Yes	0.058(−1.210,1.326)	0.812(−0.2173,1.797)
Smoking
No	Ref	Ref
Yes	0.195(−1.298,1.689)	−0.009(−1.0751.057)
Time interval after RT	0.438(0.273,0.602)⁎	—
RT dose	0.001(0.000,0.001)	—

RT, Radiotherapy.

Dash indicates the variable was not included in the model.

For the patients with RT, two other factors (gender and time interval after RT) were significantly correlated with the bilateral plaque score. Female subjects had lower scores compared with male subjects (P = .005); and the plaque score increased as the time interval increased (P < .001).

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Discussion 

The most interesting finding in this study was the difference between younger and older patients in the way their carotid arteries reacted to irradiation. In general, the other findings were similar to those reported previously.

One concern in any clinical study is that the controls match the subjects as closely as possible in order to avoid possible selection bias. In previous studies, age-matched patients without nasopharyngeal cancer¹⁸, ¹⁹, ²⁰ or nasopharyngeal cancer patients not yet treated with radiation, but not age-matched to the study subjects²¹ were used as control groups. Since we enrolled consecutive patients, it was not possible to match the age and gender of the RT and control groups. However, there was no significant difference in age or gender between the two groups, which should reduce a potential source of bias.

Our study, like previous studies,¹, ⁴, ⁵, ¹⁸, ¹⁹, ²¹ showed an increase in CAS in head and neck cancer patients after treatment with radiation, and that CAS increased as the radiation dose and the time interval after RT increased or if hyperlipidemia were present. Our study differed from other studies¹, ¹⁸, ¹⁹ in that it did not show a statistically significant association of the known cardiovascular vascular risk factors with the severity of CAS. However, the average age of our patients was only 49 years, and the majority of the subjects did not have any of the risk factors on which we collected data.

Three possible mechanisms of chronic post-radiation effects on medium and large arteries have been identified: 1) fibrosis due to a damaged vaso vasorum, 2) adventitial fibrosis producing obstruction, and 3) accelerated atherosclerosis.²² In our irradiated group, for any CAS grade, the summation of plaque scores for the bilateral carotid systems and the frequency of occurrence of CAS in more than one artery segment (158; 82.3%) was significantly higher in the irradiated than in the control group. The distribution of stenosis, with the highest plaque score at the carotid bifurcations (Fig 1), was similar to that seen in atherosclerosis. However, the stenosis was more widespread (more than two plaques, 82.3%; P < .001) in the RT patients than that seen in patients with uncomplicated atherosclerosis.

Our study (without gender stratification) showed a positive correlation between radiation dose and total plaque score that was compatible with previous reports, indicating that the dose of external neck irradiation can affect the severity and extent of radiation vasculopathy.²⁰, ²¹ Carmody et al²⁰ and Lam et al²¹ reported a higher percentage of significant stenosis (70%-90% and ≥ 50% stenosis, respectively) in the RT group (21.7% vs. 4% and 77.5% vs. 14.3%, respectively) with mean radiation dose of approximately 6000 cGy. Irradiation dosages (6225 cGy) in our study were similar to those in their reports²⁰, ²¹ and also resulted in significant CAS (2.1% had complete occlusion, 8.9% ≥ 70%, and 19.8% ≥ 50% stenosis) in RT patients. The variation in reported incidence of CAS in the three studies might be due to different intervals between irradiation and examination (4.9 years in the present study versus 6.5 years in studies by Carmody et al²⁰ and 9.2 years in a study by Lam et al²¹). Extracranial carotid disease is more common in elderly persons.²³ In the USA, an estimated five per 1000 persons aged 50-60 years and approximately 10% of persons older than 80 years have carotid stenosis greater than 50%.²³ In a study by Lam et al, the patients receiving ultrasound examination were relatively young, and there was a only 4.4-year age difference between the RT group (53.6 years) and the control group (48.8 years).²¹ Thus, the most likely cause of the higher incidence of CAS in the RT group in that study was the 9.2 year interval from irradiation to examination, compared with an interval of only 4.9 years in the present study.

Reports on the incidence of stroke after RT for head and neck cancer vary. In a study by Elerding et al,⁴ the incidence of stroke was not significantly higher than the expected incidence in a matched population observed over the same time period (63 vs. 38, n = 910; P = .39). Cheng et al¹⁸, ¹⁹ reported 67% of patients with irradiation-induced stenosis ≥ 70% to have experienced a stroke or transient ischemic attack. In the present study, only two patients had a stroke history after RT. This low incidence may have been due both to the regular follow-up of most patients at the department of radiation oncology and neurology, and to the fact that prophylactic antiplatelet agents are routinely given for those with significant carotid stenosis. A low incidence of stroke was also noted by Lam et al²¹ in their study, which observed only one patient with a stroke history. This low frequency of stroke demonstrates the importance of routine screening by noninvasive imaging and early prophylactic treatment according to the CAS risk progression as shown in Table IV.

Cheng et al found an association between CAS ≥ 70% and age ≥ 60 years, a history of cerebrovascular symptoms, previous irradiation for nasopharyngeal carcinoma or laryngeal cancer, and a time interval ≥ 5 years after RT.¹⁸ They also observed that in patients ≥ 60 years, there was a three-fold increase in the risk of CAS ≥ 70% and noted that irradiation itself was the most important factor in developing CAS. Findings consistent with these were reported in subsequent studies by Lam et al,²¹ Cheng et al,¹⁹ and in an animal study by Close et al.²⁴ The current results confirmed that time interval after RT and RT dose are causal factors in the development and progression of CAS.

In our study population, age was negatively related to plaque score, that is, patients older than the reference group developed a less severe atherosclerotic response to carotid artery irradiation than this group. However, the group younger (< 41 years) than the reference group had a more severe atherosclerotic response to irradiation than the reference group. Additionally, RT had a significantly smaller effect on stenosis in women than men. The age cut-off in this study was approximately that of the onset of menopause, so it is possible that some hormonal influence might explain the results. Also, the change in arteries seen after irradiation in animal studies is one of fibrosis, the body's repair response to tissue damage. The wound repair process slows with advancing age, and is possible that age-related changes in wound repair might explain some of our data. Further experiments, of course, are necessary to identify the precise mechanisms for the effect of age and gender on CAS after RT.

The high incidence of radiation-induced CAS in head and neck cancers indicates the importance of regular carotid duplex examination and early antiplatelet prophylaxis in patients with significant CAS (≥ 50% stenosis). Different age groups may require different radiation strategies to prevent radiation-induced CAS. Longitudinal and genetic studies may be necessary to document the progression and to develop appropriate follow-up and therapeutic strategies.

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Author contributions 

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The authors would like to thank Miss Shu-Ching Wang for her patience and time spent performing the carotid duplex examinations in these patients.

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