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Electron beam radiotherapy for tongue cancer using an intra-oral cone
Oral Oncology 48 (2012) 463–468
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Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Electron beam radiotherapy for tongue cancer using an intra-oral cone Naoya Kakimoto a,⇑, Shumei Murakami a, Atsutoshi Nakatani a, Yasuo Yoshioka b, Kimishige Shimizutani c, Souhei Furukawa a a
Department of Oral and Maxillofacial Radiology, Osaka University Graduate School of Dentistry, Suita, Osaka, Japan Department of Radiation Oncology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan c Department of Oral Radiology, Osaka Dental University, Osaka, Japan b
a r t i c l e
i n f o
Article history: Received 2 September 2011 Received in revised form 14 December 2011 Accepted 16 December 2011 Available online 10 January 2012 Keywords: Tongue cancer Radiation therapy Electrons Intra-oral cone Biological effective dose Complications
s u m m a r y To explain the adaptation technique using an intra-oral cone (IOC) for radiation therapy, and to determine the optimal schedule resulting in a high local control rate and an acceptable complication rate using direct electron beam radiation for the treatment of tongue cancer. Thirty patients with the tongue cancer (T1:T2:T3 = 16:11:3) were treated with 6–15 MeV electron radiation using an IOC. Twenty-six patients were treated with electron radiation using an IOC with or without an excisional biopsy. The other four patients were treated with a combination of the external beam radiation and electron radiation using the IOC. In order to formulate a safe and effective treatment program, we calculated the biologically effective dose (BED). The two- and five-year local control rates for all patients were 63% and 52%, respectively. The two- and five-year overall survival rates for all patients were 73% and 69%, respectively. Local control was achieved in 12 of 15 patients who were irradiated with a BED of 90.9 Gy10 or more, whereas it was not achieved in nine of the 15 patients who were treated with less than a BED of 90.9 Gy10 (p = 0.03). The application of electron radiation using an IOC for the treatment of tongue cancer provides acceptable local control and adverse effect rates, especially for elderly patients considered to be high risk for complications from anesthesia. The optimum BED10 value for the treatment of early tongue cancer using the IOC technique appears to be at least 90.9 Gy10. Ó 2011 Elsevier Ltd. All rights reserved.
Introduction It is widely accepted that radiotherapy is effective in the early stages of tongue carcinoma, which is usually curable without any concomitant functional loss.1–5 For the radical treatment of tongue carcinoma by radiotherapy, low-dose- or high-dose-rate interstitial radiotherapy has generally been the main treatment modality.1–8 The treatment outcomes in patients treated with either modality have been excellent, and they have only been associated with minimal complications. However, for patients deemed at high risk for complications from anesthesia or who have cardiovascular disease, this type of radiotherapy cannot be used. For these patients, direct electron beam radiotherapy using an intra-oral cone (IOC) may represent an alternative.9–11 Direct electron beam radiation using an IOC has also been recommended to boost the therapeutic response after external beam radiation therapy.11 For example, Wang reported that the tumor control following treatment with the electron beam
⇑ Corresponding author. Address: Department of Oral and Maxillofacial Radiology, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka 565-0871, Japan. Tel.: +81 6 6879 2967; fax: +81 6 6879 2970. E-mail address: [email protected] (N. Kakimoto). 1368-8375/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.oraloncology.2011.12.008
boost technique using an IOC was superior to that obtained using an interstitial implant for early carcinoma of the tongue.11 The aim of the present study was to explain the adaptation of electron beam radiotherapy using an IOC for tongue carcinoma patients, and to determine the optimal treatment schedule that can provide a high local control rate with acceptable complications. Methods and materials Approval from the institutional review board was obtained, and informed consent was waived for this retrospective study. Between 1981 and 2009, 33 patients with the tongue cancer were treated with 6–15 MeV electron beam radiation using an IOC at Osaka University Medical or Dental Hospital. One patient was treated for recurrent tongue cancer. Another patient was treated with the electron beam radiation using an IOC for the pre-interstitial brachytherapy, and another patient received radiation for palliative treatment. These three patients were excluded from this study. The remaining 30 patients (25 with tumors on the lateral border; two with tumors on the apex; two with tumors on the ventral surface; and one patient with a tumor on the dorsal surface) were examined for our study. All of the tumors were histopathologically confirmed to be squamous cell carcinoma. Ten of the 30 patients had inoperable
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N. Kakimoto et al. / Oral Oncology 48 (2012) 463–468
Table 1 The patient characteristics, treatments, and tongue cancer control. Case no.
