Radiotherapy and Oncology xxx (2013) xxx–xxx

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Radiotherapy and Oncology

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Original article

Radiation-induced carotid artery atherosclerosis

0167-8140/$ - see front matter � 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).

Please cite this article in press as: Gujral DM et al. Radiation-induced carotid artery atherosclerosis. Radiother Oncol (2013), http://dx.doi.org/1j.radonc.2013.08.009

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

a r t i c l e i n f o a b s t r a c t

Article history:Received 24 October 2012Received in revised form 5 June 2013Accepted 7 August 2013Available online xxxx

Keywords:Carotid arteryRadiotherapyAtherosclerosis

Purpose: Carotid arteries frequently receive significant doses of radiation as collateral structures in thetreatment 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 examinesthe 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 carotidintima-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 systematicreview. 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 relativerisk 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 modestincrease seen in a study using matched controls. CIMT was increased in irradiated carotid arteries by18–40%. Only two matched-control studies demonstrated a significant increase in CIMT of 36% and22% (p = 0.003 and <0.001, respectively). Early prospective data demonstrated a significant increase inCIMT 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.

� 2013 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology xxx (2013) xxx–xxx

Radiation-induced atherosclerosis was first described as earlyas 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 forthe 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 descendingcoronary 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 haveshown increased cardiovascular risk in these patients compared tocontrols [4,5]. Radiation damage to larger vessels, like the carotidarteries, and the underlying processes involved has received moreinterest in recent decades.

The precursor for stroke and transient ischaemic attack (TIA) isatherosclerosis, which precedes this clinical endpoint by many

years and is characterised by arterial wall thickening and plaquedevelopment with subsequent stenosis. The risk of stroke increaseswith 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, whilehistologically similar to spontaneous atherosclerosis, is a clinicallydistinct entity. The disease is limited to the irradiated area and isless 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 withhistological findings [9] and the risk of stroke [10].

Carotid intimal-medial thickness (CIMT) is a measure of thethickness of the artery wall, using B-mode ultrasound. IncreasedCIMT 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

0.1016/

2 Radiation-induced carotid atherosclerosis

included in the American College of Cardiology Foundation andAmerican Heart Association guidelines [13].

The aim of this systematic review is to investigate the incidenceof stroke in patients treated with RT to the neck compared to unir-radiated controls and to evaluate surrogate endpoints for stroke(CIMT as a measure of arterial thickening, and CAS as a measureof plaque development). We hypothesise that there is an increasedincidence of stroke in irradiated patients and that CIMT and CASwill be increased in irradiated carotid arteries compared tocontrols.

Fig. 1. Flow diagram of literature search.

Materials and methods

Search strategy

We performed a systematic search of pubmed (1st January 1970to 31st December 2010) for English language articles using thesearch terms: ‘‘carotid’’, ‘‘artery’’, and ‘‘radiotherapy’’. The abstractsor available data obtained from this search were read indepen-dently by two authors (DMG and NC) to include or exclude refer-ences for full text review. Articles reporting on patients who hadreceived RT to the neck (one or both sides) for malignant or benigndisease were eligible for inclusion. Publications had to report oncase-controlled study designs with a clearly defined control groupto be eligible for inclusion or had to be prospective studies report-ing on the incidence of CAS, CIMT, or stroke. Case reports and caseseries were excluded from this review.

Selection criteria for full text review

References were included if they described journal articlesreporting case-controlled studies investigating the following end-points: CAS, CIMT, or stroke. Relevant references not clearly iden-tifying patient populations or study design were included in theinitial review to avoid erroneous exclusion. The full-text articlesfrom the selected references were read independently by twoauthors (DMG, NC) to select the final set of articles for reviewand analysis. The reference lists of these articles were also re-viewed, and references from relevant titles were obtained and re-viewed according to the above selection criteria.

Data abstraction and analysis

The outcomes of interest were: stroke, CIMT, and CAS in case-controlled studies where patients had received RT to the neck. Eachoutcome was considered separately and the appropriateness of thecontrol groups was reviewed. The aim of the literature review wasto identify studies reporting on prevalence of stroke and interme-diate surrogate endpoints for stroke.

