Original article Radiation-induced carotid artery atherosclerosis Dorothy M. Gujral a , Navtej Chahal b , Roxy Senior b , Kevin J. Harrington a , Christopher M. Nutting a,⇑ a Head and Neck Unit, Royal Marsden Hospital; and b Department of Echocardiography, Royal Brompton Hospital, London, United Kingdom article info Article history: Received 24 October 2012 Received in revised form 5 June 2013 Accepted 7 August 2013 Available online xxxx Keywords: Carotid artery Radiotherapy Atherosclerosis abstract Purpose: Carotid arteries frequently receive significant doses of radiation as collateral structures in the treatment of malignant diseases. Vascular injury following treatment may result in carotid artery stenosis (CAS) and increased risk of stroke and transient ischaemic attack (TIA). This systematic review examines the effect of radiotherapy (RT) on the carotid arteries, looking at the incidence of stroke in patients receiv- ing neck radiotherapy. In addition, we consider possible surrogate endpoints such as CAS and carotid intima-medial thickness (CIMT) and summarise the evidence for radiation-induced carotid atherosclero- sis. Materials and methods: From 853 references, 34 articles met the criteria for inclusion in this systematic review. These papers described 9 studies investigating the incidence of stroke/TIA in irradiated patients, 11 looking at CAS, and 14 examining CIMT. Results: The majority of studies utilised suboptimally-matched controls for each endpoint. The relative risk of stroke in irradiated patients ranged from 1.12 in patients with breast cancer to 5.6 in patients trea- ted for head and neck cancer. The prevalence of CAS was increased by 16–55%, with the more modest increase seen in a study using matched controls. CIMT was increased in irradiated carotid arteries by 18–40%. Only two matched-control studies demonstrated a significant increase in CIMT of 36% and 22% (p = 0.003 and <0.001, respectively). Early prospective data demonstrated a significant increase in CIMT in irradiated arteries at 1 and 2 years after RT (p < 0.001 and <0.01, respectively). Conclusions: The incidence of stroke was significantly increased in patients receiving RT to the neck. There was a consistent difference in CAS and CIMT between irradiated and unirradiated carotid arteries. Future studies should optimise control groups. Ó 2013 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology xxx (2013) xxx–xxx Radiation-induced atherosclerosis was first described as early as 1959 [1]. Tissue necrosis and inflammation resulting in endothe- lial damage, proliferation and fibrosis as well as accelerated ath- erosclerosis are thought to be key mechanisms responsible for the injury. These mechanisms are thought to result in morpholog- ical features similar to those seen in spontaneous atherosclerosis [2]. Vascular injury to smaller vessels following radiotherapy (RT) has been well described. Historically, the left anterior descending coronary artery was exposed to significant radiation dose in pa- tients undergoing treatment for left-sided breast cancer using old- er RT techniques [3]. Subsequent longitudinal, cohort studies have shown increased cardiovascular risk in these patients compared to controls [4,5]. Radiation damage to larger vessels, like the carotid arteries, and the underlying processes involved has received more interest in recent decades. The precursor for stroke and transient ischaemic attack (TIA) is atherosclerosis, which precedes this clinical endpoint by many years and is characterised by arterial wall thickening and plaque development with subsequent stenosis. The risk of stroke increases with time. Risk factors associated with increased risk of atheroscle- rosis include: increasing age, diabetes mellitus, hypertension, hypercholesterolemia, obesity, smoking and RT to the affected ves- sels [6]. Atherosclerosis associated with radiation therapy, while histologically similar to spontaneous atherosclerosis, is a clinically distinct entity. The disease is limited to the irradiated area and is less likely to be associated with atherogenic risk factors [7]. Carotid artery stenosis (CAS) is diagnosed on Doppler ultra- sound. Grading of CAS is well defined [8], with stenosis of P70% (i.e. percentage reduction of internal carotid artery diameter) con- sidered significant and requiring intervention in case of neurolog- ical symptoms. The ultrasound features of plaques correlate with histological findings [9] and the risk of stroke [10]. Carotid intimal-medial thickness (CIMT) is a measure of the thickness of the artery wall, using B-mode ultrasound. Increased CIMT is an early marker of atherosclerosis and predicts for subse- quent risk of death from myocardial infarction and stroke [11]. In- creased CIMT is a strong predictor of future vascular events [12]. Measurement of CIMT for cardiovascular risk assessment has been 0167-8140/$ - see front matter Ó 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.radonc.2013.08.009 ⇑ Corresponding author. Address: Head and Neck Unit, Royal Marsden Hospital, Fulham Rd, London SW3 6JJ, United Kingdom. E-mail addresses: Christopher.Nutting@rmh.nhs.uk, chris.nutting@rmh.nhs.uk (C.M. Nutting). Radiotherapy and Oncology xxx (2013) xxx–xxx Contents lists available at ScienceDirect Radiotherapy and Oncology journal homepage: www.thegreenjournal.com Please cite this article in press as: Gujral DM et al. Radiation-induced carotid artery atherosclerosis. Radiother Oncol (2013), http://dx.doi.org/10.1016/ j.radonc.2013.08.009