Abstract
Background/Aim: The aim of this study was to investigate the use of spacers and their efficacy in brachytherapy with 198Au grains for buccal mucosa cancer. Patients and Methods: Sixteen patients with squamous cell carcinoma of the buccal mucosa who were treated with 198Au grain brachytherapy were included. The distance between 198Au grains, distance between 198Au grains and the maxilla or mandible, and the maximum dose/cc to the jawbone (D1cc) with and without a spacer was investigated in three out of 16 patients. Results: The median distance between 198Au grains without and with a spacer was 7.4 and 10.7 mm, respectively; this was significantly different. The median distance between 198Au grains and the maxilla without and with a spacer was 10.3 and 18.5 mm, respectively; again this was significantly different. The median distance between 198Au grains and the mandible without and with a spacer was 8.6 and 17.3 mm, respectively; the difference was significant. The D1cc to the maxilla without and with a spacer were 14.9, 68.7, and 51.8 Gy and 7.5, 21.2, and 40.7 Gy in cases 1, 2, and 3, respectively. The D1cc to the mandible without and with a spacer were 27.5, 68.7, and 85.8 Gy and 11.3, 53.6, and 64.9 Gy in cases 1, 2, and 3, respectively. No osteoradionecrosis of the jaw bones was observed in any case. Conclusion: The spacer enabled maintenance of the distance between 198Au grains, and between 198Au grains and the jawbone. In buccal mucosa cancer, using a spacer in brachytherapy with 198Au grains appears to reduce jawbone complications.
Buccal mucosa cancer accounts for 6.7-17% (1-3) of all oral cancers and is not a common disease; however, the incidence of buccal mucosa cancer is high in some regions due to the influence of betel nut chewing (4-6).
Surgery is the standard treatment modality for buccal mucosa cancer. However, surgery reportedly reduces quality of life due to postoperative tissue loss and difficulty in mouth opening (7). Nevertheless, low-dose-rate brachytherapy (LDR-BT) is highly dose-concentrating and is expected to reduce the dose to surrounding normal tissues thereby avoiding loss of quality of life (8). In the case of LDR-BT for tongue cancer, a spacer is inserted between the tongue and the mandible and maxilla to reduce the radiation dose to the jawbone. In addition, a lead plate is placed inside the spacer to further reduce the dose to the jawbone and the application of a spacer can physically maintain the same distance to the source. Therefore, using a spacer can reduce the incidence of osteonecrosis of the jaw in patients with tongue cancer treated with LDR-BT (9-11).
However, in the case of buccal mucosa cancer, it is challenging to maintain the distance between the buccal mucosa, where the radioactive sources are implanted, and the jawbone using a spacer. Therefore, in the case of brachytherapy for patients with buccal mucosa cancer, the biological effective dose to the mandible is considered to be similar for the buccal mucosa region and the mandible. However, the biological effective dose to the mandible is considered to be half of that to the tongue using a spacer in patients with tongue cancer (12).
At our Institution, spacers including a lead plate have been applied to all patients with buccal mucosa cancer treated with LDR-BT to increase the distance between the radioactive source and the jawbone and, in addition, to flatten the buccal mucosa so that the same distance is maintained as when the sources were implanted. Therefore, this study aimed to investigate the efficacy of spacers in reducing the radiation dose to the jawbone in cases of brachytherapy with 198Au grains in patients with buccal mucosa cancer.
Patients and Methods
Study population. Between November 2009 and February 2021, 16 patients with primary buccal mucosa cancer were treated with 198Au grain brachytherapy alone or in combination with external beam radiotherapy (EBRT) and/or chemotherapy. Patient characteristics are presented in Table I. Three out of the 16 patients underwent CT imaging with and without a spacer between 2 weeks and 1 month after 198Au grain brachytherapy to investigate the differences in the distance between 198Au grains, the distance between 198Au grains and the jawbone, and the radiation dose to the jawbone. The study patients included 15 males and one female aged 51-90 years (median=73.5 years). All patients had histopathologically proven squamous cell carcinoma, clinically negative cervical lymph node, and distant metastases on CT, ultrasonography, and positron-emission tomography-CT. The tumor size distribution according to the 2017 Union for International Cancer Control malignant tumors (TNM) classification (13) was Tis in two cases, T1 in five, and T2 in nine. The medical records were reviewed in July 2022. The follow-up period ranged from 18 to 147 months (median=58.5 months). Furthermore, according to the Union for International Cancer Control classification (13), the buccal mucosa was categorized into the following six regions; i) Cheek mucosa, ii) buccoalveolar sulici, upper (vestibule of mouth), iii) buccoalveolar sulici, lower (vestibule of mouth), iv) retromolar areas, v) mucosa of the upper lip, and vi) mucosa of the lower lip.
