Prospective Cohort Study of Carotid Intima-media Thickness after Irradiation Joyce Wilbers, MD,* Frank J. Hoebers, PhD,† Willem Boogerd, PhD,‡ Erik D. van Werkhoven, Msc,‡ Marlies E. Nowee, PhD,‡ Guus Hart, Msc,‡ Harry Bartelink, PhD,‡ Ewoud J. van Dijk, PhD,* Arnoud C. Kappelle, PhD,* and Lucille D. Dorresteijn, PhDx
Background: Carotid artery vasculopathy is a potential long-term complication after radiotherapy (RT) of the neck, resulting in cerebrovascular events. The underlying pathophysiology is not well understood and early markers are lacking. We aimed to study whether RT of the neck is associated with increase in carotid intimamedia thickness (IMT) and stroke in the first 2 years after RT in patients with head and neck cancer (HNC). Methods: In this prospective cohort study patients treated with RT of the neck were assessed for measurement of IMT before and 2 years after RT. Endpoints were changed in IMT and incidence of first-ever stroke. Results: Between 2003 and 2008 we included 69 patients (median age, 57 years [25%-75% quartile, 51-64 years], median dose of RT 66 Gy [interquartile range, 60-70]) with baseline and follow-up measurement of IMT. Median IMT at baseline and followup was .60 and .62 mm (ratio of geometric means 1.01; 95% confidence interval, .96-1.08; P 5 .63). Four of 69 patients suffered from a stroke. Mean interval from RT to stroke was 6.8 months. Conclusions: Our study showed no increase of carotid IMT in the first 2 years after RT of the neck in patients treated for HNC. This indicates that the IMT is not a reliable early marker for postirradiation vasculopathy. However, a high rate of strokes was observed. A longer follow-up period is needed to find the starting point of RT-induced vascular changes. Key Words: Head and neck cancer—stroke—carotid artery—carotid intima media thickness—radiotherapy. Ó 2014 by National Stroke Association
Introduction From the *Department of Neurology, Radboud University Nijmegen Medical Centre, Nijmegen; †Maastricht University Medical Center, Department of Radiation Oncology (MAASTRO clinic), GROW School for Oncology and Developmental Biology, Maastricht; ‡Department of Neurology/Radiotherapy/Biometrics, Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam; and xDepartment of Neurology, Medisch Spectrum Twente, Enschede, The Netherlands. Received March 28, 2014; revision received May 21, 2014; accepted June 15, 2014. Address correspondence to Ewoud J. van Dijk, PhD, Reinier Postlaan 4, 6525 G.C Nijmegen, Huispost 935, The Netherlands. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2014 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.06.009
Improving cancer treatment has resulted in more longterm survivors. The counterpart is an increase in late cytotoxic effects of both chemo and radiotherapy (RT). A potential devastating long-term side effect of postirradiation vasculopathy of the carotid arteries is the development of ischemic stroke (IS) or transient ischemic attack (TIA).1-3 Although the exact pathophysiology is not well understood, the proposed explanations are induction or acceleration of carotid atherosclerosis.4 It is unclear whether the composition and location of postirradiation plaques and stenosis are different from those of common atherosclerosis due to cardiovascular risk factors. The intima media thickness (IMT) of the carotid artery is a valid method to measure atherosclerosis and a predictor of
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future strokes. Previous retrospective studies showed an increase in carotid IMT after a median follow-up period of 8-10 years after neck irradiation.7-9 Moreover, irradiation of the neck was associated with an increased risk of IS.2 Prospective studies with a follow-up period between 3 months and 3 years showed conflicting results.10-12 The current prospective cohort study aimed to evaluate the changes in carotid IMT in the first 2 years after RT in head and neck cancer (HNC) patients and whether potential change in carotid IMT is associated with an increased incidence of IS in these patients.
Methods A prospective cohort study of HNC patients in 2 centers of The Netherlands (the Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam and the Radboud University Nijmegen Medical Centre, Nijmegen) was initiated. Inclusion criterion was cervical RT because of HNC. Originally, the study was designed as an openlabel multicenter Prospective Randomized Open Blinded Endpoint study to assess the effect of an hydroxymethylglutarylco-enzyme A-reductase (HMG-CoA) reductase inhibitor (atorvastatin) on carotid IMT in the first 2 years after irradiation of the neck. Because of dwindling accrual, the study was redesigned to a prospective cohort study. The initial exclusion criteria were as follows: a history of cerebrovascular disease, pregnancy or breast feeding, ongoing treatment with an HMG-coA reductase or cytochrome P450 inhibitor, active liver disease or more than 3 times the upper limit of serum transaminases, 5 times the normal level of creatine phosphokinase, serum cholesterol more than 7 mmol/L, and a life expectancy less than 2 years. All patients gave written informed consent. The protocol was approved by the local ethics committees.
according to the Modified Trial of Org 10172 in Acute Stroke Treatment classification.13
Radiation Therapy RT was usually given with a linear accelerator and 4-6 MV photons linear accelerator with the patient immobilized using a thermoplastic mask. The target area of the patients entered in this study included at least the ipsilateral neck, including part of the carotid artery system (eg, in case of parotid tumors or well lateralized oropharyngeal carcinomas). In other patients, both sides of the neck and the vascular system were irradiated (eg, in case of laryngeal or hypopharyngeal carcinoma). The radiation treatment was delivered with external beam RT using either standard techniques (parallel opposing beams or wedge-pair techniques) or intensitymodulated RT, depending on resources. The radiation dose given was typically 30-36 Gy for lymphoma, 50-60 Gy for parotid tumors (pleomorphic adenoma or parotid carcinoma), 60-70 Gy for laryngeal carcinoma, and 70 Gy for oropharyngeal and hypopharyngeal carcinoma. In most of the cases, 2 Gy per fraction was delivered up to the specified total dose. For patients with lymphoma, parotid tumors or T1N0 oropharyngeal carcinoma, a standard once-daily fractionation schedule was used. Accelerated fractionation according to the Danish Head and Neck Cancer Study Group (DAHANCA) schedule14 was used for patients with T2 or N1 oropharyngeal carcinomas, hypopharyngeal carcinomas, and larynx carcinoma patients beyond stage T1N0. In patients with T1N0 glottic laryngeal carcinomas, the fractionation schedule was 60 Gy in 25 fractions over 5 weeks to the larynx only, using 2 lateral opposing fields. In every patient separately, the total irradiation dose on the common carotid artery (CCA) and internal carotid artery (ICA) was calculated from the radiation treatment fields.
