Abstract
Background/Aim: To evaluate the association between osteoradionecrosis (ORN) of the mandible and stenosis of the external carotid artery after radiation therapy (RT) for head and neck cancer. Patients and Methods: The computed tomography images of 42 patients (36 men, six women; median age, 64.5 years) treated with RT for head and neck cancer between January 2011 and December 2015 were reviewed. The cross-sectional diameters of the bilateral external carotid arteries were measured on contrast-enhanced images taken after completion of RT. Results: Nine of the 42 included patients (21.4%) developed ORN after a median interval of 34 months from completion of RT. Univariate analysis revealed that external carotid artery diameter ≤ the median diameter was significantly associated with ORN development (p=0.008 and 0.013). In multivariate analysis, left external carotid artery diameter ≤ the median was significantly associated with ORN development (p=0.023). Conclusion: External carotid artery stenosis was significantly associated with ORN development.
Radiation therapy (RT) is frequently the treatment of choice to ensure functional preservation in patients with head and neck cancer (HNC). However, various complications may occur after RT in the head and neck region, including mandibular osteoradionecrosis (ORN) and vascular damage such as carotid artery stenosis (CAS) (1-4). Studies have reported the risk factors for ORN and CAS in patients who have undergone RT (5-7); however, studies on the association between ORN and CAS are needed. Vascular damage is a more significant risk factor for ORN than cellular damage (8). Reports have indicated that the mandible is the site of ORN in approximately 90% of cases (5, 9). The mandible is fed by the inferior alveolar artery, which is a branch of the external carotid artery (ECA). Mandibular ORN has the pathological features of ischemic necrosis resulting from intimal fibrosis and thrombosis occluding the inferior alveolar artery (10). In this study, we measured the cross-sectional diameter of the ECA on enhanced computed tomography (CT) images to assess the blood supply to the mandible and also evaluated the association between the occurrence of mandibular ORN and CAS.
Patients and Methods
Patients. We reviewed the clinical data and enhanced CT images of patients who initiated RT for HNC at our institution between January 2011 and December 2015.
Radiation therapy. Patients with an initial irradiation field that included part of the mandible were included in this study. All patients were irradiated with three-dimensional conformal RT with 4-MV photon beams from both the right and left sides; some patients also underwent irradiation from the area anterior to the supraclavicular lymph nodes. Contouring of the mandible and ECAs as organs at risk was not performed on CT images during RT planning. A radiation dose of 2 Gy was delivered once daily in all patients except two who received 1.2 Gy twice daily. The total radiation dose ranged from 40 to 72 Gy (median, 66 Gy).
Concurrent chemotherapy regimens. Systemic chemotherapy was administered in combination with RT in 39 patients; the most common regimen, which comprised docetaxel, cisplatin, and 5-fluorouracil, was administered in 25 of these patients (59.6%). Among the other regimens, docetaxel-based regimens were administered in 11 patients (26.2%) and cetuximab monotherapy was administered in three patients (7.1%). RT alone was administered in another three patients (7.1%).
Measurement of ECA diameter after RT. All included patients underwent enhanced CT 8 months or more after completion of RT to exclude those with vasoconstriction caused by edema of the perivascular soft tissue immediately after RT. The cross-sectional diameter of the ECA was measured as the distance from the lateral to medial aspect of the contrast-filled lumen in the first slice immediately after the branching point of the common carotid artery on enhanced CT images with a slice thickness of ≤5 mm (Figure 1A and B). The diameters of both the right and left ECA were measured to assess both the right and left feeding vessels of the mandible.
Statistical methods. Statistical Package for the Social Sciences ver. 21.0 (IBM Corp., Armonk, NY, USA) was used for statistical analysis. Patient age (≤ median vs. > median), sex, body mass index (≤ median vs. > median), smoking history, history of alcohol use, diabetes mellitus, site of primary tumor (oral or oropharynx vs. other sites), RT field including the mandibular ramus, RT dose (≤ median vs. > median), and diameters of the right and left ECA after RT (≤ median vs. > median) were evaluated. To determine whether these clinical factors were involved in the pathogenesis of ORN, univariate analysis using Pearson's χ2 test and multivariate analysis using Wald logistic regression analyses were conducted. A p-value of <0.05 was considered statistically significant. This study was approved by our Institutional Review Board (approval number: RK-190611-02); informed consent was obtained from all patients. The guidelines of the Helsinki Declaration were followed in this investigation.