Age
Gender
T
N
M
Tumor volume (cm3)
1 2 3 4 5 6 7
59 36 50 70 73 64 79
M F F F M F M
1 1 1 2 1 2 2
0 0 0 0 0 0 0
0 0 0 0 0 0 0
0 0 0.63 3.18 0 1.66 0.79
8 9 10
85 78 44
F F M
1 2 2
0 0 0
0 0 0
0.94 3.27 0.42
11 12
42 59
F M
2 1
0 0
0 0
1.21 0.14
13 14 15 16 17 18 19
51 73 61 76 80 84 56
M F F M M F M
2 1 1 1 1 2 2
0 0 0 0 0 0 0
0 0 0 0 0 0 0
1.15 0.53 0.09 0.51 0.56 3.73 5.5
20
81
F
1
0
0
0.31
21
77
F
2
0
0
5.65
22
53
M
1
0
0
0
23 24
67 70
M M
1 3
0 0
0 0
1.39 6.59
25
84
M
3
0
0
14.37
26
78
M
1
0
0
0.16
27
81
M
3
2
0
8.44
28 29 30
78 74 75
M M F
2 1 1
0 0 0
0 0 0
1.98 1.18 0
Systemic disease
Brain infraction
External RT
30 Gy/ 15 fr/21 d
Cardiac infraction
Brain aneurysm Cardiac pacemaker
32 Gy/ 16 fr/23 d
Brain infraction 24.5 Gy/ 7 fr/15 d Cardiac pacemaker Angina pectoris
40 Gy/ 20 fr/33 d
Electron RT using an IOC
BED10 (Gy10)
BEDcorr10 (Gy10)
BED3 (Gy3)
BEDcorr3 (Gy3)
Tongue cancer control
35 Gy/2 fr/22 d 50 Gy/10 fr/32 d 50 Gy/10 fr/33 d 75 Gy/14 fr/65 d 64 Gy/16 fr/37 d 56 Gy/14 fr/31 d 42 Gy/14 fr/31 d
97.5 75.0 75.0 117.5 89.6 78.4 90.6
87.3 60.2 59.8 87.5 72.5 64.1 65.7
243.3 133.3 133.3 216.7 149.3 130.7 134.0
233.2 118.5 118.1 186.6 132.2 116.3 109.1
s s s s
50 Gy/5 fr/36 d 56 Gy/14 fr/29 d 46.4 Gy/4 fr/ 24 d 40 Gy/4 fr/22 d 40 Gy/4 fr/20 d
100.0 78.4 102.1
83.4 65.0 91.1
216.7 130.7 232.2
200.0 117.3 221.1
s
80.0 80.0
69.8 70.8
173.3 173.3
163.2 164.1
40 Gy/4 fr/19 d 50 Gy/10 fr/34 d 50 Gy/10 fr/34 d 60 Gy/12 fr/50 d 50 Gy/5 fr/29 d 50 Gy/6 fr/31 d 59 Gy/11 fr/37 d
80.0 75.0 75.0 75.0 100.0 95.0 129.7
71.2 59.3 59.3 51.9 86.6 80.7 93.2
173.3 133.3 133.3 133.3 216.7 200.0 220.0
164.6 117.6 117.6 110.2 203.3 185.6 183.5
D s s s s s
45 Gy/5 fr/29 d
87.5
74.1
186.7
173.3
72.5 Gy/20 fr/ 45 d 34.5 Gy/5 fr/ 21 d 59 Gy/13 fr/29 d 55 Gy/10 fr/22 d
98.9
78.1
160.4
139.6
D
64.3
54.6
133.8
124.0
D
90.9 85.3
77.5 75.1
149.3 155.8
135.9 145.7
D
48 Gy/12 fr/27 d
100.3
73.0
165.1
137.8
D
68 Gy/17 fr/40 d
95.2
76.7
158.7
140.2
40 Gy/8 fr/16 d
108.0
78.9
173.3
144.2
D
96 Gy/24 fr/60 d 72 Gy/18 fr/40 d 67 Gy/15 fr/37 d
134.4 100.8 93.5
106.7 82.3 76.4
224.0 168.0 155.3
196.3 149.5 138.2
s D
RT, radiotherapy; IOC, intra-oral cone; BED, biologically effective dose; Tumor volume = (4p/3) (long diameter/20) (short diameter/20) (thickness/20) (cm3). Fr, fractions; d, days; Tongue cancer control, s, controlled; D, controlled with complication; , uncontrolled. Case no. 20, osteoradionecrosis of mandible was experienced after external beam irradiation for lymph node metastasis. Finally tongue cancer was recurred.
tumors due to the presence of systematic disease or because of their advanced age. The patient characteristics, tumor volume, treatment dose, and presence of systemic disease are shown in Table 1. The patients’ ages ranged from 36 to 85 years, with a median age of 73 years. Thirteen patients were females and 17 were males. According to the UICC TNM classification of 2002, 16 patients had stage T1 disease, 11 had T2, and three had stage T3 disease. The tumor volumes ranged from 0 (after an excisional biopsy) to 14.37 cm3. The tumor volume was calculated according to the following equation:
Tumour volume ¼ ð4p=3Þðx=20Þðy=20Þðz=20Þ ðin cm3 Þ; where x = long diameter (mm), y = short diameter (mm) and z = thickness (mm). There was one patient with neck node metastasis, however none of the patients had distant metastasis. The median followup period was 51 months from the start of the radiotherapy, and ranged from 7 to 120 months. Of the 30 patients, 21 were treated with electron beam radiation using an IOC alone. Four received electron beam radiotherapy using an IOC in combination with external beam radiation. The reasons why a combination of electron beam radiotherapy with IOC and external beam radiation was used were as follows: One patient
had a tumor with a long diameter which was more than 30 mm and had brain infraction on his past illness, therefore, the fixation of his tongue was unstable. The tumor thickness in two patients was more than 15 mm. One patient had neck lymph node metastasis. The remaining five patients were irradiated by the electron beam using an IOC after the excisional biopsy, because these patients had histopathologically-positive margins on their excised tumors. The sizes of the IOC ranged from 2 to 4 cm in diameter. The most commonly used electron energy was 9 MeV. For the thinner lesions with a thickness of less than 7 mm, or for lesions from which the excisional biopsy had been taken, a 6 MeV electron beam was used. For the larger lesions, including the T3 lesions, a 15 MeV electron beam was used. The fractionation schedule ranged from 1 fraction/2 weeks to 5 fractions/week. The total electron beam dose ranged from 34.5 to 96 Gy (Table 1). For the electron beam irradiation using an IOC, the cone was introduced through the open mouth and placed so that it covered a tumor. The lesion was immobilized by pulling the tip of the tongue out by a tongue clamp or having the patient stabilize it with their fingers over gauze during the irradiation. The angle of the mouth was expanded by pulling the lips aside with a hook to expand the oral access (Fig. 1). The tumor location in the IOC was confirmed using a periscope equipped with a linear accelerator before and after irradiation on every treatment day.
N. Kakimoto et al. / Oral Oncology 48 (2012) 463–468
The external radiotherapy was administered daily at 2 Gy, 5 days a week by a single ipsilateral portal, including the suprahyoid of the neck, using 60Co gamma rays or 4 MV X-rays. Owing to the lack of standardized treatment schemes, the patients were managed by various radiation therapy schedules regarding the total dose and the fraction size. In order to formulate a treatment program with acceptable local control and complication rates, we calculated the biologically effective dose (BED) and a corrected biologically effective dose that was corrected based on a time factor term to take into account the proliferation in tumors (BEDcorr) based on the linear quadratic model12:
BED ¼ ðndÞ½1 þ d=ða=bÞ BEDcorr ¼ ðndÞ½1 þ d=ða=bÞ ð0:693=aÞðt=T pot Þ; where BED = biologically effective dose, n = number of fractions, d = dose per fraction, BEDcorr = corrected biologically effective dose, t = treatment time (days), and Tpot = potential doubling time (days). This yielded: a/b = 10 Gy for tumors and 3 Gy for late-response normal tissues, with a = 0.3/Gy and Tpot = 5 days. The BED10, BEDcorr10, BED3, and BEDcorr3 values are showed in Table 1. Neoadjuvant chemotherapy was administered to two patients because they had a long interval from biopsy to radiation therapy
Figure 1 The set-up of the direct electron beam radiation using an IOC, a tongue clamp, and a hook.
