Introduction: Radiation-induced carotid artery stenosis (RI-CS) is known as one of long-term side effects of radiotherapy for head and neck cancer (HNC). However, the clinical time course after irradiation has been poorly understood. We aimed to investigate the natural history of radiation-induced carotid atherosclerosis, comparing the patients who received radiotherapy for HNC with the patients who were treated without radiotherapy. Methods: The patients who received treatment of HNC at Department of Otolaryngology, Head and Neck Surgery of Kyoto University Hospital, from November 2012 to July 2015 were enrolled. The patients were assigned into the RT group and the control group, depending on whether radiotherapy was planned or not. Annual carotid ultrasound was performed from the enrollment to 5 years. The increase of mean intima-media thickness (IMT) at common carotid artery from the enrollment (Δmean IMT) was evaluated. Results: Fifty-six patients in the RT group and 25 patients in the control group were enrolled. From 5-year follow-up data, the significant higher increase of Δmean IMT was consistently observed in the RT group than in the control group after 2 years. The RT group presented a 7.8-fold increase of mean IMT compared to the control group (0.060 mm per year in the RT group and 0.008 mm per year in the control group). Cumulative incidence curves obtained from the analysis of all vessels revealed that the RT group presented higher incidence of Δmean IMT ≥0.25 mm than the control group (p < 0.01). In the RT group, the patients with mean IMT ≥1.0 mm at enrollment exhibited significantly higher incidence of Δmean IMT ≥0.25 mm than the patients with mean IMT <1.0 mm (p < 0.01). Discussion: Radiotherapy for HNC induces continuous carotid mean IMT progression. The irradiated carotid arteries with mean IMT ≥1.0 mm before radiotherapy presented earlier IMT progression than those with mean IMT <1.0 mm.

© 2023 The Author(s). Published by S. Karger AG, Basel

Introduction

Health condition in cancer survivor and long-term side effects due to cancer therapy are new concerns as a recent remarkable therapeutic progress has improved the prognosis of patients suffering with cancer [1, 2]. The mortality of cancer survivors due to cardiovascular disease is over 10% [3], and cancer survivors are also exposed to the risk of cerebrovascular disease [4].

Atherosclerosis is known as one of the late complications accompanied by radiotherapy. Ischemic stroke possibly threatens the patients who underwent radiotherapy for head and neck cancer (HNC) [5, 6]. Radiation-induced carotid artery stenosis (RI-CS) is a matter of concern, and the prevention and treatment of RI-CS is important to improve the long-term prognosis of the survivors. Although some previous cross-sectional studies reported that long interval after radiotherapy is a risk of RI-CS [7, 8], carotid atherosclerosis before radiotherapy is not considered. Understanding the natural course of radiation-induced carotid atherosclerosis is crucial to preventing ischemic stroke due to RI-CS.

The current observational study aimed to reveal atherosclerotic progression of carotid arteries after radiotherapy. Annual carotid ultrasound was performed for the patients who received treatment for HNC with and without radiotherapy. The changes in carotid mean intima-media thickness (IMT) were investigated to evaluate the progression of radiation-induced carotid atherosclerosis.

Materials and MethodsPatients

The subjects were the patients who received treatment of HNC except for thyroid cancer at Department of Otolaryngology, Head and Neck Surgery of Kyoto University Hospital, from November 2012 to July 2015 and provided written informed consent before enrollment. Otolaryngologists assigned single or combined therapy to each patient. The patients were assigned into two groups: radiotherapy group (RT group) and control group, depending on whether the patients were planned to receive radiotherapy or not. Radiation oncologists in Kyoto University Hospital performed radiotherapy for the patients in the RT group according to their medical condition.

We excluded the following patients: the patients with severe stenosis or moderate symptomatic stenosis at enrollment, the patients who had received radiotherapy for their heads or necks before enrollment, the patients who did not consent to this study, and the patients who had short life expectancy. Moderate stenosis and severe stenosis were defined as 60–79% and 80–99% based on North American Symptomatic Carotid Endarterectomy (NASCET) criteria, respectively [9].