Baseline and Follow-up Patients were assessed at baseline (before RT) and after 2 years. At every visit height, weight and blood pressure were noted, patients underwent a neurologic and laboratory (C-reactive protein) examination, and the following cerebrovascular risk factors were assessed: (1) cigarette smoking; (2) hypertension, defined as using antihypertensive medication or blood pressure more than 130/80 mm Hg; (3) diabetes mellitus, defined as using antidiabetic medication or a nonfasting serum glucose more than 11.1 mmol/L, medication prescription was checked in the pharmacy database; (4) hypercholesterolemia, defined as serum total cholesterol more than 6.5 mmol/L; and (5) obesity, defined as body mass index more than 30 kg/m2. If patients had suffered from a IS or TIA, detailed medical information was collected from their neurologist and reassessed by one of the investigators (E.v.D.), including assessment of the etiology of stroke
Carotid Ultrasound In patients with laryngeal or hypopharyngeal carcinoma IMT was measured on the CCA, according to the RT field. In patients with other tumors, IMT was measured in both the CCA and the ICA, also according to the RT field. IMT was measured with a linear array transducer (iU22 Philips NZE172 probe, L17-5 Bothell, WA; Hewlett Packard Sonos 2000 probe, 7.5/5.5 Andover, MA; ALOKA 5000 Tokyo, Japan; G.E LOGIQ E9, Wauwatosa, WI), as described earlier.7 IMT pictures were digitally stored on the ultrasound machine or printed in case digital storage was not available. Printed images were then scanned with high resolution and interpolated (using Matlab 2010a, Natick, MA) to obtain the same resolution as the digitally stored images. IMT was automatically measured by 2 blinded investigators (W.R. and J.W.),
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using QLAB (Version 4.2.1; Philips, Baltimore, MD). An edge detection algorithm identified the lumen-intima and the media-adventia interface within a region of interest (selected by the operator) over a maximum of 10-mm long segment and calculated the average thickness.
Outcome The primary endpoint of the study was the change in IMT from baseline to 2 years of follow-up. The secondary endpoint was the incidence of IS or TIA.
Statistical Analyses Log transformation was applied to normalize the distributions of IMT. Log IMT values at baseline and 2 years were compared using a paired t test. To analyze the association between risk factors (and treatment arm and RT dose) and IMT, we used analysis of covariance (ANCOVA), with log IMT at 2 years as outcome and baseline log IMT as covariate. The results were then back transformed. For a fixed value of baseline IMT, the obtained coefficient is an estimate of the ratio between the geometric mean for patients with the particular risk factor compared with the geometric mean for patients without the risk factor. Supplementary ANCOVA models with age as an additional covariate and analysis of variance models with absolute change in log IMT as outcome were performed, to check whether the 2 types of models outcome gave comparable results. Because no major discrepancies were apparent, only the original ANCOVA models were reported. The incidence per person year was calculated and compared with the incidence in the Oxfordshire
Figure 1. Study design. TNM classification of malignant tumors included patients was T1/T2 (N0M0) laryngeal carcinoma, T1/T2 (N0M0) parotid carcinoma/pleomorphic adenoma, and T1/2 (N1/2M0) oro/hypopharynx carcinoma or non-Hodgkin/Hodgkin lymphoma. Abbreviations: IMT, intima-media thickness; RT, radiotherapy.
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Community Stroke Project 1981-1986 and Continue Morbidity Registration Nijmegen17 by assuming a Poisson distribution for the number of events. All analyses were performed using SAS (version 9.2; SAS Institute Inc, Cary, NC) and R version 2.15.2.1
Results Study Population From March 2003 to November 2008 we included 91 patients, of whom 69 were included in the analysis. Figure 1 shows the study design and data lost to followup. Table 1 lists the baseline characteristics. Median dose of RT on measured IMT location was 66 Gy (interquartile range, 60-70).
Intima-media Thickness Median carotid IMT at baseline was .60 mm and at 2 years of follow-up .62 mm. (ratio of geometric means, 1.01; 95% confidence interval, .96-1.08; P 5 .63). Baseline C-reactive protein (CRP), RT dose, and cerebrovascular risk factors (smoking, hypertension, diabetes mellitus, hypercholesterolemia, and obesity) were not associated with change in IMT. Age at diagnosis was significantly associated with IMT at follow-up with a multiplicative effect per 10 years of 1.10 (95% confidence interval, 1.04-1.16; P 5 .001; Table 2). IMT increase from baseline to 2 years of follow-up was not different between the patients treated with or without atorvastatin (2.04 mm vs. .01 mm, respectively, P value .96).
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Table 1. Patient baseline and treatment characteristics Characteristic
N 5 91
Gender (male) Age, y* Tumor location Larynx Parotid Oropharynx Hypopharynx Lymphoma RT cervical lymph nodes Dose on IMT location Low dose (30-55 Gy) Middle dose (55-68 Gy) High dose (68-70 Gy) CV risk factors Smoking history Never smoked Former smoker (stopped .3 y ago) Current smoker or stopped ,3 y ago NA Hypertension Diabetes mellitus Hypercholesterolemia Obesity Number CV risk factors 0 1 $2
61 (67) 57 (51-64) 46 (51) 22 (24) 16 (18) 4 (4) 3 (3) 43 (47) 17 (19) 38 (42) 36 (40)
22 (24) 18 (20) 48 (53) 3 (3) 29 (32) 5 (5) 8 (15) 3 (6) 24 (26) 37 (41) 30 (33)
Abbreviations: CV, cerebrovascular; IMT, intima-media thickness; NA, not answered; RT, radiotherapy. Data are expressed as absolute numbers of patients (%), unless otherwise indicated. CV risk factors consist of current smoking, hypertension, diabetes mellitus, hypercholesterolemia, and obesity. *Age is expressed as median (25%-75% quartile).
Cerebrovascular Accidents From baseline to 2 years of follow-up, 4 of 69 patients suffered from a IS (n 5 2) or TIA (n 5 2). Mean age at stroke was 69 years. Mean RT stroke interval was 6.8 months (Table 3) In 2 patients, the vascular territory matched with the high RT portal field.
Discussion Our study showed no increase in carotid IMT in the first 2 years after neck irradiation. This result is in accordance with prior retrospective studies that demonstrated an increase in carotid IMT after a median follow up of 8-10 years after irradiation.7-9 However, the starting point of this increase in carotid wall thickness was unclear. These prior retrospective studies lacked baseline IMT measurements; hence, other factors could be the cause of the IMT increase.