465
in order to allow for the close investigation of their whole body. None of the patients received concomitant chemotherapy during their radiation therapy. Adjuvant chemotherapy was administered to three patients who experienced a recurrence. For the statistical analyses, either the Chi square test or the Fisher’s exact probability test were used. The local control and survival rates were calculated using the Kaplan–Meier method, and the log-rank test was used to make comparisons. All analyses used the conventional p < 0.05 level of significance. Results Local control rate The 2- and 5-year local control (LC) rates for all patients were 63% and 52%, respectively. The 2- and 5-year LC rates for T1 patients were 71% and 63%, were 55% and 41% for T2 patients, and both 2- and 5-year LC rates for T3 patients were 0% (Figs. 2 and 3). There were no significant differences among any of the different disease stage groups (p = 0.21). Four of five patients who had been irradiated after the excisional biopsy were controlled. Twelve patients developed a local recurrence. Seven of these patients were successfully salvaged by the surgical excision of the recurrent tumor. Therefore, the 2- and 5-year ultimate LC rates of the patients who received radiotherapy and salvage surgery were 85% and 80%, respectively (Fig. 4).
Figure 3 The local control rates of tongue cancer treated with direct electron beam irradiation using an IOC.
Figure 2 A representative case (case 18) treated with direct electron beam radiation using an IOC. (A) a pre-irradiation photo of the lesion; (B) a photo after 20 Gy radiation; (C) a photo after 40 Gy radiation; and (D) a photo at 4 years after radiation of the lesion.
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N. Kakimoto et al. / Oral Oncology 48 (2012) 463–468
within 4 months, while the other three patients with ulceration finally healed within 13 months by conservative treatment. The remaining patients with ulceration did not fully heal by the time of death due to neck node and distant metastases. Correlation between the tumor volume and BED
Figure 4 The local control rate and ultimate local control rate for all patients with tongue cancer treated with the direct electron beam radiation using an IOC. The ultimate local control rate was calculated using the local control that was achieved using radiotherapy and salvage surgery.
Cause-specific survival rate
Fig. 6A shows the relationship between the tumor volume and BED10 for all cases. Local control was achieved in 12 of the 15 patients who were irradiated with a BED of 90.9 Gy10 or more, whereas local control was achieved in only 6 of the 15 patients who were irradiated with less than a BED of 90.9 Gy10 (p = 0.03). On the other hand, local control was achieved in 10 of the 12 patients who were irradiated with a BEDcorr of 77.5 Gy10 or more, while local control was achieved in only 8 of the 18 patients who were irradiated with less than a BEDcorr of 77.5 Gy10. There was
The 2- and 5-year cause-specific survival (CSS) rates of all patients were 76% and 71%, respectively. The 2- and 5-year CSS rates for T1 patients were both 86%, and were 68% and 57% for T2 patients and 0% for both the 2- and 5-year CSS rates for T3 patients. There were no significant differences among any of the different disease stage groups (p = 0.054). Disease-free survival rate The 2- and 5-year disease-free survival (DFS) rates for all patients were 52% and 39%, respectively. The 2- and 5-year DFS rates for T1 patients were 58% and 50%, were 36% and 27% for T2 patients, and 0% for both the 2- and 5-year DFS rates for T3 patients. There were no significant differences among any of the different disease stage groups (p = 0.11). Overall survival rate The 2- and 5-year overall survival (OS) rates for all patients were 73% and 69%, respectively. The 2- and 5-year OS rates for T1 patients were both 80%, were 68% and 57% for T2 patients, and 0% for both the 2- and 5-year OD rates for T3 patients (Fig. 5). There were no significant differences among any of the different disease stage groups (p = 0.22). Complications Of the 30 patients treated with direct electron beam radiation using an IOC, nine patients experienced soft tissue ulceration, and one patient experienced osteoradionecrosis. Eight soft tissue ulcerations occurred between 6 and 8 months after direct electron beam radiation using an IOC. Another patient experienced soft tissue ulceration at 34 months after direct electron beam radiation using an IOC. This patient continued to smoke tobacco during this follow-up term. Five patients with ulceration successfully healed
Figure 5 The overall survival rates of tongue cancer patients treated with direct electron beam radiation using an IOC.
Figure 6 The relationship between the BED10 and tumor volume with regard to the local control by the direct electron beam radiation using an IOC. (A) All cases; (B) T1 cases; (C) T2 cases.
N. Kakimoto et al. / Oral Oncology 48 (2012) 463–468
a marginally significant difference in the local control rates between the patients who were irradiated with a BEDcorr of at least 77.5 Gy10 and those who received less than 77.5 Gy10 (p = 0.06). For T1 cases, local control was achieved in six of the seven patients who were irradiated with a BED of 90.9 Gy10 or more, whereas local control was achieved in only five of the nine patients who were irradiated with less than a BED of 90.9 Gy10 (p = 0.31) (Fig. 6B). For T2 cases, local control was achieved in 4 of the 6 patients who were irradiated with a BED of 90.9 Gy10 or more, whereas local control was achieved in only 1 of the 5 patients who were irradiated with less than a BED of 90.9 Gy10 (p = 0.24) (Fig. 6C). Fig. 7(A–C) shows the relationship between the tumor volume and the BED3 for all cases, T1 cases, and T2 cases, respectively. Complications were still observed even when the patients were irradiated with either low BED3 or BEDcorr3.
Figure 7 The relationship between the BED3 and tumor volume with regard to the complications induced by direct electron beam radiation using an IOC. (A) All cases; (B) T1 cases; (C) T2 cases.