Patient characteristics.
Treatment. 198Au grain brachytherapy was planned based on ultrasonographic images and Lugol staining in addition to inspection and palpation to identify the lesion area. One of the five T1 and six of seven T2 cases were treated with EBRT before 198Au grain brachytherapy. Before brachytherapy, EBRT was primarily applied to T2 or infiltrative-type tumors. Four patients received chemotherapy before 198Au brachytherapy. The chemotherapy regimens were S-1 (tegafur, gimeracil, and oteracil potassium) in two cases, a combination of cisplatin and 5-fluorouracil in one case, and tegafur and uracil in one case. In addition, EBRT was administered at doses of 30 Gy (2 Gy/fraction, 5 fractions/week, 15 fractions) or 40 Gy (2 Gy/fraction, 5 fractions/week, 20 fractions) through a lateral field, lateral parallel opposed fields or orthogonal fields to a volume encompassing the primary site and the upper neck area. The median interval between the end of EBRT and the beginning of 198Au brachytherapy was 15 days (range=8-22 days) to alleviate any acute mucosal reaction. The initial 198Au grain activity was approximately 185 MBq ± 10% per grain at implantation. Grain implantation was performed at noon on Wednesday in the case of 198Au grain brachytherapy alone. In most cases treated with the combination of EBRT and 198Au brachytherapy, 198Au grains were implanted 24 h after the day when activity measured 185 MBq ± 10% per grain to control the total dose to the tumor site. The interstitial implantation technique was used in all cases. For all patients, spacers were introduced to flatten the buccal mucosa surface by insertion between the buccal mucosa and jawbone, as well as to reduce exposure to the maxilla and mandible. The spacers were made of silicon rubber material for dental impressions and had a thickness of 1 cm (Figure 1). Furthermore, a lead plate with a thickness of 4 mm was placed in the silicon spacer to reduce the dose delivered to the jawbones.
Example of the spacers used in study. The spacer was made of silicone rubber material for dental impressions to a thickness of 1 cm. A 4-mm-thick lead plate was inserted inside the spacer. The spacer was designed to be inserted between the buccal mucosa and the upper and lower gingiva, and fixed with the upper and lower teeth.
Analysis of the distance between 198Au grains and 198Au grains and the jawbone, and the radiation dose to jawbones. The distance between 198Au grains and between 198Au grains and the maxilla/mandible were measured on CT images from the three most recent cases (see Table I, cases 1-3) in which CT was performed with and without a spacer, and statistically analyzed to investigate the effect of the spacer. In addition, the lead plate inserted in the spacer was removed to avoid the effect of metallic artifacts when the CT images were taken. CT images were acquired using a 16-slice CT scanner (Light Speed 16; GE Healthcare, Chicago, IL, USA). Furthermore, CT was performed using a tube voltage of 120 kV, tube current of 210 mA, and slice thickness of 2.5 mm. The CT images reconstructed from these data to a slice thickness of 0.625 mm were imported into a treatment planning system (Eclipse, Varian Medical Systems, Palo Alto, CA, USA) to create the dose distribution and calculate the maximum dose per unit volume (D1cc) to the jawbone.
Assessment of buccal mucosa and jawbone complications and treatment outcomes. The incidence of oral mucositis of the buccal mucosa and jawbone complications was also investigated. The complication classification system used was based on that described by the Common Terminology Criteria for Adverse Events version 5.0 for acute oral mucositis (14) and the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer for bone (15). The treatment outcome was assessed by the local control rate.
Statistical analysis. Comparisons of the distance between 198Au gains and between 198Au grains and the maxilla/mandible were conducted between groups with and without a spacer. The two groups were statistically compared using the Wilcoxon rank-sum test. The local control rate was calculated by the Kaplan–Meier method. Statistical significance was set at a value of p<0.05. All statistical analyses were performed using JMP Pro version 15.0 (SAS Institute, Cary, NC, USA).
Ethical approval. The Hiroshima University Ethics Committee approved this study (registration E-458) and the study was conducted in accordance with the Declaration of Helsinki. Informed consent was obtained in the form of opt-out in according to the local institutional Ethics Committee guidelines.