Results
Patient characteristics are shown in Table I. A total of 42 patients [36 (85.7%) men, six (14.3%) women] who met the inclusion criteria of the study were enrolled. The age at initiation of RT ranged from 38 to 81 years (median, 64.5 years). With regard to ORN, the absence of local neoplastic disease was confirmed with direct visualization or imaging of the oral cavity; the development of ORN was observed in nine patients (21.4%). The time from completion of RT to development of ORN ranged from 13 to 66 months (median, 34 months). Enhanced CT images acquired from 8 to 69 months (median, 35 months) after completion of RT were used for the measurement of ECA diameter. The diameter of the right ECA ranged from 4.15 to 7.95 mm (median, 5.83 mm); the left ECA diameter ranged from 0 to 7.33 mm (median, 5.715 mm). In one patient with an ECA diameter of 0 mm, thrombus formation was present in the ECA but was not visualized on CT images. The results of univariate analysis of factors associated with the development of ORN are shown in Table II. The χ2 test revealed that development of ORN was significantly more likely among patients with a right or left ECA with a diameter ≤ the median value in the cohort (p=0.008 right and p=0.013 left). Development of ORN was significantly more likely among patients with oral and oropharyngeal cancers than among those with neoplastic disease at other sites (p=0.005). The results of multivariate analysis of factors associated with the development of ORN are shown in Table II. According to logistic regression analyses, development of ORN was significantly more common among patients with a left ECA with a diameter ≤ the median value (p=0.023 and p=0.013) and with oral and oropharyngeal cancers. No significant differences were observed for any other parameters.
Discussion
The incidence of ORN after RT for HNC has decreased with advances in RT techniques such as intensity-modulated RT. However, studies have reported a wide range of ORN incidences (1.2-18.2%) even in recent years (5, 11, 12). Approximately 90% of ORN cases occur in the mandible, a finding that may be attributed to differences in the anatomic structures and blood supply of the maxilla versus mandible (9, 10, 13). ORN has the pathological features of ischemic necrosis resulting from intimal fibrosis and thrombosis of the inferior alveolar artery, which is a branch of the ECA; the pathogenic mechanism of ORN is thought to be associated with microvascular thrombosis (10, 14). To date, however, few studies have focused on the association between ORN and findings on vascular imaging. A single report indicated that patients with ORN had a significantly higher rate of calcified carotid artery atherosclerosis on radiographs than nonirradiated controls (15). Smoking and tooth extraction are considered possible risk factors for ORN (2, 5, 16). Although various other clinical parameters are potential risk factors, including alcohol use, diabetes mellitus, low body mass index, and the site of primary tumor, analysis to determine whether CAS is a risk factor is needed (5, 17-19). One study reported that smoking is a risk factor for CAS (20); smoking is also a risk factor for ORN. Therefore, we hypothesized that ORN may be associated with the presence of CAS.
Patient characteristics.
The reported incidence of CAS after RT for HNC ranges widely from 18% to 38% (21, 22). The sites of CAS are the common and internal carotid arteries in 56.1% to 77.5% of cases and the ECA in 17.1% to 45% of cases (23, 24). The pathogenic mechanism of CAS after RT involves combinations of pathological conditions such as direct vessel damage, atherosclerosis, intimal proliferation, necrosis of the media, and peri-adventitial fibrosis (25, 26), which are chronic changes that occur at least 1 to 2 years after RT. The incidence of these changes increases over time after RT as follows: at 2 years, 4% to 11%; at 5 years, 20%; at 8 years, 29% (3, 27).
Measurement of cross-sectional diameter from the lateral to medial aspect of the external carotid artery (ECA). (A) Patient with osteoradionecrosis whose right ECA has a diameter of 4.51 mm. (B) Patient without osteoradionecrosis whose right ECA has a diameter of 7.23 mm.
Univariate and multivariate analyses of factors related to mandibular osteoradionecrosis.
In this study, we found that there was a significant association between the two complications of ORN and CAS after RT and that stenosis, defined as ECA diameter ≤ the median value, was a significant risk factor for ORN. We measured the ECA diameter at a median of 35 months after completion of RT, which is considered an early timepoint and not adequate to assess CAS after RT. Our results suggest that ORN is likely to occur in patients with stenosis of the ECA before RT. A study using color Doppler ultrasound reported that the diameter of the common carotid arteries decreased after RT, indicating development of stenosis immediately after completion of RT (28). However, this finding does not confirm whether stenosis of the ECA in our cases was caused by RT.
Our study has some limitations. First, we were unable to assess the status of the ECA before RT because enhanced CT was not performed before RT in all patients. Second, color Doppler ultrasound, which enables more accurate assessment of CAS, was not performed. In the future, we plan to investigate the association between the severity of ECA stenosis and the incidence of ORN after RT by using additional data from enhanced CT performed before RT and color Doppler ultrasound.
Acknowledgements
The Authors thank Rebecca Tollefson, DVM, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript and helping to draft the abstract.
Footnotes
Authors' Contributions
NI treated the patients and measured of ECA diameters and was a major contributor to writing the manuscript. TM, TA, MS, and MO took part in the treatment. All Authors read and approved the final manuscript.
Conflicts of Interest
Drs. Ishibashi, Maebayashi, Aizawa, Sakaguchi and Okada declare that they have no competing interests.
- Received July 29, 2019.
- Revision received August 23, 2019.
- Accepted August 26, 2019.
- Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
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