Results

The initial database search produced 853 references [Fig. 1].During screening, the abstracts or available data from 43 of theseinitially satisfied the selection criteria and their full-text articleswere obtained. Nine of the 43 were excluded after reading the fulltext articles due to lack of a control group (N = 6) and repeatedreporting of studies (N = 3) (for these studies, the earlier publica-tions did not include defined control groups and were excludedin favour of the updated versions which were reported as case-con-trolled studies). Two studies were prospective studies reporting onthe change in CIMT over time and will be discussed separately.Therefore, a total of 34 studies were included in this review.

Please cite this article in press as: Gujral DM et al. Radiation-induced carotidj.radonc.2013.08.009

Stroke/TIA

The studies reporting on the incidence of stroke and/or TIA inpatients who had received RT to the neck are highlighted in Table 1[14–22]. Seven of the 9 studies showed an increased incidence ofstroke in irradiated patients with the relative risk (RR)/hazard ratio(HR) for stroke/TIA ranging from 1.12 [17] in patients with breastcancer to 5.6 [14] in patients with head and neck cancer. The mainpoint to note is that, for all of these studies, there was a lack of anappropriately matched control group. Five of the 9 studies[14,15,17–19] utilised large population databases as a controlgroup, matched primarily for age and sex [23–26] and the other4 studies used a defined group as controls. The study by Dor-resteijn et al. [14] compared stroke rates in patients treated forhead and neck cancer to those reported in the Oxfordshire Commu-nity Stroke Project (OCSP) [23]. The authors stated that, at the timeof the study, there were no large Dutch studies documenting theincidence of stroke in the population and that the expected ratesof stroke in the Netherlands and United Kingdom were similar.Therefore, they felt it was justified to use the expected stroke ratesfrom the large, published OCSP as age- and sex-matched controls.The study by Haynes et al. [15] compared stroke rates in Americanpatients treated for head and neck cancer to the expected inci-dence, based on population data from Stockholm [24]. This studyshowed a RR of stroke of 2.09 (95% confidence interval (CI) 1.28–3.22) in patients with head and neck cancer treated with RT(p = 0.0007). It is important to note, however, that these patientswere only matched for age, gender, and smoking status and, there-fore, the true RR may be more conservative as the other risk factorsfor atherosclerosis are not accounted for.

Carotid artery stenosis

Early studies utilised older techniques such as angiography andpanoramic radiographs as diagnostic tools and are summarised inTable 2 [27–29]. These studies demonstrated a significantly in-creased prevalence of CAS in irradiated patients (17–25%) com-pared to those who did not receive RT.

Retrospective studies examining the prevalence of CAS in irradi-ated patients using Doppler ultrasound are listed in Table 2 [7,30–36]. Nine of the 10 studies demonstrated a significantly increasedprevalence of CAS in patients with irradiated carotid arteries; 5studies used unmatched controls. The difference in CAS rangedfrom 16% [7] to 55% [33]. The study by Halek et al. [7] showed ahigher prevalence of CAS in the irradiated distal carotid artery

artery atherosclerosis. Radiother Oncol (2013), http://dx.doi.org/10.1016/

Table 1Studies investigating the incidence of neurological events in patients treated with cervical radiotherapy.

Study No. ofpatients

No of controls Radiation dose(Gy)

Interval fromradiotherapy(months)

Incidence of stroke/TIA(patients) (%)

Incidence ofstroke/TIA(controls)

Relative risk (95%CI) or Hazardratio (HR) (95%CI)

p Value

Total Mean/median(range)

Median(range)Tumour

type

Dorresteijn2002[14]

367 OCSPa (50–66 Gy) 93.6 (6–271.2)

14/367 (3.8%) 2.5/367 (0.7%) 5.6 (3.1–9.4)

Head andneck

(age/sex match)

Haynes2002[15]

413 Stockholmb

Project (age/gender/smokingmatched)

Mean 64.1 Gy 33.5 (2–146) 20/413 (4.8%) Not stated 2.09 (1.28–3.22) p = 0.0007

Head andneck

(40–80 Gy)

Bowers2005[16]

1926 3846 40 Gy (29.8–48 Gy) (pts whodevelopedstroke)

Mean 234(SD 70.8)

24/1386 (1.73%) 9/3846 (0.23%) 5.62 (2.59–12.25) p < 0.0001

Hodgkin Siblings Median timetostroke = 210

1386 –mantle RT

Nilsson2005[17]