Results
Figure 2 shows the three-dimensional construction images of CT with and without spacers in cases 1-3. The distance between 198Au grains, the distance between 198Au grains and the maxilla/mandible, and the D1cc to the maxilla/mandible are presented in Table II. Figure 3 shows the distance between 198Au grains, and the distance between 198Au grains and the maxilla/mandible for each grain by case.
Three-dimensional construction frontal (F) and lateral (L) computed tomographic scans of the three study cases with and without a spacer. Arrowheads indicate the spacers. In case 3, the left side of the removable denture was dislocated and tilted (arrow). Therefore, most 198Au grains were located posterior to the spacer (lateral view).
Distance and radiation dose per unit volume (D1cc) with and without a spacer as assessed in three cases by computed tomography.
Box-and-whisker plots of the distance between 198Au grains, 198Au grain and the maxilla, and 198Au grain and the mandible without and with a spacer. The use of a spacer significantly increased the distance between 198Au grains in cases 2 and 3 (p=0.0283 and p=0.0103), between 198Au grains and the maxilla in cases 1 and 2 (p=0.016 and p=0.034), and between 198Au grains and the mandible in case 1 (p=0.045). *Significantly different at p<0.05.
Distance between 198Au grains. In the three CT cases, a significant difference was observed in the distance between 198Au grains without and with a spacer (p=0.0004) (Table II); the distance between 1998Au grains was significantly greater with a spacer. Regarding the distance between 198Au grains for each case, the mean distance between 198Au grains increased in all three cases, however, the increase was statistically significant in cases 2 and 3 when the spacer was used (p=0.0283 and p=0.0103), respectively (Figure 3).
Distance between 198Au grains and the maxilla/mandible. A significant difference was found in the distance between 198Au grains and the maxilla without and with a spacer in a total of three cases (p=0.0002) (Table II). In addition, a significant difference was found in the distance between 198Au grains and the mandible without and with a spacer (p=0.0024) (Table II). Regarding the distance between 198Au grains and the maxilla/mandible for each case, in case 1, significant differences were observed in the distance between 198Au grains and the maxilla/mandible without and with a spacer (p=0.016 and p=0.045), respectively (Figure 3). In case 2, a significant difference was found in the distance between 198Au grains and the maxilla without and with a spacer (p=0.034). Hence, the distance between 198Au grains and the maxilla/mandible in case 1 and the maxilla in case 2 was statistically greater with the use of spacers, whereas no significant difference was observed in the distance between 198Au grains and the mandible without and with a spacer in case 2 (p=0.0756). In case 3, no significant differences were found in the distance between 198Au grains and the maxilla/mandible without and with a spacer (p=0.1826 and p=0.0891), respectively (Figure 3).
Radiation dose (D1cc) to the maxilla and mandible. The D1cc to the maxilla without and with a spacer were 14.9, 68.7, and 51.8 Gy and 7.5, 21.1, and 40.7 Gy in cases 1, 2, and 3, respectively. In addition, the D1cc to the mandible without and with a spacer were 27.5, 68.7, and 85.8 Gy and 11.3, 53.6, and 64.9 Gy in cases 1, 2, and 3, respectively. The use of a spacer reduced the D1cc radiation dose to both the maxilla and mandible.
Complications of soft tissues and the jawbone. Oral mucositis of grades 1, 2, and 3 occurred in 1/16, 14/16, and 1/16 of patients, respectively (Table III). Notably, no jawbone complications occurred (Table III).
Complications of soft tissues and the jawbone.
Treatment outcomes. The 5-year local control rate was 93.3%. Local recurrence occurred 90 and 97 months after brachytherapy in two cases (cases 5 and 7); one was controlled by brachytherapy with 198Au grains again (case 5) and the other was controlled by photoimmunotherapy (case 7). Of the 16 patients followed up for more than 1 year or until death, two patients with T2 disease died; of these two, one died of late cervical lymph node metastasis 15 months after brachytherapy (case 9), and another died of abdominal aortic aneurysm rupture 57 months after brachytherapy (case 16). In addition, late cervical lymph node metastasis occurred in five cases (cases 5, 7, 9, 10, and 15), and four of these were controlled by neck dissection (cases 5, 7, 10, and 15).