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Regional control Neck lymph node metastasis developed in 11 of the 29 N0 patients. Three patients were salvaged by surgery for their neck lymph node metastasis. Five other patients were treated surgically, but could not be saved. Three patients were deemed to be inoperable because of the size or location of the metastasis, the presence of systemic disease, or because of their advanced age. Discussion The tongue is the most prominent site of carcinomas of the oral cavity.13 With the improvement of surgical reconstruction, the number of patients treated with surgery for tongue cancer has increased steadily since 1980.14,15 However, radiotherapy continues to play an important role in the management of the tongue carcinoma because of its better cosmetic and functional results.16 At our hospital, low-dose- or high-dose-rate interstitial brachytherapy with 192Iridium has traditionally been used as the main treatment modality for tongue cancer. The results of these treatments have generally been excellent, and they have also only been associated with few complications.8,17,18 However, these modalities are often unsuitable for high risk patients.11 In contrast, the IOC technique is applicable even for very elderly patients with high anesthesia risks, because it is a painless and non-traumatic procedure. In this study, the 2- and 5-year LC rates were 63% and 52%, and the 2- and 5-year ultimate LC rates (with radiotherapy and salvage surgery) were 85% and 80%, respectively, for all 30 patients. Of particular importance, local control without salvage surgery was achieved in 12 of the 15 patients who received a BED of 90.9 Gy10 or more, and 10 of 12 patients who were irradiated with a BEDcorr of 77.5 Gy10 or more. A high local control rate can therefore be expected for patients who can be administered a total BED10 with a value over 90.9 Gy10 and a BEDcorr10 with a value over 77.5 Gy10. The reported 2- and 5-year LC rates of interstitial brachytherapy for early mobile tongue cancer ranged from 80% to 90%.1–5 In our hospital, the LC rate for low-dose-rate interstitial brachytherapy of early mobile tongue cancer was 84%, while that for high-doserate interstitial brachytherapy was 87%.8 The LC rate for the T1 and T2 patients in the present study who were treated with direct electron beam radiation using an IOC for early tongue cancer was inferior to that of interstitial brachytherapy. These findings contrast with the results reported by Wang,11 but they correlate with the results reported by Akine.19 However, the LC rate for patients who received BED of more than 90.9 Gy10 or BEDcorr of more than 77.5 Gy10 using the IOC technique was nearly equivalent to that of interstitial brachytherapy. However, since the placement of the IOC in the patient requires meticulous technique and skill, we believe that interstitial brachytherapy is a more reliable treatment for tongue cancer than the IOC technique. In addition, T3 tongue cancers were not controlled by the IOC technique, but are well-controlled by interstitial brachytherapy.18 We therefore suggest that the main radiation therapy for mobile tongue cancer should remain interstitial brachytherapy. However, the IOC technique has been shown to still be suitable for elderly patients or others with high anesthesia risks, especially those with early-stage disease. Yamazaki et al. reported that age and dental factors, including prosthesis irritation, are potentially important prognostic factors for local control of early stage oral tongue cancer by brachytherapy.20 This is also considered to be applicable for the IOC technique. In this study, the median age of patients was 73 years old, and 19 of the 30 patients were older than 65. In addition, 10 of the 30 patients were inoperable cases due to the presence of systemic disease or because of their advanced age. Therefore, if age is important prognostic
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N. Kakimoto et al. / Oral Oncology 48 (2012) 463–468
factor for the radiotherapy of tongue cancer, the population of this study is disadvantaged in terms of local control. The complications of external beam radiation therapy for tongue cancer include xerostomia, mucositis, diminished taste acuity, osteonecrosis and so on.21 Recently, the sparing of the parotid glands with intensity modulated radiation therapy has significantly reduced the incidence of xerostomia.22,23 The main complication of direct electron beam radiation using an IOC for tongue cancer observed in our study was the development of soft tissue ulcers. Although we thought that the BED3 or BEDcorr3 might have had an impact on complications, there were no significant correlations between these factors and the complication rate or type in this study. As the placement of the IOC in the patient requires meticulous technique and skill, it is very difficult to reproduce the day-to-day geometric concentration of the electron beam. As a result, soft tissue ulcers were still experienced even by patients with a small BED3 or BEDcorr3, while they were not experienced by other patients with a large BED3 or BEDcorr3. The one patient who developed osteoradionecrosis in the mandible had been treated by external beam radiation for lymph node metastasis after initial treatment using an IOC. We assumed that the osteoradionecrosis had been caused by this external beam radiation for the neck lymph node metastasis, but this is still open for interpretation. The incidence of regional metastasis of N0 early tongue cancer has been reported to be about 30%.24,25 When the depth of invasion of the primary tumor of the tongue exceeded 4 mm, occult metastasis in the cervical lymph nodes occurred in from 37.5% to 45% of patients.26,27 The incidence of occult regional metastasis was about 38% in the present study. This result was similar to the findings of the previous reports about early tongue cancer patients. In conclusion, direct electron beam radiotherapy using an IOC for tongue cancer was therefore found to be an acceptable treatment, especially for patients with a high anesthesia risks. While this treatment is not recommended for patients with advanced disease, those with T1 or T2 disease should experience a significant benefit from this treatment regimen. The optimum BED10 and BEDcorr10 values for early tongue cancer treated using the IOC technique were at least 90.9 Gy10 for BED10 and at least 77.5 Gy10 for BEDcorr10. Further studies in a larger number of patients are needed to confirm the efficacy and complication rates associate with this treatment. Conflict of interest statement None declared. Acknowledgment The authors would like to thank the late Professor Takehiro Inoue for his valuable guidance. References 1. Mazeron JJ, Crook JM, Benck V, Marinello G, Martin M, Raynal M, et al. Iridium 192 implantation of T1 and T2 carcinomas of the mobile tongue. Int J Radiat Oncol Biol Phys 1990;19(6):1369–76. 2. Pernot M, Malissard L, Aletti P, Hoffstetter S, Forcard JJ, Bey P. Iridium-192 brachytherapy in the management of 147 T2N0 oral tongue carcinomas treated with irradiation alone: comparison of two treatment techniques. Radiother Oncol 1992;23(4):223–8.
