Academic Editors: Fabrizio D’Ascenzo and Dimitrios Farmakis
Head and neck cancer (HNC) shares some risk factors with cardiovascular disease.
Neck radiotherapy (RT) causes carotid artery injury and stenosis. In HNC patients
treated with RT, the prevalence rate of severe (
Head and neck cancer (HNC) accounts for approximately 900,000 new cases and 400,000 deaths annually worldwide . Squamous cell carcinoma is the most common histology of HNC, and it usually develops in the mucosal surfaces of the oral cavity, pharynx, and larynx. Tumors originating from the salivary gland, nasal cavity, or paranasal sinus are less frequently observed. Patients with HNC are at high risk of neck nodal metastasis because the neck is rich in lymphatic drainage. Thus, neck irradiation is indicated in more than half of patients with HNC. For patients with oral cavity cancer who have adverse risk factors, such as close margin or perineural invasion, postoperative radiotherapy (RT) can be beneficial for locoregional control. To preserve organs or manage unresectable HNC tumors, definitive RT is the mainstay local treatment . After diagnosis and treatment, the primary HNC accounted for 73.4% of deaths within the first 5 years. However, death from competing causes became more common . Nearly one in three patients with HNC die from competing etiologies, and the most common causes include cardiovascular disease (CVD) and lung cancer and other types [4, 5].
HNC and CVD have similar risk factors such as male sex, low fruit and vegetable
intake, and tobacco and alcohol use . In HNC patients, the prevalence rates of
carotid artery disease and any CVD, which can possibly be underestimated, are 3%
and 26%, respectively . Cardio-oncology, a multidisciplinary approach for the
detection, monitoring, and treatment of cardiovascular dysfunction in patients
with cancer, has been an important issue in recent years [8, 9, 10]. That is,
anthracycline and trastuzumab for breast cancer, androgen deprivation therapy for
prostate cancer, and heart radiation dose for esophageal or breast cancer are
associated with CVD [9, 11, 12, 13, 14]. In treating HNC, the RT dose is up to 70 Gy,
which can damage the carotid artery leading to stenosis. Carotid artery stenosis
does not cause significant symptoms if the lumen narrowing is
Although there are published reviews and consensus reports focusing on the cardio-oncology, post-irradiated carotid artery stenosis in HNC is not commonly discussed [17, 18, 19, 20]. Due to improvement in long-term HNC tumor control, radiation-related late toxicity is increasingly considered. The current review aimed to comprehensively assess existing data about the prevalence, pathogenesis, risk factors, diagnosis, and treatment of post-irradiation artery stenosis. In addition, we collected Taiwanese data and information about future perspectives. With consideration of the high prevalence rate of carotid artery stenosis after neck irradiation in HNC patients, duplex ultrasonography should be included in the follow-up workup.
In the general population, the prevalence rates of asymptomatic moderate
|First author/Reference no.||Year||Cancer||RT group||Non-RT group||Median FUI (years)||Endpoints||Results|
||2009||HN||192||98||2||19.8% vs 0%|
|Dorresteijn ||2002||HN||367||-||7.7||Cumulative risk of stroke||15-year 12%|
|Haynes ||2002||HN||413||-||Not mentioned||Rate of stroke||5-year 12%|
|Carpenter ||2018||HN||366||-||4.1||2-year 11%, 5-year 20%, 8-year 29%|
|Liao ||2019||NPX||837 (12 studies)||1091||4–14||Risk ratio of overall,
|Texakalidis ||2020||HN||1479 (19 studies)||-||2–13||25%, 12%, 4%|
|1-year 4%, 2-year 12%, 3-year 21%|
|Smith ||2008||HN||1983 (RT alone),||2056 (surgery alone)||2.4||10-year cerebrovascular events||34% vs 25% vs 26%|
|2823 (surgery + RT)|
||2011||HN||4391 (RT or CT), 2880 (surgery + adjuvant)||2901 (surgery alone)||5.8||Stroke||3.8% vs 3.2% vs 4.3%|
||2015||Oral||11,905 (RT or CT), 3967 (surgery + adjuvant)||5981 (surgery alone)||Not mentioned||Ischemic stroke||7.4% vs 6.1% vs 6.5%|
Another approach is to use cerebrovascular events as the end point. Higher risk
of stroke in patients treated with neck RT implies that the radiation causes the
development of carotid artery stenosis. Dorresteijn et al. 
followed-up 367 patients with HNC who received RT before the age of 60 years.