A recent review pointed to the problem that the long latent interval from treatment to the development of clinical complications makes investigation of this process difficult.4 The strength of our study was the prospective design and the precise computer-assisted measurement of the IMT. By our knowledge, this is the largest and longest prospective postneck irradiation cohort study with baseline and follow-up IMT measurements. Although the present study was done in a heterogeneous group of patients with different malignancies of the head and neck region, the RT treatment protocols were homogeneous, and because of this, our results have high external validity. Information bias was minimalized, because baseline and follow-up IMT were separately assessed by 1 investigator, unaware which one was baseline or follow-up. Our study contradicts the conflicting results of prior small prospective studies, with only a short follow-up period after RT. The first described prospective study of a small group of 36 HNC patients, found a significant increase in the IMT of both the left (.67 vs. .84 mm) and right (.70 vs. .87 mm) carotid artery 1 year after irradiation, with a further increase in a subgroup of 12 patients 2 years after RT.10 Characteristics (RT dosage or cerebrovascular risk factors) of this subgroup were not described. Average RT dose was 60 Gy and therefore comparable with our study. However, compared with our data, the IMT was not measured digitally, the mean age of the study population was 3.5 years higher and possible confounding factors were not taken into account. Another prospective study of 19 patients treated for HNC with a mean age of 55 years and a dose of 66 Gy, showed no significant increase in IMT from baseline to only 6 months after RT.11 A larger prospective study of 96 patients with a mean age of 59.3 years, treated for non-Hodgkin lymphoma (n 5 54) or Hodgkin disease (n 5 42) with chemotherapy and external beam RT of a mantle field (total dose of upper body 36-40 Gy) showed a significant decrease in IMT 3 years after RT compared with the first year after RT.12 However, baseline IMT and dosage of RT on the IMT location were lacking, and 21% of patients were lost to follow up, which was a potential selection bias. The temporary increase of IMT in the first year after RT was attributed to edema, but regression toward the mean could be another explanation. Taken these results together, we think IMT is not a reliable early marker for RT-induced carotid artery vasculopathy. Limitations of the present study were a potential underestimation of IMT change, firstly because of regression dilution bias as a consequence of 2 blinded separated measurements instead of a single measurement of change in IMT, and secondly, there could be selective follow-up and we included patients with a relative favorable vascular risk profile, because patients with former TIA/ stroke and those who were on HMG-coA reductase inhibitors were excluded.
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Table 2. Estimated multiplicative effect of baseline characteristics and RT dosage on 2 year IMT value, adjusted for baseline IMT Characteristic
Multiplicative effect* (95% CI)
P value
1.03 (.91-1.17) .98 (.82-1.17) 1.00 (.72-1.41) 1.05 (.91-1.21) 1.06 (.80-1.40) 1.09 (.95-1.26) 1.10 (1.04-1.16) 1.01 (.94-1.09)
.67 .80 .98 .53 .71 .22 .0012 .85 .16z
Baseline characteristics Current smoking Hypercholesterolemia Obesity Hypertension Diabetes mellitus Any cerebrovascular risk factory Age (per 10 y) Log CRP value (per standard deviation) Tumor type Parotid carcinoma versus larynx carcinoma Pleomorphic parotid adenoma versus larynx carcinoma Oropharynx carcinoma versus larynx carcinoma Hypopharynx carcinoma versus larynx carcinoma Hodgkin lymphoma versus larynx carcinoma Radiotherapy treatment RT dose 55-68 Gy versus 30-55 Gy RT dose 68-71 Gy versus 30-55 Gy
.76 (.61-.95) .88 (.72-1.08) .90 (.75-1.08) 1.13 (.82-1.56) 1.02 (.78-1.34) .89z 1.02 (.85-1.22) 1.04 (.87-1.25)
Abbreviations: CI, confidence interval; IMT, intima-media thickness; RT, radiotherapy. *The coefficient is an estimate of the ratio between the geometric mean for patients with the particular risk factor compared with the geometric mean for patients without the risk factor. yCerebrovascular risk factors consist of current smoking, hypertension, diabetes mellitus, hypercholesterolemia, and obesity. zMultiple degrees of freedom test.
The underlying pathophysiology of RT-induced vasculopathy needs to be further elucidated, but RT typically damages all the 3 layers of the vessel wall.18 Histopathologic studies showed that RT-induced vasculopathy differed from the common atherosclerosis in a trend toward greater lipid and calcium content of the plaques, more thickening and fibrotic changes of the adventitia, and more pronounced thinning of the media.19 Inflammation plays a central role in the inception and progression of atherosclerosis, and plasma CRP is a systemic
biomarker associated with local atherosclerosis and a predictor of future cardiovascular events.20 We did not find a correlation between CRP before and after RT or between baseline CRP and change in IMT. However, the change in CRP could be too small and the power of the study insufficient to rule out such a relationship. The annual incidence rate of first-ever IS or TIA in our cohort was both 15 of 1000 patient-years. These are relative high numbers compared with community-based studies, like the Oxfordshire Community Stroke Project,
Table 3. Demographics, treatment, and stroke characteristics in patients diagnosed with a stroke Baseline/Treatment characteristics
Sex M M F F Mean
Stroke characteristics
Vascular Dose RT on IMT territory: Time interval Type of stroke Tumor RF* Age, y location, Gy IMT,y mm Type Age, y Dose RT, Gy RT/stroke, mo (TOAST) Larynx Larynx Parotid Larynx
1 1 2 1
71 78 53 71 68.3
CCA: 66 CCA: 60 ICA: 60 CCA: 66
.00 1.16 2.07 1.30
IS IS TIA TIA
72 78 54 72 69
L CA: 66 VA: 6 L CA: 0 L CA: 66
9.2 6.8 3.3 7.9 6.8
LAA SVO UD UD
Abbreviations: CA, carotid artery; CCA, common carotid artery; F, female; ICA, internal carotid artery; IMT, intima-media thickness; IS, ischemic stroke; L, left; LAA, large artery atherosclerosis; M, male; RF, risk factors (number); RT, radiotherapy; SVO, small vessel occlusion; TIA, transient ischemic attack; TOAST, Trial of Org 10172 in Acute Stroke Treatment; UD, undetermined; VA, vertebral artery. *Number of risk factors consisting of current smoking, hypertension, diabetes mellitus, hypercholesterolemia, and obesity. yIMT change between baseline and 2 year.