3. Shibuya H, Hoshina M, Takeda M, Matsumoto S, Suzuki S, Okada N. Brachytherapy for stage I & II oral tongue cancer: an analysis of past cases focusing on control and complications. Int J Radiat Oncol Biol Phys 1993;26(1):51–8. 4. Fein DA, Mendenhall WM, Parsons JT, McCarty PJ, Stringer SP, Million RR, et al. Carcinoma of the oral tongue: a comparison of results and complications of treatment with radiotherapy and/or surgery. Head Neck 1994;16(4):358–65. 5. Matsuura K, Hirokawa Y, Fujita M, Akagi Y, Ito K. Treatment results of stage I and II oral tongue cancer with interstitial brachytherapy: maximum tumor thickness is prognostic of nodal metastasis. Int J Radiat Oncol Biol Phys 1998;40(3):535–9. 6. Lau HY, Hay JH, Flores AD, Threlfall WJ. Seven fractions of twice daily high doserate brachytherapy for node-negative carcinoma of the mobile tongue results in loss of therapeutic ratio. Radiother Oncol 1996;39(1):15–8. 7. Leung TW, Wong VY, Wong CM, Tung SY, Lui CM, Leung LC, et al. High dose rate brachytherapy for carcinoma of the oral tongue. Int J Radiat Oncol Biol Phys 1997;39(5):1113–20. 8. Inoue T, Yoshida K, Yoshioka Y, Shimamoto S, Tanaka E, Yamazaki H, et al. Phase III trial of high- vs low-dose-rate interstitial radiotherapy for early mobile tongue cancer. Int J Radiat Oncol Biol Phys 2001;51(1):171–5. 9. Fayos JV, Lampe I. Peroral irradiation of carcinoma of the oral tongue. Radiology 1969;93(2):387–94. 10. Wang CC, Doppke KP, Biggs PJ. Intra-oral cone radiation therapy for selected carcinomas of the oral cavity. Int J Radiat Oncol Biol Phys 1983;9(8):1185–9. 11. Wang CC. Radiotherapeutic management and results of T1N0, T2N0 carcinoma of the oral tongue: evaluation of boost techniques. Int J Radiat Oncol Biol Phys 1989;17(2):287–91. 12. Hall EJ, Giaccia AJ. Time, dose and fractionation in radiotherapy. In: Hall EJ, Giaccia AJ, editors. Radiobiology for the radiologist. Philadelphia: Lippincott Williams and Wilkins; 2006. p. 378–97. 13. Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer statistics, 2011. CA Cancer J Clin 2001;51(1):15–36. 14. Franceschi D, Gupta R, Spiro RH, Shah JP. Improved survival in the treatment of squamous carcinoma of the oral tongue. Am J Surg 1993;166(4):360–5. 15. Haddadin KJ, Soutar DS, Oliver RJ, Webster MH, Robertson AG, MacDonald DG. Improved survival for patients with clinically T1/T2, no tongue tumors undergoing a prophylactic neck dissection. Head Neck 1999;21(6):517–25. 16. Yoshimura R, Shibuya H, Miura M, Watanabe H, Ayukawa F, Hayashi K, et al. Quality of life of oral cancer patients after low-dose-rate interstitial brachytherapy. Int J Radiat Oncol Biol Phys 2009;73(3):772–8. 17. Yamazaki H, Inoue T, Yoshida K, Tanaka E, Yoshioka Y, Nakamura H, et al. Lymph node metastasis of early oral tongue cancer after interstitial radiotherapy. Int J Radiat Oncol Biol Phys 2004;58(1):139–46. 18. Kakimoto N, Inoue T, Inoue T, Murakami S, Furukawa S, Yoshida K, et al. Results of low- and high-dose-rate interstitial brachytherapy for T3 mobile tongue cancer. Radiother Oncol 2003;68(2):123–8. 19. Akine Y, Tokita N, Ogino T, Tsukiyama I, Egawa S, Saikawa M, et al. Stage I–II carcinoma of the anterior two-thirds of the tongue treated with different modalities: a retrospective analysis of 244 patients. Radiother Oncol 1991;21(1):24–8. 20. Yamazaki H, Inoue T, Yoshida K, Kotsuma T, Yoshioka Y, Koizumi M, et al. Assessment of influence of smoking, drinking, leukoplakia and dental irritation on local control of early oral tongue carcinoma treated with brachytherapy: age and dental factors are potential prognostic factors. Tumori 2009;95(4):461–6. 21. Cooper JS. The oral cavity. In: Cox JD, Ang KK, editors. Radiation oncology rationale technique results. Louis: St. Mosby; 2003. p. 219–54. 22. Stock M, Dorr W, Stromberger C, Mock U, Koizar S, Potter R, et al. Investigations on parotid gland recovery after imrt in head and neck tumor patients. Strahlenther Onkol 2010;186(12):665–71. 23. Nutting CM, Morden JP, Harrington KJ, Urbano TG, Bhide SA, Clark C, et al. Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer (parsport): a phase 3 multicentre randomised controlled trial. Lancet Oncol 2011;12(2):127–36. 24. Prince S, Bailey BM. Squamous carcinoma of the tongue: review. Br J Oral Maxillofac Surg 1999;37(3):164–74. 25. Keski-Santti H, Atula T, Tornwall J, Koivunen P, Makitie A. Elective neck treatment versus observation in patients with T1/T2 N0 squamous cell carcinoma of oral tongue. Oral Oncol 2006;42(1):96–101. 26. Kurokawa H, Yamashita Y, Takeda S, Zhang M, Fukuyama H, Takahashi T. Risk factors for late cervical lymph node metastases in patients with stage I or II carcinoma of the tongue. Head Neck 2002;24(8):731–6. 27. Okamoto M, Nishimine M, Kishi M, Kirita T, Sugimura M, Nakamura M, et al. Prediction of delayed neck metastasis in patients with stage i/ii squamous cell carcinoma of the tongue. J Oral Pathol Med 2002;31(4):227–33.