Data Collection

The patients’ characteristics were surveyed, and initial carotid ultrasound was performed at registration. The patients in the RT group received radiotherapy after initial examination. Annual carotid ultrasound was performed to evaluate the change in IMT up to 5 years from the registration. The observation was discontinued when ischemic stroke due to RI-CS occurred or a surgical intervention was conducted for remarkable RI-CS progression. When patients in the control group received radiotherapy after registration, we discontinued their follow-up, instead of crossover to the RT group.

Carotid ultrasound was performed with a 7.5 MHz linear probe PLT-704SBT (Canon Medical System, Tochigi, Japan). Mean IMT was recorded as the average of the following three points of IMT on the far wall of the common carotid artery (CCA): the thickest portion, its 1 cm proximal and distal points in the sagittal view of the vessel. The increase of mean IMT from initial examination (Δmean IMT) was evaluated as a major outcome. We compared transition of Δmean IMT in 5-year observation between the two groups. Cumulative incidence curves were applied to analyze overall patients including discontinued cases. Radiation dose at CCA bifurcation was calculated with the planning image of radiotherapy, and the doses of >40 Gy and ≤40 Gy were defined as high dose and low dose, respectively. This protocol was reviewed and approved by the Kyoto University Graduate School and Faculty of Medicine Ethics Committee (approval no. E1453).

Statistical Analysis

Data were analyzed with GraphPad Prism version 9 software (GraphPad, Inc., San Diego, CA, USA). The Mann-Whitney U test and the Fisher’s exact test were applied for continuous and categorical variables, respectively. Cumulative incidence curves were analyzed with the log-rank test. A p value <0.05 was considered to indicate statistical significance.

ResultsPatients Characteristics

A total of 81 patients were enrolled, and 56 patients and 25 patients were assigned into the RT group and the control group, respectively (Table 1). No patients met exclusion criteria at enrollment. Pharyngeal cancer was the most common in the RT group, while lip and oral cancer in the control group. Squamous cell tumor was the pathological majority in both groups. No patients with Hodgkin lymphoma were observed in either group. The RT group contained the patients with high stage of cancer (stage III and IV) more frequently than the control group but with no significant differences. Out of the comorbidities at enrollment, ischemic stroke including TIA was observed at significantly higher rate in the control group than in the RT group (the RT group: 0.0%, the control group: 12.0%, p = 0.03). Compared with the RT group, diabetes was more common in the control group, but no significant differences were observed (the RT group: 10.7%, the control group: 28.0%, p = 0.10). Hypertension, dyslipidemia, ischemic heart disease, and atrial fibrillation were similar between the two groups. Surgery was performed in the control group at significantly higher rate than in the RT group (the RT group: 34.0%, the control group: 100%, p < 0.0001), while no significant differences were found in chemotherapy (the RT group: 76.8%, the control group: 72.0%, p = 0.78). Intensity-modulated radiation therapy was commonly applied in radiotherapy (45 out of 56 patients). Median total dose of radiotherapy was 70 Gy (range, 44–72 Gy), and 96 out of 112 vessels in the RT group were irradiated at over 40 Gy. Initial examination presented thicker mean IMT in RT group than in the control group (the RT group: 0.837 ± 0.337 mm, the control group 0.972 ± 0.497 mm, p = 0.03). Asymptomatic stenosis over 50% based on NASCET criteria was found in 3 lesions in the RT group and 0 lesions in the control group, respectively. No significant differences about incidence of pre-existing plaque (>1.5 mm) at enrollment were demonstrated between the two groups. One vessel (2.0%) in the control group and 0 vessels (0.0%) in the RT group presented ulceration at enrollment.

Table 1.