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in which the rates are, respectively, 1.60 of 1000 and .35 of 1000.15,16 However, the absolute low number of incident cases in our cohort and the indirect comparison withhold us from further speculation. The low absolute number of strokes in our cohort lacks statistical power for further analysis. The mean time between RT and ischemic event (6.8 months) is very short, and there is no relation between IMT increases. Possible other explanations for this high incidence rate of stroke (compared with the community) are as follows: a merely high incidence in the HNC patients, related to cerebrovascular risk factors, a hypercoagulable state in oncologic patients, or an acute RT-induced temporarily inflammatory reaction instead of IMT increase. It is known that neck irradiation is associated with at least a doubled relative risk of IS or TIA on the long term (4-18 years after RT).18 Two mechanisms of RTinduced vasculopathy should be distinguished; besides the chronic stenotic form of disease, which may take several years to develop, acute vascular complications as a consequence of periarterial inflammation and plaque rupture can occur within a short follow-up period after RT.21 The fact that 2 of the 4 patients who suffered from a stroke had symptoms compatible with a vascular territory outside the high portal RT field implicates that this study population has already a high chance to develop a stroke, probably because of not RT associated causes, like a hypercoagulable state as a consequence of a paraneoplastic effect22 or lifestyle factors. Increased IMT is associated with vascular risk factors.5,23 In a retrospective cohort study among 5 years survivors of Hodgkin disease, hypertension, diabetes, and hypercholesterolemia were associated with the occurrence of IS, whereas smoking and overweight were not.3 We found no correlation between baseline cerebrovascular risk factors and change in IMT. However, the most frequent baseline risk factor was smoking, and most patients stopped smoking for a period during and after RT. In conclusion, the present study showed no increase in carotid IMT within the first 2 years after neck irradiation. These results suggest that carotid IMT is not a reliable early marker of RT-induced carotid vasculopathy. Because IMT can increase during a longer time interval, we will increase the follow-up period of the present cohort. Acknowledgments: We would like to thank S. Bossmann and M. van Zanten for data collection, W. Raijmann for performing the IMT measurements, and M. Massa and H. van Dijk for the computer-assisted analysis of the IMT measurements.
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References 1. Bowers DC, McNeil DE, Liu Y, et al. Stroke as a late treatment effect of Hodgkin’s disease: a report from the
Childhood Cancer Survivor Study. J Clin Oncol 2005;23: 6508-6515. Dorresteijn LD, Kappelle AC, Boogerd W, et al. Increased risk of ischemic stroke after radiotherapy on the neck in patients younger than 60 years. J Clin Oncol 2002;20: 282-288. De Bruin ML, Dorresteijn LD, van’t Veer MB, et al. Increased risk of stroke and transient ischemic attack in 5-year survivors of Hodgkin lymphoma. J Natl Cancer Inst 2009;101:928-937. Gujral DM, Shah BN, Chahal NS, et al. Clinical features of radiation-induced carotid atherosclerosis. Clin Oncol 2013. Bots ML, Hoes AW, Koudstaal PJ, et al. Common carotid intima-media thickness and risk of stroke and myocardial infarction: the Rotterdam Study. Circulation 1997;96: 1432-1437. Hollander M, Hak AE, Koudstaal PJ, et al. Comparison between measures of atherosclerosis and risk of stroke: the Rotterdam Study. Stroke 2003;34:2367-2372. Dorresteijn LD, Kappelle AC, Scholz NM, et al. Increased carotid wall thickening after radiotherapy on the neck. Eur J Cancer 2005;41:1026-1030. Brown PD, Foote RL, McLaughlin MP, et al. A historical prospective cohort study of carotid artery stenosis after radiotherapy for head and neck malignancies. Int J Radiat Oncol Biol Phys 2005;63:1361-1367. So NM, Lam WW, Chook P, et al. Carotid intima-media thickness in patients with head and neck irradiation for the treatment of nasopharyngeal carcinoma. Clin Radiol 2002;57:600-603. Muzaffar K, Collins SL, Labropoulos N, et al. A prospective study of the effects of irradiation on the carotid artery. Laryngoscope 2000;110:1811-1814. Pereira Lima MN, Biolo A, Foppa M, et al. A prospective, comparative study on the early effects of local and remote radiation therapy on carotid intima-media thickness and vascular cellular adhesion molecule-1 in patients with head and neck and prostate tumors. Radiother Oncol 2010. Bilora F, Pietrogrande F, Campagnolo E, et al. Are Hodgkin and non-Hodgkin patients at a greater risk of atherosclerosis? A follow-up of 3 years. Eur J Cancer Care(Engl) 2010;19:417-419. Adams HP, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. Stroke 1993;24: 35-41. Overgaard J, Hansen HS, Specht L, et al. Five compared with six fractions per week of conventional radiotherapy of squamous-cell carcinoma of head and neck: DAHANCA 6 and 7 randomised controlled trial. Lancet 2003;362:933-940. Bamford J, Sandercock P, Dennis M, et al. A prospective study of acute cerebrovascular disease in the community: the Oxfordshire Community Stroke Project 1981-86. 1. Methodology, demography and incident cases of firstever stroke. J Neurol Neurosurg Psychiatry 1988;51: 1373-1380. Dennis MS, Bamford JM, Sandercock PA, et al. Incidence of transient ischemic attacks in Oxfordshire, England. Stroke 1989;20:333-339. Lopata RG, Nillesen MM, Hansen HH, et al. Performance evaluation of methods for two-dimensional displacement and strain estimation using ultrasound radio frequency data. Ultrasound Med Biol 2009;35: 796-812.
IMT AFTER NECK IRRADIATION 18. Plummer C, Henderson RD, O’Sullivan JD, et al. Ischemic stroke and transient ischemic attack after head and neck radiotherapy: a review. Stroke 2011;42: 2410-2418. 19. Virmani R, Farb A, Carter AJ, et al. Pathology of radiation-induced coronary artery disease in human and pig. Cardiovasc Radiat Med 1999;1:98-101. 20. Ross R. Atherosclerosis–an inflammatory disease. N Engl J Med 1999;340:115-126.