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Electron beam radiotherapy for tongue cancer using an intra-oral cone Naoya Kakimoto a,⇑, Shumei Murakami a, Atsutoshi Nakatani a, Yasuo Yoshioka b, Kimishige Shimizutani c, Souhei Furukawa a a
Department of Oral and Maxillofacial Radiology, Osaka University Graduate School of Dentistry, Suita, Osaka, Japan Department of Radiation Oncology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan c Department of Oral Radiology, Osaka Dental University, Osaka, Japan b
a r t i c l e
i n f o
Article history: Received 2 September 2011 Received in revised form 14 December 2011 Accepted 16 December 2011 Available online 10 January 2012 Keywords: Tongue cancer Radiation therapy Electrons Intra-oral cone Biological effective dose Complications
s u m m a r y To explain the adaptation technique using an intra-oral cone (IOC) for radiation therapy, and to determine the optimal schedule resulting in a high local control rate and an acceptable complication rate using direct electron beam radiation for the treatment of tongue cancer. Thirty patients with the tongue cancer (T1:T2:T3 = 16:11:3) were treated with 6–15 MeV electron radiation using an IOC. Twenty-six patients were treated with electron radiation using an IOC with or without an excisional biopsy. The other four patients were treated with a combination of the external beam radiation and electron radiation using the IOC. In order to formulate a safe and effective treatment program, we calculated the biologically effective dose (BED). The two- and five-year local control rates for all patients were 63% and 52%, respectively. The two- and five-year overall survival rates for all patients were 73% and 69%, respectively. Local control was achieved in 12 of 15 patients who were irradiated with a BED of 90.9 Gy10 or more, whereas it was not achieved in nine of the 15 patients who were treated with less than a BED of 90.9 Gy10 (p = 0.03). The application of electron radiation using an IOC for the treatment of tongue cancer provides acceptable local control and adverse effect rates, especially for elderly patients considered to be high risk for complications from anesthesia. The optimum BED10 value for the treatment of early tongue cancer using the IOC technique appears to be at least 90.9 Gy10. Ó 2011 Elsevier Ltd. All rights reserved.
Introduction It is widely accepted that radiotherapy is effective in the early stages of tongue carcinoma, which is usually curable without any concomitant functional loss.1–5 For the radical treatment of tongue carcinoma by radiotherapy, low-dose- or high-dose-rate interstitial radiotherapy has generally been the main treatment modality.1–8 The treatment outcomes in patients treated with either modality have been excellent, and they have only been associated with minimal complications. However, for patients deemed at high risk for complications from anesthesia or who have cardiovascular disease, this type of radiotherapy cannot be used. For these patients, direct electron beam radiotherapy using an intra-oral cone (IOC) may represent an alternative.9–11 Direct electron beam radiation using an IOC has also been recommended to boost the therapeutic response after external beam radiation therapy.11 For example, Wang reported that the tumor control following treatment with the electron beam
⇑ Corresponding author. Address: Department of Oral and Maxillofacial Radiology, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka 565-0871, Japan. Tel.: +81 6 6879 2967; fax: +81 6 6879 2970. E-mail address: [email protected] (N. Kakimoto). 1368-8375/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.oraloncology.2011.12.008
boost technique using an IOC was superior to that obtained using an interstitial implant for early carcinoma of the tongue.11 The aim of the present study was to explain the adaptation of electron beam radiotherapy using an IOC for tongue carcinoma patients, and to determine the optimal treatment schedule that can provide a high local control rate with acceptable complications. Methods and materials Approval from the institutional review board was obtained, and informed consent was waived for this retrospective study. Between 1981 and 2009, 33 patients with the tongue cancer were treated with 6–15 MeV electron beam radiation using an IOC at Osaka University Medical or Dental Hospital. One patient was treated for recurrent tongue cancer. Another patient was treated with the electron beam radiation using an IOC for the pre-interstitial brachytherapy, and another patient received radiation for palliative treatment. These three patients were excluded from this study. The remaining 30 patients (25 with tumors on the lateral border; two with tumors on the apex; two with tumors on the ventral surface; and one patient with a tumor on the dorsal surface) were examined for our study. All of the tumors were histopathologically confirmed to be squamous cell carcinoma. Ten of the 30 patients had inoperable
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Table 1 The patient characteristics, treatments, and tongue cancer control. Case no.
Age
Gender
T
N
M
Tumor volume (cm3)
1 2 3 4 5 6 7
59 36 50 70 73 64 79
M F F F M F M
1 1 1 2 1 2 2
0 0 0 0 0 0 0
0 0 0 0 0 0 0
0 0 0.63 3.18 0 1.66 0.79
8 9 10
85 78 44
F F M
1 2 2
0 0 0
0 0 0
0.94 3.27 0.42
11 12
42 59
F M
2 1
0 0
0 0
1.21 0.14
13 14 15 16 17 18 19
51 73 61 76 80 84 56
M F F M M F M
2 1 1 1 1 2 2
0 0 0 0 0 0 0
0 0 0 0 0 0 0
1.15 0.53 0.09 0.51 0.56 3.73 5.5
20
81
F
1
0
0
0.31
21
77
F
2
0
0
5.65
22
53
M
1
0
0
0
23 24
67 70
M M
1 3
0 0
0 0
1.39 6.59
25
84
M
3
0
0
14.37
26
78
M
1
0
0
0.16
27
81
M
3
2
0
8.44
28 29 30
78 74 75
M M F
2 1 1
0 0 0
0 0 0
1.98 1.18 0
Systemic disease
Brain infraction
External RT
30 Gy/ 15 fr/21 d
Cardiac infraction
Brain aneurysm Cardiac pacemaker
32 Gy/ 16 fr/23 d
Brain infraction 24.5 Gy/ 7 fr/15 d Cardiac pacemaker Angina pectoris
40 Gy/ 20 fr/33 d
Electron RT using an IOC
BED10 (Gy10)
BEDcorr10 (Gy10)
BED3 (Gy3)
BEDcorr3 (Gy3)
Tongue cancer control
35 Gy/2 fr/22 d 50 Gy/10 fr/32 d 50 Gy/10 fr/33 d 75 Gy/14 fr/65 d 64 Gy/16 fr/37 d 56 Gy/14 fr/31 d 42 Gy/14 fr/31 d
97.5 75.0 75.0 117.5 89.6 78.4 90.6
87.3 60.2 59.8 87.5 72.5 64.1 65.7
243.3 133.3 133.3 216.7 149.3 130.7 134.0
233.2 118.5 118.1 186.6 132.2 116.3 109.1
s s s s
50 Gy/5 fr/36 d 56 Gy/14 fr/29 d 46.4 Gy/4 fr/ 24 d 40 Gy/4 fr/22 d 40 Gy/4 fr/20 d
100.0 78.4 102.1
83.4 65.0 91.1
216.7 130.7 232.2
200.0 117.3 221.1
s
80.0 80.0
69.8 70.8
173.3 173.3
163.2 164.1
40 Gy/4 fr/19 d 50 Gy/10 fr/34 d 50 Gy/10 fr/34 d 60 Gy/12 fr/50 d 50 Gy/5 fr/29 d 50 Gy/6 fr/31 d 59 Gy/11 fr/37 d
80.0 75.0 75.0 75.0 100.0 95.0 129.7
71.2 59.3 59.3 51.9 86.6 80.7 93.2
173.3 133.3 133.3 133.3 216.7 200.0 220.0
164.6 117.6 117.6 110.2 203.3 185.6 183.5
D s s s s s
45 Gy/5 fr/29 d
87.5
74.1
186.7
173.3
72.5 Gy/20 fr/ 45 d 34.5 Gy/5 fr/ 21 d 59 Gy/13 fr/29 d 55 Gy/10 fr/22 d
98.9
78.1
160.4
139.6
D
64.3
54.6
133.8
124.0
D
90.9 85.3
77.5 75.1
149.3 155.8
135.9 145.7
D
48 Gy/12 fr/27 d
100.3
73.0
165.1
137.8
D
68 Gy/17 fr/40 d
95.2
76.7
158.7
140.2
40 Gy/8 fr/16 d
108.0
78.9
173.3
144.2
D
96 Gy/24 fr/60 d 72 Gy/18 fr/40 d 67 Gy/15 fr/37 d
134.4 100.8 93.5
106.7 82.3 76.4
224.0 168.0 155.3
196.3 149.5 138.2
s D
RT, radiotherapy; IOC, intra-oral cone; BED, biologically effective dose; Tumor volume = (4p/3) (long diameter/20) (short diameter/20) (thickness/20) (cm3). Fr, fractions; d, days; Tongue cancer control, s, controlled; D, controlled with complication; , uncontrolled. Case no. 20, osteoradionecrosis of mandible was experienced after external beam irradiation for lymph node metastasis. Finally tongue cancer was recurred.