Characteristics of all participants

Thirty-five patients in the RT group discontinued this study; 19 patients died, 14 patients abandoned the protocol, and 2 patients reached the endpoint. One patient presented with an ischemic stroke due to acute carotid thrombotic occlusion at 27 months after radiotherapy. The other has asymptomatic stenosis at enrollment and received carotid artery stenting (CAS) for progressive carotid artery stenosis at 15 months after radiotherapy. In the control group, 10 patients abandoned the protocol and 3 patients discontinued because of additional radiotherapy. No new stenosis lesions over 50% based on NASCET criteria were detected in both groups during 5-year observation.

Transition of Mean IMT during 5-Year Observation

Twenty-one patients in the RT group and 12 patients in the control group completed 5 years of follow-up, and 42 vessels from the RT group and 24 vessels from the control group were analyzed (Table 2). Mean IMT at initial examination presented no significant differences between the two groups (the RT group: 0.849 ± 0.275 mm, the control group: 0.931 ± 0.338 mm, p = 0.24). Δmean IMT (the increase of mean IMT from initial examination) was stagnant at a lower value than 0.1 mm in the control group, while the RT group presented a gradual increase of Δmean IMT (Fig. 1a). Significant differences of Δmean IMT between the two groups were consistently observed from 2 years to 5 years after registry (1 year, the RT group: 0.076 ± 0.185 mm, the control group: −0.016 ± 0.184 mm, p = 0.10; 2 years, the RT group: 0.184 ± 0.215 mm, the control group: 0.047 ± 0.267 mm, p < 0.001; 3 years, the RT group: 0.241 ± 0.304 mm, the control group: 0.033 ± 0.172 mm, p < 0.001; 4 years, the RT group: 0.239 ± 0.280 mm, the control group: 0.033 ± 0.229 mm; p < 0.01, 5 years, the RT group: 0.299 ± 0.372 mm, the control group: 0.038 ± 0.297 mm, p < 0.001). The annual increase of mean IMT was 0.060 mm per year in the RT group and 0.008 mm per year in the control group. The RT group presented a 7.8-fold increase of mean IMT compared to the control group. The RT group was sub-analyzed based on radiation dose at CCA bifurcation. No apparent differences were observed in initial mean IMT between high dose group (0.853 ± 0.277 mm, n = 37) and low dose group (0.818 ± 0.288 mm, n = 5). The arteries irradiated at high dose presented higher increase of mean IMT than those irradiated at low dose, but there were no significant differences (Fig. 1b).

Table 2.

Characteristics of the patients who completed 5-year observation

Fig. 1.

Increase of mean IMT from initial examination (Δmean IMT) during 5-year observation after radiotherapy. The comparison between the RT group and the control group (a) and the comparison depending on radiation dose at CCAs (high dose; >40 Gy, low dose; ≤40 Gy, b). ** Indicates p < 001. IMT, intima-media thickness.

Incidence of ΔMean IMT ≥0.25 mm

Cumulative incidence curves for Δmean IMT ≥0.25 mm demonstrated that the RT group presented a significantly higher incidence of Δmean IMT ≥0.25 mm compared to the control group (the RT group: n = 112 and the control group: n = 50, HR: 2.89, 95% CI: 1.46–5.72; p < 0.01, Fig. 2a). The RT group and the control group were sub-analyzed according to initial mean IMT, respectively. In the RT group, the patients with initial mean IMT ≥1.0 mm presented more frequently with an incidence of Δmean IMT ≥0.25 mm than those with initial mean IMT <1.0 mm (initial mean IMT <1.0 mm: n = 88 and initial mean IMT ≥1.0 mm: n = 24, HR: 4.54, 95% CI: 1.48–13.9; p < 0.01, Fig. 2b). In contrast, an incidence of Δmean IMT ≥0.25 mm was similar regardless of the presence of initial mean IMT ≥1.0 mm in the control group (initial mean IMT <1.0 mm: n = 36 and initial mean IMT ≥1.0 mm: n = 14, HR: 2.78, 95% CI: 0.475–16.2; p = 0.26, Fig. 2c). From sub-analysis along radiation dose in the RT group, no apparent differences in an incidence of Δmean IMT ≥0.25 mm were found between high dose group (n = 96) and low dose group (n = 16) (HR: 1.08, 95% CI: 0.348–3.34; p = 0.63, Fig. 2d).