25171 Backgroundpopulation(unmatched)

Not stated 64.8 (IQR27.6–124.8)

7% 6.30% 1.12 (1.07–1.17) NotstatedAny breast

cancerdiagnosis

Hooning2006[18]

4368 CMRNc Mean 50 Gy Median 212.4 164/4368 = 3.8% 217.6/4368 = 5% HR 1.04 (0.69–1.58) – stroke

p = NS

Breast (Age/sexmatched)

HR 1.45 (0.85–2.46) - TIA

1061 –SCFd RT

135/1061 = 12.7% 175/1061 = 16.5%

Jagsi 2006[19]

826 NHDSe Not stated 81.6 (1.2–243.6)

Overall – 2.4% Not stated HR 1.9 (0.9–3.7)CVA or TIA

p = 0.072

Breast (age/sex/racematched)

SCF RT = 10/222 = 4.5% HR 2.8 (1.2–6.7)CVA alone

222 – SCFRT

p = 0.021

Woodward2006[20]

471 5281 Not stated 90 15 yr freedom fromhospitalisation forstroke = 81.6%

15 yr freedomfromhospitalisation forstroke = 79%

HR 1.0 (0.6–1.68)for stroke

Breast –SCF RT

Breast – no SCF RT 12 yr actuarial causespecific strokesurvival = 95.4%

12 yr actuarialcause specificstrokesurvival = 95.1%

Unmatched

p = 0.13Smith 2008

[21]4806 2056 Not stated 28.8 (IQR

16.8–52.8)42.8/1000 person yrs 30.7/1000 person

yrsp < 0.001

Head andneck – RTor RT + Sx

Head and neck –Sx alone(unmatched)

DeBruin2009[22]

1787 414 40 Gy (36–44 Gy)

208.8 (61.2–451.2)

SCF ± neck = 5/136 (3.7%) 8/414 = 1.9% HR 2.3 (0.7–7.6) NotstatedHodgkin –

neck RTHodgkin – noneck RT(unmatched)

Mediastinum + neck = 75/1651 (4.5%)

HR 2.5 (1.1–5.6)

a OCSP – Oxfordshire Community Stroke project [23].b Stockholm Project [24].c CMRN – Continuous Morbidity Registration-Nijmegen [25].d SCF – supraclavicular fossa.e NHDS – National Hospital Discharge Survey [26].

D.M. Gujral et al. / Radiotherapy and Oncology xxx (2013) xxx–xxx 3

and not the irradiated internal or external carotid artery. Brownet al. [34] demonstrated a significant difference in CAS in patientswho had been irradiated more than 15 years earlier. Patients whohad received RT tended to develop more haemodynamically signif-icant lesions [30].

Later studies [34,35] more appropriately used the unirradiatedside of the neck as an internal matched control, thereby accountingfor all the other risk factors of atherosclerosis. Woodward et al.[35] showed no difference in prevalence of CAS in irradiated versusunirradiated carotid arteries in breast cancer patients receiving RT

Please cite this article in press as: Gujral DM et al. Radiation-induced carotidj.radonc.2013.08.009

to the supraclavicular fossa. However, as the study was underpow-ered to show a difference and closed after accruing fewer than half(n = 46) the required number of patients, no firm conclusions canbe drawn from this study. The second study [34] showed a moremodest difference in CAS than earlier studies (16%).

CIMT

Details of retrospective studies investigating CIMT, the majorityof which used suboptimal age and sex matched controls, are

artery atherosclerosis. Radiother Oncol (2013), http://dx.doi.org/10.1016/

Table 2Case-controlled studies investigating the prevalence of carotid artery stenosis based on radiographs, catheter angiography, or Doppler ultrasound.