tumors due to the presence of systematic disease or because of their advanced age. The patient characteristics, tumor volume, treatment dose, and presence of systemic disease are shown in Table 1. The patients’ ages ranged from 36 to 85 years, with a median age of 73 years. Thirteen patients were females and 17 were males. According to the UICC TNM classification of 2002, 16 patients had stage T1 disease, 11 had T2, and three had stage T3 disease. The tumor volumes ranged from 0 (after an excisional biopsy) to 14.37 cm3. The tumor volume was calculated according to the following equation:
Tumour volume ¼ ð4p=3Þðx=20Þðy=20Þðz=20Þ ðin cm3 Þ; where x = long diameter (mm), y = short diameter (mm) and z = thickness (mm). There was one patient with neck node metastasis, however none of the patients had distant metastasis. The median followup period was 51 months from the start of the radiotherapy, and ranged from 7 to 120 months. Of the 30 patients, 21 were treated with electron beam radiation using an IOC alone. Four received electron beam radiotherapy using an IOC in combination with external beam radiation. The reasons why a combination of electron beam radiotherapy with IOC and external beam radiation was used were as follows: One patient
had a tumor with a long diameter which was more than 30 mm and had brain infraction on his past illness, therefore, the fixation of his tongue was unstable. The tumor thickness in two patients was more than 15 mm. One patient had neck lymph node metastasis. The remaining five patients were irradiated by the electron beam using an IOC after the excisional biopsy, because these patients had histopathologically-positive margins on their excised tumors. The sizes of the IOC ranged from 2 to 4 cm in diameter. The most commonly used electron energy was 9 MeV. For the thinner lesions with a thickness of less than 7 mm, or for lesions from which the excisional biopsy had been taken, a 6 MeV electron beam was used. For the larger lesions, including the T3 lesions, a 15 MeV electron beam was used. The fractionation schedule ranged from 1 fraction/2 weeks to 5 fractions/week. The total electron beam dose ranged from 34.5 to 96 Gy (Table 1). For the electron beam irradiation using an IOC, the cone was introduced through the open mouth and placed so that it covered a tumor. The lesion was immobilized by pulling the tip of the tongue out by a tongue clamp or having the patient stabilize it with their fingers over gauze during the irradiation. The angle of the mouth was expanded by pulling the lips aside with a hook to expand the oral access (Fig. 1). The tumor location in the IOC was confirmed using a periscope equipped with a linear accelerator before and after irradiation on every treatment day.
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The external radiotherapy was administered daily at 2 Gy, 5 days a week by a single ipsilateral portal, including the suprahyoid of the neck, using 60Co gamma rays or 4 MV X-rays. Owing to the lack of standardized treatment schemes, the patients were managed by various radiation therapy schedules regarding the total dose and the fraction size. In order to formulate a treatment program with acceptable local control and complication rates, we calculated the biologically effective dose (BED) and a corrected biologically effective dose that was corrected based on a time factor term to take into account the proliferation in tumors (BEDcorr) based on the linear quadratic model12:
BED ¼ ðndÞ½1 þ d=ða=bÞ BEDcorr ¼ ðndÞ½1 þ d=ða=bÞ ð0:693=aÞðt=T pot Þ; where BED = biologically effective dose, n = number of fractions, d = dose per fraction, BEDcorr = corrected biologically effective dose, t = treatment time (days), and Tpot = potential doubling time (days). This yielded: a/b = 10 Gy for tumors and 3 Gy for late-response normal tissues, with a = 0.3/Gy and Tpot = 5 days. The BED10, BEDcorr10, BED3, and BEDcorr3 values are showed in Table 1. Neoadjuvant chemotherapy was administered to two patients because they had a long interval from biopsy to radiation therapy
Figure 1 The set-up of the direct electron beam radiation using an IOC, a tongue clamp, and a hook.
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in order to allow for the close investigation of their whole body. None of the patients received concomitant chemotherapy during their radiation therapy. Adjuvant chemotherapy was administered to three patients who experienced a recurrence. For the statistical analyses, either the Chi square test or the Fisher’s exact probability test were used. The local control and survival rates were calculated using the Kaplan–Meier method, and the log-rank test was used to make comparisons. All analyses used the conventional p < 0.05 level of significance. Results Local control rate The 2- and 5-year local control (LC) rates for all patients were 63% and 52%, respectively. The 2- and 5-year LC rates for T1 patients were 71% and 63%, were 55% and 41% for T2 patients, and both 2- and 5-year LC rates for T3 patients were 0% (Figs. 2 and 3). There were no significant differences among any of the different disease stage groups (p = 0.21). Four of five patients who had been irradiated after the excisional biopsy were controlled. Twelve patients developed a local recurrence. Seven of these patients were successfully salvaged by the surgical excision of the recurrent tumor. Therefore, the 2- and 5-year ultimate LC rates of the patients who received radiotherapy and salvage surgery were 85% and 80%, respectively (Fig. 4).