Fig. 2.

Cumulative incidence curves for increase of mean IMT ≥0.25 mm from initial examination (Δmean IMT). a The comparison between the RT group and the control group. Sub-analysis of the RT group (b) and the control group (b) according to initial mean IMT. d The comparison of the RT group between the high dose group and the low group (high dose; >40 Gy, low dose; ≤40 Gy). IMT, intima-media thickness.

Plaque Properties

Out of the patients who completed 5-year observation, new ulcers developed in 7.1% of the RT group and 8.3% of the control group presented (p = 1.00). Diffuse wall thickness occurred in 4 vessels (9.5%) after radiotherapy but not in the control group. No cases presented carotid artery dissection. Of the vessels without plaque at enrollment, 88.9% in the RT group and 63.6% in the control group presented new carotid plaque, but the difference was not statistically different (p = 0.16).

Discussion

The current study demonstrated a continuous increase of carotid mean IMT after radiotherapy for HNC and a rapid increase of mean IMT in the patients with mean IMT ≥1.0 mm before radiotherapy. Radiation-induced atherosclerosis is generally recognized as a long-term effect. Long interval after radiotherapy is associated with increased thickening of IMT [10] and a risk of RI-CS [7, 8]. However, a previous short-term observational study reported that IMT increases early after radiotherapy [11]. The incidence curve in this study showed earlier increase of mean IMT in the RT group than in the control group, and this supports early atherogenesis after radiotherapy. The cut-off of Δmean IMT ≥0.25 mm is worth 5-year progression of mean IMT for healthy Japanese because their annual increase of mean IMT is reported to be 0.009 mm per year [12]. Furthermore, the RT group presented linear progression of mean IMT in 5-year observational data, suggesting that radiation induces continuous acceleration of carotid atherosclerosis. Annual increase of the control group in the current study was about the same as that of the general population, while the RT group exhibited much higher increase of mean IMT. This emphasizes the effect of radiotherapy for HNC on carotid atherosclerosis rather than the effects of HNC itself and other therapy for HNC. Moreover, it is a noteworthy result that the RT group presented higher increase of mean IMT even though risk factors for atherosclerosis were similar or rather higher in the control group.

Second, earlier progression of mean IMT after radiotherapy was observed in the patients with thick initial mean IMT compared to the patients with thin initial mean IMT. This suggests that the patients with pre-existing atherosclerosis would exhibit a rapid increase of mean IMT and face RI-CS in short or middle term after radiotherapy. Although this study could not indicate whether radiation changes plaque characteristics, it has been shown pathologically and ultrasonographically that RI-CS presented unstable plaque more frequently than unirradiated carotid artery stenosis [13, 14]. US screening after radiotherapy was recommended in the previous study because of an increased risk of carotid artery stenosis [15, 16]. The results from this study add the necessity of screening carotid atherosclerosis before radiotherapy to elucidate the patients with pre-existing atherosclerosis, and such patients should be observed carefully after radiotherapy. Stratifying follow-up intervals according to the presence or absence of stenosis may be useful in terms of cost-effectiveness [17]. The importance of carotid artery screening before and after radiotherapy should be known not only to neurologists and neurosurgeons but also to radiation oncologists and otolaryngologists because they face the patients with HNC before radiotherapy.