Study No ofpatients

No of controls Radiationdose (Gy)

Interval fromradiotherapy (months)

Investigation % with Stenosis(patients)

% with Stenosis(controls)

p Value

Total Mean/median(range)

Mean/median (range)Tumour type

Silverberg1978 [27]

9 40 (44–68.2 Gy) Not stated Catheter 88.90% 65% p = 0.007

Lymphoma 4 unmatched AngiographyBreast 3Head + Neck2

Moritz 1990[30]

53 38 >50 Gy 28 DuplexDoppler

30% (mod-severestenosisa)

6% (mod-severestenosis)

p < 0.005

Head + neck UnmatchedDubec 1998

[31]45 348 (35–62.5 Gy) P60 Duplex

Doppler38% (P50%stenosis)

3.8 (P50%stenosis)

p = 0.00001

Head + Neck41

Unmatched

Thyroid 4Friedlander

1998 [28]61 61 (42–72 Gy) 36 Panoramic

radiographs27.90% 4.90% p = 0.001

Head + Neck Age matchedCarmody 1999

[32]23 46 60.6+/-1.8 Gy Mean 78 Duplex doppler 21.7% (70–90%

stenosis)4% (70–90%stenosis)

p = 0.037

Head + neck Age matchedFreymiller

2000 [29]17 309 53.2 Gy Mean 69.7 Panoramic

radiographs53% 5.90% p = 0.0003

Head + Neck Age matched (45–71 Gy) (37–133)Lam 2001 [33] 71 51 56.4 Gy (48–240) Duplex

Doppler78.90% 23.60% p < 0.01

Nasopharynx UnmatchedHalak 2002 [7] 30 100 Not stated Median 150 Duplex

DopplerECAb 79.6% 64.40% P > 0.3

Head + Neck17

Unmatched (36–636) PICAc 71.4% 78.00% P > 0.5

Lymphoma 7 DCCAd 17.8% 1.00% p < 0.0002Breast 2Othera 4

Brown 2005[34]

44 44(unirradiatedside)

(30–64.8 Gy) Median 90 DuplexDoppler

Events/100person yrs

Head + Neck35

(48–278.4) 610 yrs – 0.6 0.6 p = 0.5

Skin (SCCe) 5 10–15yrs – 4.8 0 p = 0.03Othera 4 >15 yrs – 21.3 5.3 p = 0.003

Woodward2008 [35]

46 46(unirradiatedside)

50 Gy Median 175 DuplexDoppler

4.30% 6.50% p = NS

Breast

Meeske 2009[36]

30 30 Mean 37.2 Gy Mean 180 DuplexDoppler

Hodgkin 17 Age/sex/racematch

(18–66 Gy) (72–420) 18–29 Gy 19% 2% p < 0.001

RMSf 6 30–66 Gy 18% p < 0.001Other 7

a Other – melanoma, sarcoma, benign.b ECA – external carotid artery.c PICA - proximal internal carotid artery.d DCCA – distal common carotid artery.e SCC – squamous cell carcinoma.f RMS - rhabdomyosarcoma.

4 Radiation-induced carotid atherosclerosis

presented in Table 3[2,36–46]. Early studies using unmatchedcontrols [37–39], demonstrated a significant increase in CIMT inirradiated carotid arteries of around 18–40%.

Later publications [41,42] studied patients who had receivedhemi-neck RT, using the contralateral neck as internal controls.Both studies were performed in head and neck cancer patientsand demonstrated a significant increase in CIMT of 36% and 22%,respectively. Those differences are similar to those seen in studiesshowing significant differences in CAS (table 2). Conversely, Gian-icolo et al. [46] showed no significant difference in mean CIMT in19 irradiated patients (mean interval from RT of 35 months) com-pared to 19 healthy controls (p = 0�4).

Prospective data

In a prospective study, Muzaffar et al. [47] evaluated 36 patientsfollowing neck irradiation for head and neck cancer. The CIMT andthe size of plaques were measured prior to irradiation and at one

Please cite this article in press as: Gujral DM et al. Radiation-induced carotidj.radonc.2013.08.009

and two years following irradiation. On comparison with age andsex-matched controls from epidemiologic studies, there was a sig-nificant increase in CIMT in the treated patients at one year(p < 0�001) and at 2 years after RT (p < 0.01). A more recent studyby Bilora et al. [48], demonstrated no significant increases in CIMT3 years after radiotherapy in the common carotid artery, carotidbulb, and internal carotid artery (p > 0.05 for all comparisons) inlymphoma patients.

Discussion

This systematic review demonstrates an increased incidence ofstoke/TIA in patients receiving RT to the neck. Seven of the 9 stud-ies reported a significantly increased incidence of stroke in irradi-ated patients, with the RR ranging from 1.12 in patients with breastcancer to 5.6 in patients treated for head and neck cancer. Twostudies [18,20] showed no significant difference in stroke rates.Both studies were based on patients with breast cancer: the study

artery atherosclerosis. Radiother Oncol (2013), http://dx.doi.org/10.1016/

Table 3Case-controlled studies investigating the effect of radiotherapy on carotid artery intima-medial thickness.