Results showed that the 15-year cumulative risk of stroke was 12.0%. Haynes
et al.  retrospectively evaluated 413 patients with HNC treated with
neck irradiation. In total, 20 patients had stroke (crude incidence of 4.8%) in
the follow-up period, ranging from 2 and 146 months. The 5-year actuarial rate of
stroke was 12%, and the relative risk was 2.09 compared with expected data.
Smith et al.  identified 6862 patients who were aged
The pathogenesis of radiation-induced vascular disease is not fully elucidated.
However, it is likely multifactorial (Fig. 1). Some of the mechanisms are
endothelial injury and dysfunction, which are characterized by impaired
endothelium-dependent relaxation with a lack of nitric oxide synthase expression
[35, 36, 37]. Moreover, radiation induces endothelial cells to release von Willebrand
factor, which enhances platelet adhesion and predisposes to arterial thrombosis
. Radiation, even at low doses, induces the release of pro-inflammatory
cytokines (such as interleukin [IL]-1, IL-6, tumor necrosis factor alpha, and
tumor growth factor beta [TGF-
Pathogenesis of radiation-induced vascular stenosis. Two major mechanisms, endothelial dysfunction and occlusion of vasa vasorum contributed to the result.
There are several hypotheses for the development of classic atherosclerosis, including ‘response to injury’, ‘oxidized low density lipoprotein’, and ‘inflammation’. Atherosclerosis is associated with many risk factors, such as obesity, hypercholesterolemia, hypertension, diabetes, and smoking [44, 45]. On the other hand, some characteristics of radiation-induced carotid artery stenosis differed from those of classic atherosclerosis. Patients with post-RT carotid artery stenosis had fewer atherosclerotic risk factors. In human pathological studies, medial thinning and adventitia fibrosis were observed in the vessels after irradiation . Less inflammatory, more fibrotic, and a smaller lipid core size were associated with radiation-induced plaque . Lam et al.  investigated the distribution of plaques, and results showed that the most often affected sites were the common carotid arteries in patients treated with irradiation, while the carotid bulb in controls. Post-irradiated stenotic lesions might more likely affect the carotid artery diffusely and occur bilaterally, and maximal stenosis could commonly develop at the end of the stenotic area [49, 50].
Neck irradiation can induce carotid artery stenosis. Even with moderate-dose RT, atherosclerosis may develop . For example, patients treated for Hodgkin lymphoma with 40-Gy irradiation had a higher incidence of TIA or stroke in the long-term follow-up, with a risk ratio of approximately 5 [52, 53]. Patients with HNC can receive a higher neck radiation dose, ranging from 50 to 70 Gy, depending on the definitive or adjuvant setting. A positive correlation was noted between dose and atherosclerotic activity .
However, the dose-effect relationship, which may be confounded with other risk
factors and follow-up interval, remains unclear. Dorth et al. 
retrospectively reviewed patients with HNC who underwent carotid ultrasonography.
They found an insignificant dose-effect that might be correlated with carotid
artery stenosis with every 10 Gy increase in mean RT dose, with a hazard ratio of
1.4. A study included patients who received ipsilateral neck RT and compared the
prevalence of carotid stenosis and intima-media thickness on each side .
Results found increased intima-media thickness and a higher grade of carotid bulb
abnormality at a dose of
Moreover, the interval after RT plays an important role in the development of
carotid stenosis. Cheng et al.  revealed that time interval from RT
is an independent predictor of severe carotid artery stenosis via a multivariate
logistic regression analysis. Dorresteijn et al.  compared the risk
of ischemic stroke between patients receiving neck irradiation and normal
population. After adjusting for sex, age, and other risk factors for stroke, the
relative risk was 3.7 within the 10-year follow-up, which increased to 10.1 after
Although the pathogenesis varies, radiation-induced carotid artery stenosis cannot be totally spared from classic atherosclerosis. The risk factors of patients with ischemic stroke include hypertension, dyslipidemia, diabetes mellitus, obesity, smoking, and alcohol consumption . A meta-analysis included prospective or retrospective observational studies reviewing patients with a history of head and neck RT. A research compared the baseline characteristics between patients with stenosis and those without. Results showed that diabetes and smoking could be the possible risk factors of severe carotid stenosis, with odds ratios of 3.67 and 4.48, respectively. However, no such significant difference was noted in terms of the incidence of hypertension and coronary artery disease .