While coronary events increase according to radiation dose to the heart [18], dose dependency on carotid atherosclerosis has not been demonstrated [17]. Since the number of the vessels irradiated at low dose was limited, radiation dose was treated as a categorical variable, applying 40 Gy at CCA bifurcation as a cut-off. Children’s Oncology Group Long-Term Follow-Up Guidelines recommend carotid US screening 10 years after radiotherapy to survivors who received ≥40 Gy to their necks [19]. From 5-year observational data, the carotid arteries irradiated at low dose also presented gradual increase of mean IMT. However, no statistical differences were demonstrated between low dose group and high dose group. Larger sample number of low dose group and longer follow-up might be necessary to ascertain dose dependency.

Childhood cancer survivors who received radiotherapy for HNC presented thicker mean IMT than the age- and sex-matched control [20], and even low dose exposure during childhood increases carotid IMT, stenosis, and stroke [21-23]. Therefore, RI-CS would be an important issue from super long-term perspective for young cancer survivor, whose long-life expectancy would be estimated. Although carotid endarterectomy (CEA) and CAS are effective surgical treatments for carotid artery stenosis, both methods for RI-CS contain some risks. CEA for RI-CS was classified as high risk due to cranial nerve injury [24], while higher rate of in-stent restenosis was reported in CAS for RI-CS than for carotid artery stenosis without radiation [25, 26]. Opinions are divided regarding the superiority of CEA and CAS for RI-CS [24, 27-29]. The indication for surgery should be determined on an individual case because RI-CS has a variety of lesion characteristics [30, 31]. Ideally, occurrence of RI-CS should be prevented, but this requires elucidation of the underlying mechanisms of RI-CS. Several mechanisms have been proposed by basic experiments, and more recently, intraplaque DNA accumulation and cell senescence were demonstrated in vivo [32, 33].

The current study contains some limitations. First, irradiated areas depend on the localization of cancer not confined to CCA bifurcation. Lesions outside the range of ultrasound image could not be evaluated, although radiation for neck and cancer possibly induces diffuse atherosclerotic lesions [13, 31]. Second, the patient background such as cancer stage and type distribution of cancer was heterogeneous because the application of radiotherapy was dependent on the condition of cancer. Therefore, the difference of background might affect the results of the current study. Moreover, progression of RI-CS possibly varies by types of HNC [34]. A larger number of subjects are required to perform multivariable analysis. In addition to high mortality due to advanced cancer, this might reflect the difficulty of keeping the patients motivated. It is important to announce the risk of RI-CS to the patients who received radiotherapy for HNC.

Conclusion

Radiotherapy for HNC induces continuous progression of carotid mean IMT, and the cases with thick mean IMT at radiotherapy presented earlier mean IMT progression. Careful observation is reasonable after radiotherapy for HNC, especially in the patients with carotid atherosclerosis before radiotherapy.

Statement of Ethics

This protocol was reviewed and approved by the Kyoto University Graduate School and Faculty of Medicine Ethics Committee (approval no. E1453). Written informed consent was obtained from all the participants.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

No external funding was received to conduct this study.

Author Contributions

Ichiro Tateya, Michio Yoshimura, Yasutaka Fushimi, Eri Toda Kato, Kazumichi Yoshida, and Susumu Miyamoto contributed to conception and design. Ichiro Tateya and Kazumichi Yoshida contributed to enrollment of the participants. Michio Yoshimura contributed to radiotherapy for head and neck cancer. Eri Toda Kato contributed to physiological examination. Kazumichi Yoshida contributed to execution of the study. Yu Yamamoto, Masakazu Okawa, Keita Suzuki, and Kazumichi Yoshida contributed to interpretation of the data. Yu Yamamoto and Kazumichi Yoshida contributed to statistical analysis and drafting. Masakazu Okawa, Keita Suzuki, Ichiro Tateya, Michio Yoshimura, Yasutaka Fushimi, Eri Toda Kato, and Susumu Miyamoto contributed to critical revision of the manuscript. Kazumichi Yoshida and Susumu Miyamoto contributed to supervision. All authors read and approved the final version of the manuscript.

Data Availability Statement

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

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