2707 21. Jurado JA, Bashir R, Burket MW. Radiation-induced peripheral artery disease. Catheter Cardiovasc Interv 2008; 72:563-568. 22. Rogers LR. Cerebrovascular complications in patients with cancer. Semin Neurol 2010;30:311-319. 23. Lorenz MW, Markus HS, Bots ML, et al. Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation 2007;115:459-467.
Background: Carotid artery vasculopathy is a potential long-term complication after radiotherapy (RT) of the neck, resulting in cerebrovascular events. The underlying pathophysiology is not well understood and early markers are lacking. We aimed to study whether RT of the neck is associated with increase in carotid intimamedia thickness (IMT) and stroke in the first 2 years after RT in patients with head and neck cancer (HNC). Methods: In this prospective cohort study patients treated with RT of the neck were assessed for measurement of IMT before and 2 years after RT. Endpoints were changed in IMT and incidence of first-ever stroke. Results: Between 2003 and 2008 we included 69 patients (median age, 57 years [25%-75% quartile, 51-64 years], median dose of RT 66 Gy [interquartile range, 60-70]) with baseline and follow-up measurement of IMT. Median IMT at baseline and followup was .60 and .62 mm (ratio of geometric means 1.01; 95% confidence interval, .96-1.08; P 5 .63). Four of 69 patients suffered from a stroke. Mean interval from RT to stroke was 6.8 months. Conclusions: Our study showed no increase of carotid IMT in the first 2 years after RT of the neck in patients treated for HNC. This indicates that the IMT is not a reliable early marker for postirradiation vasculopathy. However, a high rate of strokes was observed. A longer follow-up period is needed to find the starting point of RT-induced vascular changes. Key Words: Head and neck cancer—stroke—carotid artery—carotid intima media thickness—radiotherapy. Ó 2014 by National Stroke Association
Introduction From the *Department of Neurology, Radboud University Nijmegen Medical Centre, Nijmegen; †Maastricht University Medical Center, Department of Radiation Oncology (MAASTRO clinic), GROW School for Oncology and Developmental Biology, Maastricht; ‡Department of Neurology/Radiotherapy/Biometrics, Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam; and xDepartment of Neurology, Medisch Spectrum Twente, Enschede, The Netherlands. Received March 28, 2014; revision received May 21, 2014; accepted June 15, 2014. Address correspondence to Ewoud J. van Dijk, PhD, Reinier Postlaan 4, 6525 G.C Nijmegen, Huispost 935, The Netherlands. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2014 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.06.009
Improving cancer treatment has resulted in more longterm survivors. The counterpart is an increase in late cytotoxic effects of both chemo and radiotherapy (RT). A potential devastating long-term side effect of postirradiation vasculopathy of the carotid arteries is the development of ischemic stroke (IS) or transient ischemic attack (TIA).1-3 Although the exact pathophysiology is not well understood, the proposed explanations are induction or acceleration of carotid atherosclerosis.4 It is unclear whether the composition and location of postirradiation plaques and stenosis are different from those of common atherosclerosis due to cardiovascular risk factors. The intima media thickness (IMT) of the carotid artery is a valid method to measure atherosclerosis and a predictor of
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future strokes. Previous retrospective studies showed an increase in carotid IMT after a median follow-up period of 8-10 years after neck irradiation.7-9 Moreover, irradiation of the neck was associated with an increased risk of IS.2 Prospective studies with a follow-up period between 3 months and 3 years showed conflicting results.10-12 The current prospective cohort study aimed to evaluate the changes in carotid IMT in the first 2 years after RT in head and neck cancer (HNC) patients and whether potential change in carotid IMT is associated with an increased incidence of IS in these patients.
Methods A prospective cohort study of HNC patients in 2 centers of The Netherlands (the Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam and the Radboud University Nijmegen Medical Centre, Nijmegen) was initiated. Inclusion criterion was cervical RT because of HNC. Originally, the study was designed as an openlabel multicenter Prospective Randomized Open Blinded Endpoint study to assess the effect of an hydroxymethylglutarylco-enzyme A-reductase (HMG-CoA) reductase inhibitor (atorvastatin) on carotid IMT in the first 2 years after irradiation of the neck. Because of dwindling accrual, the study was redesigned to a prospective cohort study. The initial exclusion criteria were as follows: a history of cerebrovascular disease, pregnancy or breast feeding, ongoing treatment with an HMG-coA reductase or cytochrome P450 inhibitor, active liver disease or more than 3 times the upper limit of serum transaminases, 5 times the normal level of creatine phosphokinase, serum cholesterol more than 7 mmol/L, and a life expectancy less than 2 years. All patients gave written informed consent. The protocol was approved by the local ethics committees.
according to the Modified Trial of Org 10172 in Acute Stroke Treatment classification.13
Radiation Therapy RT was usually given with a linear accelerator and 4-6 MV photons linear accelerator with the patient immobilized using a thermoplastic mask. The target area of the patients entered in this study included at least the ipsilateral neck, including part of the carotid artery system (eg, in case of parotid tumors or well lateralized oropharyngeal carcinomas). In other patients, both sides of the neck and the vascular system were irradiated (eg, in case of laryngeal or hypopharyngeal carcinoma). The radiation treatment was delivered with external beam RT using either standard techniques (parallel opposing beams or wedge-pair techniques) or intensitymodulated RT, depending on resources. The radiation dose given was typically 30-36 Gy for lymphoma, 50-60 Gy for parotid tumors (pleomorphic adenoma or parotid carcinoma), 60-70 Gy for laryngeal carcinoma, and 70 Gy for oropharyngeal and hypopharyngeal carcinoma. In most of the cases, 2 Gy per fraction was delivered up to the specified total dose. For patients with lymphoma, parotid tumors or T1N0 oropharyngeal carcinoma, a standard once-daily fractionation schedule was used. Accelerated fractionation according to the Danish Head and Neck Cancer Study Group (DAHANCA) schedule14 was used for patients with T2 or N1 oropharyngeal carcinomas, hypopharyngeal carcinomas, and larynx carcinoma patients beyond stage T1N0. In patients with T1N0 glottic laryngeal carcinomas, the fractionation schedule was 60 Gy in 25 fractions over 5 weeks to the larynx only, using 2 lateral opposing fields. In every patient separately, the total irradiation dose on the common carotid artery (CCA) and internal carotid artery (ICA) was calculated from the radiation treatment fields.