Asymptomatic carotid artery stenosis is commonly diagnosed via duplex ultrasonography, which comprises the Doppler and B-modes. Doppler ultrasonography can evaluate the velocity and direction of the blood flow using a color scale. The B-mode shows two-dimensional images with a grayscale, which provides information about the plaque features and thickness of the arterial wall. The severity of stenosis depends on the peak systolic velocity and the presence of plaques. Other criteria, such as collateral flow, prestenotic flow, and poststenotic flow disturbances, can increase the reliability of results . The European Society of Cardiology recommends ultrasonography as the first-line examination, and a threshold of 70% stenosis was set for the indication of revascularization .
The development of carotid artery stenosis may take years. However, the assessment of CIMT is useful in predicting cardiovascular diseases . Using high-resolution B-mode ultrasonography, the vascular structure can be visualized. CIMT is evaluated using a longitudinal image of the carotid artery with a double-line pattern, which comprises the lumen–intima and media–adventitia interfaces. Previous studies have shown that radiation increases the CIMT via a dose-effect [60, 61]. In patients treated with neck irradiation, duplex ultrasonography and CIMT assessment are useful for the early detection of carotid artery stenosis.
Digital subtraction angiography is the gold standard for diagnosing vascular
stenosis. However, the procedure is invasive and time-consuming. Noninvasive
imaging modalities, such as computed tomography angiography (CTA) and magnetic
resonance angiography (MRA), have evolved, and they replaced the diagnostic role
of digital subtraction angiography and became a complement of ultrasonography
. CTA provides three-dimensional images with a better spatial resolution than
duplex ultrasonography. The sensitivity and specificity of detecting severe
carotid artery stenosis via dual-source CTA are
Although the pathogenesis of radiation-induced carotid artery stenosis differs from that of classical atherosclerosis, lifestyle modification (e.g., weight control and smoking cessation) and risk factors (e.g., hypertension, diabetes mellitus, dyslipidemia) control are still important for preventing TIA and ischemic stroke . Currently, there is no large clinical trial investigating medical treatment specifically for radiation-induced carotid stenosis. Based on in vitro studies, statins had anti-inflammatory and anti-thrombotic effects on irradiated endothelial cells, which may be considered in therapeutic strategies . A retrospective cohort study showed that the use of statins after RT was associated with a significant reduction in the incidence of stroke, with a hazard ratio of 0.68 . In addition, the use of perioperative statins can reduce the incidence of cerebrovascular events and mortality among patients undergoing carotid endarterectomy (CEA) . Other medications, such as angiotensin-converting enzyme inhibitors and antiplatelet drugs, may have benefits .
In some cases, intervention is indicated for symptomatic patients. CEA is an
invasive surgery for removing plaques from the carotid artery to improve blood
flow. Randomized trials have shown the benefit of CEA among symptomatic patients
with high-grade (
Cancer is the leading cause of death in Taiwan. The incidence of head and neck
(oral cavity, oropharynx, and hypopharynx) squamous cell cancers is relatively
high, with a crude rate of 34 per 100,000 people in 2018. There were 8170 newly
diagnosed cases and 3027 deaths, accounting for 7% of new cancer cases and 6.2%
of all cancer-related deaths . HNC originated from the oral cavity are in
majority and associated with the consumption of cigarette, alcohol, and betel
quid . Although the incidence of human papillomavirus (HPV)-associated
oropharyngeal cancer is increasing, the HPV-positivity rate is still
In some institutions, duplex ultrasonography is performed regularly to assess
the patency of carotid arteries among patients treated with neck irradiation.
Chang et al.  conducted a prospective, cross-sectional study to
evaluate the prevalence of radiation-induced carotid artery stenosis via carotid
duplex sonography. In total, 290 consecutive patients with HNC were enrolled.