Study No of patients No of controls Radiation dose(Gy)

Interval fromradiotherapy(months)

Investigation Mean IMTa

(patients)Mean IMT (controls) p Value

Total Mean/Median(range)

Mean/median(range)Tumour type

Feehs 1991[36]

29 9 Mean 60.4 Gy(40–87.2 Gy)

Mean 102 B mode IMT mean 1.28 ± SE0.06 mm

IMT mean 0.90 ± SE0.05 mm

p = 0.003

Head + neck Unmatched (36–204)King 1999

[37]42 33 (22–40 Gy) 156 B-mode Median 0.51 mm

(range 0.32–1.99)Median 0.43 mm(range 0.32–0.61)

p < 0.005

Hodgkin Unmatched (61.2–273.6)Heikens

2000 [38]26 29 Mean 54 Gy Median 192 (108–

300)DuplexDoppler

Brain Unmatched (30–62 Gy) CCA 0.57 mm (SD 1.1) 0.58 mm (SD 1.2) p = NSBulb 0.63 mm (SD 1.6) 0.53 mm (SD 1.1) p = 0.02ICA 0.5 mm (SD 1.3) 0.57 (SD 3.2) p = NS

Cheng 2002[2]

46 46 (50–60 Gy) Median 136 DuplexDoppler

Mean0.96 mm ± 0.34 (SD)

Mean0.80 mm ± 0.19 (SD)

p = 0.008

Nasopharynx19

Age/sexmatch

(64–336)

Larynx 20Oropharynx 3Parotid 2Oral cavity 2

So 2002 [39] 51 51 N/S Mean 92.4 B-mode 2.2 mm ± SD 1.5 0.7 mm ± SD 0.15 p < 0.05

Nasopharynx Age/sexmatch

Dorresteijn2005 [40]

42 42(unirradiatedside)

(40–66 Gy) Median 117.6 (40.8–326.4)

B-mode Mean 1.13 mm ± SD0.85 mm

Mean 0.83 mm ± SD0.51 mm

p = 0.031

Parotid

Martin 2005[41]

40 40(unirradiatedside)

(30–60 Gy) Mean 101 DuplexDoppler

35% 12.50%

Lymphoma 14 (24–217) All doses 0.104 mm 0.085 mm p = 0.046Tonsil 18 High dose 0.126 mm 0.081 mm p = 0.031Parotid 8 Low dose 0.089 mm 0.087 mm p = 0.861

Bilora [42]2006

42 42 (36–40 Gy) Mean 60 DuplexDoppler

Mean 1.42 mm Mean 0.90 mm p < 0.05

Lymphoma Age/sexmatch

(24–144)

Shariat 2008[43]

13 13 (46–70 Gy) Mean 37.2 B-mode 0.74 mm (SD0.1767 mm)

0.46 (SD0.1304 mm)

p < 0.001

Nasopharynx11 Age/sex/racematch

(12–96)

Larynx 1Oral cavity 1

Meeske2009 [44]

30 30 Mean 37.2 Gy Mean 180 DuplexDoppler

Hodgkin 17 Age/sex/racematch

(18–66 Gy) (72–420) 18–29 Gy 0.43 mm (SD 0.09) 0.41 mm (SD 0.06) p < 0.01

RMSd 6 0.48 mm (SD 0.14)Othere 7 30–66 Gy p < 0.0001

Shai [45]2009

145 150 Mean 0.09 Gy Mean 614.8 DuplexDoppler

0.68 mm (SD 0.16) 0.61 mm (SD 0.17) p < 0.001

Tinea capitis Age/sex/DMb/IHDc match

Gianicolo2010 [46]

19 19 Mean 40.1 Gy(25–70 Gy)

Mean 34.8 DuplexDoppler

0.59 mm ± 0.16 0.56 mm ± 0.16 p = 0.4

Lymphoma 11 Age/sex/racematch

(1–72)

Head + Neck 6Breast 2

a IMT – intima-medial thickness.b DM – diabetes mellitus.c IHD – ischaemic heart disease.d RMS – rhabdomyosarcoma.e Other – not specified.