Baseline and Follow-up Patients were assessed at baseline (before RT) and after 2 years. At every visit height, weight and blood pressure were noted, patients underwent a neurologic and laboratory (C-reactive protein) examination, and the following cerebrovascular risk factors were assessed: (1) cigarette smoking; (2) hypertension, defined as using antihypertensive medication or blood pressure more than 130/80 mm Hg; (3) diabetes mellitus, defined as using antidiabetic medication or a nonfasting serum glucose more than 11.1 mmol/L, medication prescription was checked in the pharmacy database; (4) hypercholesterolemia, defined as serum total cholesterol more than 6.5 mmol/L; and (5) obesity, defined as body mass index more than 30 kg/m2. If patients had suffered from a IS or TIA, detailed medical information was collected from their neurologist and reassessed by one of the investigators (E.v.D.), including assessment of the etiology of stroke
Carotid Ultrasound In patients with laryngeal or hypopharyngeal carcinoma IMT was measured on the CCA, according to the RT field. In patients with other tumors, IMT was measured in both the CCA and the ICA, also according to the RT field. IMT was measured with a linear array transducer (iU22 Philips NZE172 probe, L17-5 Bothell, WA; Hewlett Packard Sonos 2000 probe, 7.5/5.5 Andover, MA; ALOKA 5000 Tokyo, Japan; G.E LOGIQ E9, Wauwatosa, WI), as described earlier.7 IMT pictures were digitally stored on the ultrasound machine or printed in case digital storage was not available. Printed images were then scanned with high resolution and interpolated (using Matlab 2010a, Natick, MA) to obtain the same resolution as the digitally stored images. IMT was automatically measured by 2 blinded investigators (W.R. and J.W.),
IMT AFTER NECK IRRADIATION
using QLAB (Version 4.2.1; Philips, Baltimore, MD). An edge detection algorithm identified the lumen-intima and the media-adventia interface within a region of interest (selected by the operator) over a maximum of 10-mm long segment and calculated the average thickness.
Outcome The primary endpoint of the study was the change in IMT from baseline to 2 years of follow-up. The secondary endpoint was the incidence of IS or TIA.
Statistical Analyses Log transformation was applied to normalize the distributions of IMT. Log IMT values at baseline and 2 years were compared using a paired t test. To analyze the association between risk factors (and treatment arm and RT dose) and IMT, we used analysis of covariance (ANCOVA), with log IMT at 2 years as outcome and baseline log IMT as covariate. The results were then back transformed. For a fixed value of baseline IMT, the obtained coefficient is an estimate of the ratio between the geometric mean for patients with the particular risk factor compared with the geometric mean for patients without the risk factor. Supplementary ANCOVA models with age as an additional covariate and analysis of variance models with absolute change in log IMT as outcome were performed, to check whether the 2 types of models outcome gave comparable results. Because no major discrepancies were apparent, only the original ANCOVA models were reported. The incidence per person year was calculated and compared with the incidence in the Oxfordshire
Figure 1. Study design. TNM classification of malignant tumors included patients was T1/T2 (N0M0) laryngeal carcinoma, T1/T2 (N0M0) parotid carcinoma/pleomorphic adenoma, and T1/2 (N1/2M0) oro/hypopharynx carcinoma or non-Hodgkin/Hodgkin lymphoma. Abbreviations: IMT, intima-media thickness; RT, radiotherapy.
2703 15,16
Community Stroke Project 1981-1986 and Continue Morbidity Registration Nijmegen17 by assuming a Poisson distribution for the number of events. All analyses were performed using SAS (version 9.2; SAS Institute Inc, Cary, NC) and R version 2.15.2.1
Results Study Population From March 2003 to November 2008 we included 91 patients, of whom 69 were included in the analysis. Figure 1 shows the study design and data lost to followup. Table 1 lists the baseline characteristics. Median dose of RT on measured IMT location was 66 Gy (interquartile range, 60-70).
Intima-media Thickness Median carotid IMT at baseline was .60 mm and at 2 years of follow-up .62 mm. (ratio of geometric means, 1.01; 95% confidence interval, .96-1.08; P 5 .63). Baseline C-reactive protein (CRP), RT dose, and cerebrovascular risk factors (smoking, hypertension, diabetes mellitus, hypercholesterolemia, and obesity) were not associated with change in IMT. Age at diagnosis was significantly associated with IMT at follow-up with a multiplicative effect per 10 years of 1.10 (95% confidence interval, 1.04-1.16; P 5 .001; Table 2). IMT increase from baseline to 2 years of follow-up was not different between the patients treated with or without atorvastatin (2.04 mm vs. .01 mm, respectively, P value .96).
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Table 1. Patient baseline and treatment characteristics Characteristic
N 5 91
Gender (male) Age, y* Tumor location Larynx Parotid Oropharynx Hypopharynx Lymphoma RT cervical lymph nodes Dose on IMT location Low dose (30-55 Gy) Middle dose (55-68 Gy) High dose (68-70 Gy) CV risk factors Smoking history Never smoked Former smoker (stopped .3 y ago) Current smoker or stopped ,3 y ago NA Hypertension Diabetes mellitus Hypercholesterolemia Obesity Number CV risk factors 0 1 $2
61 (67) 57 (51-64) 46 (51) 22 (24) 16 (18) 4 (4) 3 (3) 43 (47) 17 (19) 38 (42) 36 (40)
22 (24) 18 (20) 48 (53) 3 (3) 29 (32) 5 (5) 8 (15) 3 (6) 24 (26) 37 (41) 30 (33)
Abbreviations: CV, cerebrovascular; IMT, intima-media thickness; NA, not answered; RT, radiotherapy. Data are expressed as absolute numbers of patients (%), unless otherwise indicated. CV risk factors consist of current smoking, hypertension, diabetes mellitus, hypercholesterolemia, and obesity. *Age is expressed as median (25%-75% quartile).
Cerebrovascular Accidents From baseline to 2 years of follow-up, 4 of 69 patients suffered from a IS (n 5 2) or TIA (n 5 2). Mean age at stroke was 69 years. Mean RT stroke interval was 6.8 months (Table 3) In 2 patients, the vascular territory matched with the high RT portal field.
Discussion Our study showed no increase in carotid IMT in the first 2 years after neck irradiation. This result is in accordance with prior retrospective studies that demonstrated an increase in carotid IMT after a median follow up of 8-10 years after irradiation.7-9 However, the starting point of this increase in carotid wall thickness was unclear. These prior retrospective studies lacked baseline IMT measurements; hence, other factors could be the cause of the IMT increase.