With a median 2-year interval after RT, the incidence rates of
Other studies used data from different databases to assess the correlation
between neck irradiation and ischemic stroke. Li et al.  conducted a
case-control study including 319 patients with ischemic stroke with or without
NPC after neck irradiation. Patients treated with RT were younger but with higher
proportions of carotid artery disease (42% vs 11%; p
Considering the treatment of carotid artery stenosis, CAS, rather than CEA, is indicated for patients with severe radiation-associated carotid stenosis. Huang et al.  reported the long-term outcomes of carotid artery stenting. The procedures were performed on 129 patients with a mean follow-up of 42.7 months. Between the radiation and non-irradiated groups, there were no significant differences in primary end points, including 30-day major complications and 5-year freedom from mortality, ipsilateral recurrent stroke, and major adverse cardiovascular events. Results showed that the outcomes of carotid artery stenting did not change based on the history of neck irradiation, except for asymptomatic carotid restenosis.
The best method for preventing radiation-induced carotid artery stenosis is lowering the radiation dose as much as possible. Precision and personalized medicine play an important role in cancer treatment. The radiation dose could be reduced or omitted in some cases. For example, patients with NPC commonly present with bilateral cervical lymph node metastases. Thus, prophylactic whole neck irradiation is indicated. However, recent studies showed that selective neck irradiation with a lower elective dose is feasible among patients with NPC [84, 85]. In HPV-positive oropharyngeal cancer, phase II trials revealed that dose de-escalation had a comparable locoregional tumor control with less toxicity [86, 87]. Proton beam, with physical advantage of Bragg peak, can achieve a rapid fall-off of the radiation dose to the surrounding organ. A pilot study showed that intensity-modulated proton therapy could reduce the dose to the vertebral artery in the NPC treatment plan . Carotid artery sparing could be achieved in early-stage laryngeal cancer . Proton therapy can reduce the dose at the carotid artery, particularly in the sequence of gross tumor boost without prophylactic neck irradiation.
Early detection is important for identifying asymptomatic patients who presented with post-irradiation carotid artery stenosis. Although duplex ultrasonography and CIMT are good screening tools, some novel biomarkers are still under investigation. Because inflammation is a key process in atherosclerosis, the association between CVD and several inflammatory markers was assessed . For example, a study showed that high-sensitivity C-reactive protein was an independent predictor of future cardiovascular events . Similarly, fluorodeoxyglucose (FDG)-positron emission tomography scan is also a useful tool for detecting carotid plaque inflammation, which is a marker of symptomatic carotid artery disease . Chen et al.  conducted a pilot study including patients with HNC treated with chemoradiation and arranged pre- and 3 months post-RT. Results showed a significantly higher FDG uptake in the carotid artery, which can be an early biomarker of radiation-induced vascular injury.
Previously, radiation-induced fibrosis was believed to be an inevitable and
irreversible process. However, new treatments involving the pathway of
radiation-induced fibrosis have been assessed. For example, TGF-
In summary, in patients with HNC treated with RT, the prevalence of severe
carotid artery stenosis is
Fig. 2 shows the possible approach for patients with HNC receiving neck
irradiation. Clinicians should identify and control the risk factors associated
with carotid artery stenosis. Personalized RT planning design could reduce the
carotid artery dose. Screening is essential for detecting symptom-free carotid
artery stenosis that causes unexpected disability or death. Patients who are aged
Approach for patients with head and neck cancer treated with radiotherapy. Abbreviations: CTA, computed tomography angiography; CVD, cardiovascular disease; HPV+OPC, human papillomavirus positive oropharyngeal cancer; LN, lymph node; NPC, nasopharyngeal cancer; MRA, magnetic resonance angiography; RT, radiotherapy.
PWS and YWW conceive the idea. DYK prepared and wrote the original draft. CHH and LJL provided help and advice on data collection and contributed to language changes in the manuscript. All authors read and approved the final manuscript.
This research received no external funding.
The authors declare no conflict of interest. Yen-Wen Wu and Pei-Wei Shueng are serving as Guest editors of this journal. We declare that Yen-Wen Wu and Pei-Wei Shueng had no involvement in the peer review of this article and have no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Fabrizio D’Ascenzo and Dimitrios Farmakis.
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