Discussion
Regarding complications, grade 3 mucositis occurred in one, case 3, out of 16 patients. Notably, none of the patients had jawbone disorder. In case 3, the removable denture was tilted (Figure 2), with the spacer in front of the 198Au grains. The removable dentures were not stable, the spacer made it more likely that the dentures would dislocate, the patient did not like wearing the removable denture and spacer, and the time that the patient wore the spacer was short. Therefore, the buccal mucosa was loosened and the 198Au grains became concentrated for a long time without the spacer, and it was considered that grade 3 mucositis occurred in this case because the buccal mucosa was irradiated with a higher dose. Therefore, the patient should also consulta dentist regarding denture fit before undergoing brachytherapy.
Since an 198Au grain provides a dose to 5 mm of the surroundings tissue, at our Institution, 198Au grains are planned to be placed at 10-mm intervals in brachytherapy for oral cancer (11, 16-18). When 198Au grains were implanted, the buccal mucosa was pulled and grains were implanted at 10-mm intervals with the mucosal surface flattened, such that the same mucosal surface condition was required after 198Au grain implantation. However, without a spacer, the buccal mucosa may become loose and 198Au grains concentrated, resulting in higher doses than expected in specific areas. According to the present study, the distance between 198Au grains without and with a spacer was 7.4 mm and 10.7 mm, respectively. Therefore, it is considered that spacers were properly mounted, and it was possible to maintain the distance between 198Au grains as planned.
The spacer was designed and attached to maintain a distance of at least 10 mm between 198Au grains and the jawbone. Here, the total length in the three cases showed that the distance between 198Au grains and the jawbone increased significantly when a spacer was applied, from an average of 10.3 mm to 18.5 mm and 8.6 mm to 17.3 mm in the maxilla and mandible, respectively. The spacer used in this study was considered to meet the requirement of separating the 198Au grains from the jawbone and preventing osteonecrosis of the jaw.
The use of spacer resulted in a reduction of D1cc radiation dose to both the maxilla and mandible. According to a previous report, the dose to the jawbone was further reduced by 10-20% by inserting a 4-mm-thick lead plate (19). Considering the radiation-attenuating effect of the 4-mm-thick lead plate inserted into the spacer, the dose was reduced to a level less likely to cause jawbone complications when using a spacer. In contrast, the D1cc to the mandible in case 2 was 53.6 Gy with the spacer and to the maxilla and mandible in case 3 were 40.7 and 64.9 Gy with the spacer, respectively. The D1cc to the jawbone was high regardless of whether a spacer was present; was not unexpected. It was challenging to reduce the radiation dose to the jawbone as the 198Au grains had to be implanted at a position adjacent to it because the lesion had spread over the buccoalveolar sulici, upper (vestibule of the mouth) (case 3), buccoalveolar sulici, lower (vestibule of the mouth) (case 2 and 3), and retromolar areas (case 2 and 3) in addition to the cheek mucosa.
This study has some limitations. Firstly, although a 4-mm-thick lead plate was inserted into the spacer used, it was removed from the spacer to avoid metal artifacts during CT. Therefore, the attenuating effect of the lead plate was excluded from the dose evaluation. Secondly, the attenuating effect of silicon, the material used for the spacer, could not be examined. Finally, since there were only three patients for whom CT was performed with and without a spacer to evaluate the position of 198Au grains and radiation dose to the jawbones, statistical analysis could not be sufficiently performed to show the relationship between spacer use and oral mucositis and jawbone complications. Moreover, careful consideration should also be given to the exposure from the two CT scans.
Conclusion
In 198Au grain brachytherapy in patients with buccal mucosa cancer, the proper use of a spacer enabled maintenance of the distance between 198Au grains and the spacing between 198Au grains and the jawbone; subsequently, the radiation dose to the jawbone was reduced. Our results showed that the use of spacer in 198Au grain brachytherapy for buccal mucosal cancer causes no jaw bone complications; however, it has been suggested that inappropriate use of spacers leads to concentration of the 198Au grains, leading to mucosal damage.
Acknowledgements
The Authors would like to express their gratitude to all the staff members at the Department of Radiation Oncology.
Footnotes
Authors’ Contributions
Masaru Konishi contributed to the conceptualization, methodology, software, the data curation, writing – original draft preparation and reviewing and editing; Junichi Hirokawa, Shota Miyoshi, Tsuyoshi Katsuta, Nobuki Imano, Ikuno Nishibuchi, Yuji Murakami, Kiichi Shimabukuro, Takeo Nakashima, Yuki Takeuchi, to the data curation and the writing – reviewing and editing; Naoya Kakimoto and Yasushi Nagata, to the writing – reviewing and editing.
Conflicts of Interest
The Authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article.
- Received February 8, 2023.
- Revision received February 23, 2023.
- Accepted February 24, 2023.
- Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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