A recent review pointed to the problem that the long latent interval from treatment to the development of clinical complications makes investigation of this process difficult.4 The strength of our study was the prospective design and the precise computer-assisted measurement of the IMT. By our knowledge, this is the largest and longest prospective postneck irradiation cohort study with baseline and follow-up IMT measurements. Although the present study was done in a heterogeneous group of patients with different malignancies of the head and neck region, the RT treatment protocols were homogeneous, and because of this, our results have high external validity. Information bias was minimalized, because baseline and follow-up IMT were separately assessed by 1 investigator, unaware which one was baseline or follow-up. Our study contradicts the conflicting results of prior small prospective studies, with only a short follow-up period after RT. The first described prospective study of a small group of 36 HNC patients, found a significant increase in the IMT of both the left (.67 vs. .84 mm) and right (.70 vs. .87 mm) carotid artery 1 year after irradiation, with a further increase in a subgroup of 12 patients 2 years after RT.10 Characteristics (RT dosage or cerebrovascular risk factors) of this subgroup were not described. Average RT dose was 60 Gy and therefore comparable with our study. However, compared with our data, the IMT was not measured digitally, the mean age of the study population was 3.5 years higher and possible confounding factors were not taken into account. Another prospective study of 19 patients treated for HNC with a mean age of 55 years and a dose of 66 Gy, showed no significant increase in IMT from baseline to only 6 months after RT.11 A larger prospective study of 96 patients with a mean age of 59.3 years, treated for non-Hodgkin lymphoma (n 5 54) or Hodgkin disease (n 5 42) with chemotherapy and external beam RT of a mantle field (total dose of upper body 36-40 Gy) showed a significant decrease in IMT 3 years after RT compared with the first year after RT.12 However, baseline IMT and dosage of RT on the IMT location were lacking, and 21% of patients were lost to follow up, which was a potential selection bias. The temporary increase of IMT in the first year after RT was attributed to edema, but regression toward the mean could be another explanation. Taken these results together, we think IMT is not a reliable early marker for RT-induced carotid artery vasculopathy. Limitations of the present study were a potential underestimation of IMT change, firstly because of regression dilution bias as a consequence of 2 blinded separated measurements instead of a single measurement of change in IMT, and secondly, there could be selective follow-up and we included patients with a relative favorable vascular risk profile, because patients with former TIA/ stroke and those who were on HMG-coA reductase inhibitors were excluded.
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Table 2. Estimated multiplicative effect of baseline characteristics and RT dosage on 2 year IMT value, adjusted for baseline IMT Characteristic
Multiplicative effect* (95% CI)
P value
1.03 (.91-1.17) .98 (.82-1.17) 1.00 (.72-1.41) 1.05 (.91-1.21) 1.06 (.80-1.40) 1.09 (.95-1.26) 1.10 (1.04-1.16) 1.01 (.94-1.09)
.67 .80 .98 .53 .71 .22 .0012 .85 .16z
Baseline characteristics Current smoking Hypercholesterolemia Obesity Hypertension Diabetes mellitus Any cerebrovascular risk factory Age (per 10 y) Log CRP value (per standard deviation) Tumor type Parotid carcinoma versus larynx carcinoma Pleomorphic parotid adenoma versus larynx carcinoma Oropharynx carcinoma versus larynx carcinoma Hypopharynx carcinoma versus larynx carcinoma Hodgkin lymphoma versus larynx carcinoma Radiotherapy treatment RT dose 55-68 Gy versus 30-55 Gy RT dose 68-71 Gy versus 30-55 Gy
.76 (.61-.95) .88 (.72-1.08) .90 (.75-1.08) 1.13 (.82-1.56) 1.02 (.78-1.34) .89z 1.02 (.85-1.22) 1.04 (.87-1.25)
Abbreviations: CI, confidence interval; IMT, intima-media thickness; RT, radiotherapy. *The coefficient is an estimate of the ratio between the geometric mean for patients with the particular risk factor compared with the geometric mean for patients without the risk factor. yCerebrovascular risk factors consist of current smoking, hypertension, diabetes mellitus, hypercholesterolemia, and obesity. zMultiple degrees of freedom test.
The underlying pathophysiology of RT-induced vasculopathy needs to be further elucidated, but RT typically damages all the 3 layers of the vessel wall.18 Histopathologic studies showed that RT-induced vasculopathy differed from the common atherosclerosis in a trend toward greater lipid and calcium content of the plaques, more thickening and fibrotic changes of the adventitia, and more pronounced thinning of the media.19 Inflammation plays a central role in the inception and progression of atherosclerosis, and plasma CRP is a systemic
biomarker associated with local atherosclerosis and a predictor of future cardiovascular events.20 We did not find a correlation between CRP before and after RT or between baseline CRP and change in IMT. However, the change in CRP could be too small and the power of the study insufficient to rule out such a relationship. The annual incidence rate of first-ever IS or TIA in our cohort was both 15 of 1000 patient-years. These are relative high numbers compared with community-based studies, like the Oxfordshire Community Stroke Project,
Table 3. Demographics, treatment, and stroke characteristics in patients diagnosed with a stroke Baseline/Treatment characteristics
Sex M M F F Mean
Stroke characteristics
Vascular Dose RT on IMT territory: Time interval Type of stroke Tumor RF* Age, y location, Gy IMT,y mm Type Age, y Dose RT, Gy RT/stroke, mo (TOAST) Larynx Larynx Parotid Larynx
1 1 2 1
71 78 53 71 68.3
CCA: 66 CCA: 60 ICA: 60 CCA: 66
.00 1.16 2.07 1.30
IS IS TIA TIA
72 78 54 72 69
L CA: 66 VA: 6 L CA: 0 L CA: 66
9.2 6.8 3.3 7.9 6.8
LAA SVO UD UD
Abbreviations: CA, carotid artery; CCA, common carotid artery; F, female; ICA, internal carotid artery; IMT, intima-media thickness; IS, ischemic stroke; L, left; LAA, large artery atherosclerosis; M, male; RF, risk factors (number); RT, radiotherapy; SVO, small vessel occlusion; TIA, transient ischemic attack; TOAST, Trial of Org 10172 in Acute Stroke Treatment; UD, undetermined; VA, vertebral artery. *Number of risk factors consisting of current smoking, hypertension, diabetes mellitus, hypercholesterolemia, and obesity. yIMT change between baseline and 2 year.