D.M. Gujral et al. / Radiotherapy and Oncology xxx (2013) xxx–xxx 5

by Hooning et al. [18] showed no significant difference in incidentstroke rates in 4368 treated patients, a finding that was also truefor the subgroup of 1061 patients who had been treated with RTto the supraclavicular fossa (SCF). The authors suggest several rea-sons for this: women in late menopause may be afforded protec-tion against cerebrovascular disease, a diagnosis of breast cancermay trigger a healthier lifestyle after treatment, and regular mon-itoring may allow more aggressive management of risk factorssuch as hypertension. The second study [35] showed no significantincrease in stroke in 471 patients with breast cancer treated with

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RT to the SCF. The control group, although a cohort of breast cancerpatients, were unmatched and this may partially explain this re-sult, in addition to the reasons stated above. The hypothesis thatbreast cancer patients experience a lower risk of stroke than headand neck cancer patients because irradiation of the SCF delivers adose of 45–50 Gy to only 7 cm of the proximal carotid artery [20]is not borne out by other studies in breast cancer and lymphomapatients [16,17,19,22] that do show a significant increase instroke/TIA in these patients. Two of the 3 head and neck cancerstudies [14,15], did make some attempt to use matched controls

artery atherosclerosis. Radiother Oncol (2013), http://dx.doi.org/10.1016/

6 Radiation-induced carotid atherosclerosis

and to appreciate the other risk factors for stroke or TIA. Table 1highlights the difficulty in investigating stroke/TIA as an endpointin radiation-induced carotid atherosclerosis. However, despite thelack of a matched control group, these studies generally show in-creased rates of neurological sequelae after RT. It is unlikely thata prospective study using a matched control group to determinethe RR of stroke will be undertaken due to the long latent intervalfrom radiation treatment to the development of stroke. Conse-quently, it is reasonable to look at surrogate endpoints that occurat earlier time points in matched case-controlled studies to inves-tigate the risk of radiation-induced vascular damage.

The lack of suitable matched controls is also highlighted in theearlier studies investigating CAS and CIMT. The use of unmatchedcontrols is an inherent weakness and does not account for theother risk factors of atherosclerosis, which would be necessary inorder to demonstrate an effect attributable solely to radiation.Recently, CIMT has been used as a surrogate endpoint for stroke.Mean CIMT correlates with degree of CAS [49]. The study byHeikens et al. [39] highlighted a significant difference in CIMT inthe bulb of the carotid artery, but not other arterial sections. Thatstudy did not give an indication of the radiation dose received bythe carotid arteries, as patients received craniospinal irradiation.However, the minimum dose prescribed to the craniospinalaxis was 30 Gy. The small sample size makes it difficult to drawrobust conclusions, but this study does suggest an increased CIMTafter RT. In the only negative study by Gianicolo et al. [46], it isimportant to note that fewer patients were recruited with ashorter mean interval from RT (with a minimum follow-up ofone month following treatment) than previous studies. Thesefactors may explain the difference in results from other reportedseries.

An important factor associated with significant carotid diseaseis the time interval after RT. Cheng et al. [50] demonstrated thatpatients who had undergone treatment more than five years previ-ously had an 8�5 times greater risk of having CAS of P70% thanthose with fewer than five years of follow-up. These authors, there-fore, advocated routine screening in patients who have received RTto the neck more than five years previously. Brown et al. [34] dem-onstrated a significant increase in CAS in patients who had beenirradiated 10–15 years (p = 0.03) and more than 15 years previ-ously (p = 0.003), but no significant increase was noted in patientstreated fewer than 10 years previously (p = 0.5).

Whether the length of carotid artery that is irradiated or thesection of irradiated artery is related to the development of athero-sclerosis requires further investigation. In the study by Dorresteijnet al. [14], 162 of the 367 patients in the cohort had T1 or T2 larynxcancers, and were treated with a 5 � 5 cm field using parallel-op-posed lateral beams. In the whole group, 14 cases of stroke oc-curred (RR, 5.6; 95% confidence interval [CI], 3.1–9.4): eight inpatients with laryngeal carcinoma (RR, 5.1; 95% CI, 2.2–10.1).Therefore, the length/volume/diameter of carotid artery does notappear to be important. Rather, the carotid artery behaves as a se-rial organ and it is the dose of RT to a particular section of arteryresulting in endothelial damage and subsequent accelerated ath-erosclerosis that is important. In other words, a focal point of crit-ical stenosis in the carotid artery may be just as clinicallysignificant as a diffusely narrowed artery and the risk of strokewould be related to the degree of stenosis at any one point of theartery.

The studies investigating CIMT and CAS have predominantlyshown a difference of around 20–50% in these endpoints betweenirradiated and unirradiated carotid arteries. The hypothesis thatradiation-induced injury results in increased arterial wall thicken-ing (increased CIMT) followed by plaque development in a propor-tion of patients (development of CAS) and lead to the development

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of stroke/TIA in a subset of these patients, seems feasible from thecurrent data. It is reasonable to surmise that patients without in-creased CIMT are less likely to develop significant CAS and, conse-quently, are less likely to suffer a stroke.

The effect of increasing radiation dose on the incidence of caro-tid atherosclerosis has not been well characterised. Radiation dosesassociated with the development of atherosclerosis range from 35–44 Gy (patients undergoing radiotherapy for Hodgkin and non-Hodgkin lymphoma) to 50–80 Gy (patients undergoing RT forbreast cancer (SCF irradiation) or squamous cell carcinoma of thehead and neck) [38,51]. The latency period (i.e. time from radiationtherapy to neurological symptoms) also varies significantly be-tween patients [52]. There is some evidence to suggest that latencymay be dose-dependent [53]. Bowers et al. [16] reported a medianinterval of 17�5 years to stroke onset in patients treated with amedian of 40 Gy for Hodgkin disease. Dorresteijn et al. [14], onthe other hand, reported a median interval of 10 � 9 years to strokeonset in head and neck cancer patients who received 60–70 Gy.However, the relationship between latency and radiation dose isnot clear and requires further investigation.

Gianicolo et al. [46] showed that CIMT increases with increasingdoses of radiation to the neck over a range of 25–70 Gy. Martinet al. [42] noted increased CIMT at doses greater than 35 Gy, sug-gesting a dose effect with regard to vessel wall changes and dam-age. The retrospective study designs, small sample sizes and shortintervals from RT make it difficult to draw robust conclusions fromthese studies. At present, we do not understand what dose of radi-ation will render a significant risk of atherosclerosis or what doseconstraint would be appropriate for carotid-sparing radiotherapyin specific clinical scenarios, such as T1 or T2 glottic cancers wherenodal treatment is not required. It seems sensible that plan homo-geneity be evaluated for all other clinical scenarios to reduce hot-spots on the carotid arteries.

Measurement of CIMT has been a useful new techniqueenabling investigators to predict future risk of stroke and it hasbeen adopted as a surrogate end-point in many cardiovascularstudies [12]. The increase in CIMT seen in irradiated carotidarteries is most likely to represent the accelerated atherosclerosisthat occurs after treatment. Although further prospectivevalidation studies are required, it is reasonable to surmise thatCIMT may be a surrogate for stroke in this setting. The data alsoindicate that significant increase in CIMT occurs over a shortertime-frame (1–2 years for patients with head and neck cancer),making this an attractive endpoint on which to base studies ofradiation-induced vascular injury. Emerging new techniques,including ultrasound-based techniques such as speckle trackingto measure arterial stiffness (an early marker of atherosclerosis)and contrast-enhanced ultrasound to measure arterial inflamma-tion (a very early marker of arterial wall injury) [54,55], mayprovide useful tools to detect changes to the carotid artery at aneven earlier stage, and these may form suitable, earlier surrogatesfor atherosclerosis. Hopefully, these techniques may play a role inthe evaluation of patients with radiation-induced carotid arterydisease.

Conclusion

Carotid artery irradiation is a significant risk factor for athero-sclerosis and subsequent stroke or TIA. Although the body of evi-dence is limited, this risk appears to be related to radiation doseand interval from radiotherapy. The use of earlier surrogate end-points for neurological events with the advent of new imagingtechniques may provide greater understanding of the underlyingprocesses.

artery atherosclerosis. Radiother Oncol (2013), http://dx.doi.org/10.1016/

D.M. Gujral et al. / Radiotherapy and Oncology xxx (2013) xxx–xxx 7

Funding

None.

Conflict of Interest Notification

We declare no conflicts of interest.

Acknowledgements

None.

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