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in which the rates are, respectively, 1.60 of 1000 and .35 of 1000.15,16 However, the absolute low number of incident cases in our cohort and the indirect comparison withhold us from further speculation. The low absolute number of strokes in our cohort lacks statistical power for further analysis. The mean time between RT and ischemic event (6.8 months) is very short, and there is no relation between IMT increases. Possible other explanations for this high incidence rate of stroke (compared with the community) are as follows: a merely high incidence in the HNC patients, related to cerebrovascular risk factors, a hypercoagulable state in oncologic patients, or an acute RT-induced temporarily inflammatory reaction instead of IMT increase. It is known that neck irradiation is associated with at least a doubled relative risk of IS or TIA on the long term (4-18 years after RT).18 Two mechanisms of RTinduced vasculopathy should be distinguished; besides the chronic stenotic form of disease, which may take several years to develop, acute vascular complications as a consequence of periarterial inflammation and plaque rupture can occur within a short follow-up period after RT.21 The fact that 2 of the 4 patients who suffered from a stroke had symptoms compatible with a vascular territory outside the high portal RT field implicates that this study population has already a high chance to develop a stroke, probably because of not RT associated causes, like a hypercoagulable state as a consequence of a paraneoplastic effect22 or lifestyle factors. Increased IMT is associated with vascular risk factors.5,23 In a retrospective cohort study among 5 years survivors of Hodgkin disease, hypertension, diabetes, and hypercholesterolemia were associated with the occurrence of IS, whereas smoking and overweight were not.3 We found no correlation between baseline cerebrovascular risk factors and change in IMT. However, the most frequent baseline risk factor was smoking, and most patients stopped smoking for a period during and after RT. In conclusion, the present study showed no increase in carotid IMT within the first 2 years after neck irradiation. These results suggest that carotid IMT is not a reliable early marker of RT-induced carotid vasculopathy. Because IMT can increase during a longer time interval, we will increase the follow-up period of the present cohort. Acknowledgments: We would like to thank S. Bossmann and M. van Zanten for data collection, W. Raijmann for performing the IMT measurements, and M. Massa and H. van Dijk for the computer-assisted analysis of the IMT measurements.
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References 1. Bowers DC, McNeil DE, Liu Y, et al. Stroke as a late treatment effect of Hodgkin’s disease: a report from the
Childhood Cancer Survivor Study. J Clin Oncol 2005;23: 6508-6515. Dorresteijn LD, Kappelle AC, Boogerd W, et al. Increased risk of ischemic stroke after radiotherapy on the neck in patients younger than 60 years. J Clin Oncol 2002;20: 282-288. De Bruin ML, Dorresteijn LD, van’t Veer MB, et al. Increased risk of stroke and transient ischemic attack in 5-year survivors of Hodgkin lymphoma. J Natl Cancer Inst 2009;101:928-937. Gujral DM, Shah BN, Chahal NS, et al. Clinical features of radiation-induced carotid atherosclerosis. Clin Oncol 2013. Bots ML, Hoes AW, Koudstaal PJ, et al. Common carotid intima-media thickness and risk of stroke and myocardial infarction: the Rotterdam Study. Circulation 1997;96: 1432-1437. Hollander M, Hak AE, Koudstaal PJ, et al. Comparison between measures of atherosclerosis and risk of stroke: the Rotterdam Study. Stroke 2003;34:2367-2372. Dorresteijn LD, Kappelle AC, Scholz NM, et al. Increased carotid wall thickening after radiotherapy on the neck. Eur J Cancer 2005;41:1026-1030. Brown PD, Foote RL, McLaughlin MP, et al. A historical prospective cohort study of carotid artery stenosis after radiotherapy for head and neck malignancies. Int J Radiat Oncol Biol Phys 2005;63:1361-1367. So NM, Lam WW, Chook P, et al. Carotid intima-media thickness in patients with head and neck irradiation for the treatment of nasopharyngeal carcinoma. Clin Radiol 2002;57:600-603. Muzaffar K, Collins SL, Labropoulos N, et al. A prospective study of the effects of irradiation on the carotid artery. Laryngoscope 2000;110:1811-1814. Pereira Lima MN, Biolo A, Foppa M, et al. A prospective, comparative study on the early effects of local and remote radiation therapy on carotid intima-media thickness and vascular cellular adhesion molecule-1 in patients with head and neck and prostate tumors. Radiother Oncol 2010. Bilora F, Pietrogrande F, Campagnolo E, et al. Are Hodgkin and non-Hodgkin patients at a greater risk of atherosclerosis? A follow-up of 3 years. Eur J Cancer Care(Engl) 2010;19:417-419. Adams HP, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. Stroke 1993;24: 35-41. Overgaard J, Hansen HS, Specht L, et al. Five compared with six fractions per week of conventional radiotherapy of squamous-cell carcinoma of head and neck: DAHANCA 6 and 7 randomised controlled trial. Lancet 2003;362:933-940. Bamford J, Sandercock P, Dennis M, et al. A prospective study of acute cerebrovascular disease in the community: the Oxfordshire Community Stroke Project 1981-86. 1. Methodology, demography and incident cases of firstever stroke. J Neurol Neurosurg Psychiatry 1988;51: 1373-1380. Dennis MS, Bamford JM, Sandercock PA, et al. Incidence of transient ischemic attacks in Oxfordshire, England. Stroke 1989;20:333-339. Lopata RG, Nillesen MM, Hansen HH, et al. Performance evaluation of methods for two-dimensional displacement and strain estimation using ultrasound radio frequency data. Ultrasound Med Biol 2009;35: 796-812.
IMT AFTER NECK IRRADIATION 18. Plummer C, Henderson RD, O’Sullivan JD, et al. Ischemic stroke and transient ischemic attack after head and neck radiotherapy: a review. Stroke 2011;42: 2410-2418. 19. Virmani R, Farb A, Carter AJ, et al. Pathology of radiation-induced coronary artery disease in human and pig. Cardiovasc Radiat Med 1999;1:98-101. 20. Ross R. Atherosclerosis–an inflammatory disease. N Engl J Med 1999;340:115-126.
2707 21. Jurado JA, Bashir R, Burket MW. Radiation-induced peripheral artery disease. Catheter Cardiovasc Interv 2008; 72:563-568. 22. Rogers LR. Cerebrovascular complications in patients with cancer. Semin Neurol 2010;30:311-319. 23. Lorenz MW, Markus HS, Bots ML, et al. Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation 2007;115:459-467.