Figure 3 The local control rates of tongue cancer treated with direct electron beam irradiation using an IOC.
Figure 2 A representative case (case 18) treated with direct electron beam radiation using an IOC. (A) a pre-irradiation photo of the lesion; (B) a photo after 20 Gy radiation; (C) a photo after 40 Gy radiation; and (D) a photo at 4 years after radiation of the lesion.
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within 4 months, while the other three patients with ulceration finally healed within 13 months by conservative treatment. The remaining patients with ulceration did not fully heal by the time of death due to neck node and distant metastases. Correlation between the tumor volume and BED
Figure 4 The local control rate and ultimate local control rate for all patients with tongue cancer treated with the direct electron beam radiation using an IOC. The ultimate local control rate was calculated using the local control that was achieved using radiotherapy and salvage surgery.
Cause-specific survival rate
Fig. 6A shows the relationship between the tumor volume and BED10 for all cases. Local control was achieved in 12 of the 15 patients who were irradiated with a BED of 90.9 Gy10 or more, whereas local control was achieved in only 6 of the 15 patients who were irradiated with less than a BED of 90.9 Gy10 (p = 0.03). On the other hand, local control was achieved in 10 of the 12 patients who were irradiated with a BEDcorr of 77.5 Gy10 or more, while local control was achieved in only 8 of the 18 patients who were irradiated with less than a BEDcorr of 77.5 Gy10. There was
The 2- and 5-year cause-specific survival (CSS) rates of all patients were 76% and 71%, respectively. The 2- and 5-year CSS rates for T1 patients were both 86%, and were 68% and 57% for T2 patients and 0% for both the 2- and 5-year CSS rates for T3 patients. There were no significant differences among any of the different disease stage groups (p = 0.054). Disease-free survival rate The 2- and 5-year disease-free survival (DFS) rates for all patients were 52% and 39%, respectively. The 2- and 5-year DFS rates for T1 patients were 58% and 50%, were 36% and 27% for T2 patients, and 0% for both the 2- and 5-year DFS rates for T3 patients. There were no significant differences among any of the different disease stage groups (p = 0.11). Overall survival rate The 2- and 5-year overall survival (OS) rates for all patients were 73% and 69%, respectively. The 2- and 5-year OS rates for T1 patients were both 80%, were 68% and 57% for T2 patients, and 0% for both the 2- and 5-year OD rates for T3 patients (Fig. 5). There were no significant differences among any of the different disease stage groups (p = 0.22). Complications Of the 30 patients treated with direct electron beam radiation using an IOC, nine patients experienced soft tissue ulceration, and one patient experienced osteoradionecrosis. Eight soft tissue ulcerations occurred between 6 and 8 months after direct electron beam radiation using an IOC. Another patient experienced soft tissue ulceration at 34 months after direct electron beam radiation using an IOC. This patient continued to smoke tobacco during this follow-up term. Five patients with ulceration successfully healed
Figure 5 The overall survival rates of tongue cancer patients treated with direct electron beam radiation using an IOC.
Figure 6 The relationship between the BED10 and tumor volume with regard to the local control by the direct electron beam radiation using an IOC. (A) All cases; (B) T1 cases; (C) T2 cases.
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a marginally significant difference in the local control rates between the patients who were irradiated with a BEDcorr of at least 77.5 Gy10 and those who received less than 77.5 Gy10 (p = 0.06). For T1 cases, local control was achieved in six of the seven patients who were irradiated with a BED of 90.9 Gy10 or more, whereas local control was achieved in only five of the nine patients who were irradiated with less than a BED of 90.9 Gy10 (p = 0.31) (Fig. 6B). For T2 cases, local control was achieved in 4 of the 6 patients who were irradiated with a BED of 90.9 Gy10 or more, whereas local control was achieved in only 1 of the 5 patients who were irradiated with less than a BED of 90.9 Gy10 (p = 0.24) (Fig. 6C). Fig. 7(A–C) shows the relationship between the tumor volume and the BED3 for all cases, T1 cases, and T2 cases, respectively. Complications were still observed even when the patients were irradiated with either low BED3 or BEDcorr3.
Figure 7 The relationship between the BED3 and tumor volume with regard to the complications induced by direct electron beam radiation using an IOC. (A) All cases; (B) T1 cases; (C) T2 cases.
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Regional control Neck lymph node metastasis developed in 11 of the 29 N0 patients. Three patients were salvaged by surgery for their neck lymph node metastasis. Five other patients were treated surgically, but could not be saved. Three patients were deemed to be inoperable because of the size or location of the metastasis, the presence of systemic disease, or because of their advanced age. Discussion The tongue is the most prominent site of carcinomas of the oral cavity.13 With the improvement of surgical reconstruction, the number of patients treated with surgery for tongue cancer has increased steadily since 1980.14,15 However, radiotherapy continues to play an important role in the management of the tongue carcinoma because of its better cosmetic and functional results.16 At our hospital, low-dose- or high-dose-rate interstitial brachytherapy with 192Iridium has traditionally been used as the main treatment modality for tongue cancer. The results of these treatments have generally been excellent, and they have also only been associated with few complications.8,17,18 However, these modalities are often unsuitable for high risk patients.11 In contrast, the IOC technique is applicable even for very elderly patients with high anesthesia risks, because it is a painless and non-traumatic procedure. In this study, the 2- and 5-year LC rates were 63% and 52%, and the 2- and 5-year ultimate LC rates (with radiotherapy and salvage surgery) were 85% and 80%, respectively, for all 30 patients. Of particular importance, local control without salvage surgery was achieved in 12 of the 15 patients who received a BED of 90.9 Gy10 or more, and 10 of 12 patients who were irradiated with a BEDcorr of 77.5 Gy10 or more. A high local control rate can therefore be expected for patients who can be administered a total BED10 with a value over 90.9 Gy10 and a BEDcorr10 with a value over 77.5 Gy10. The reported 2- and 5-year LC rates of interstitial brachytherapy for early mobile tongue cancer ranged from 80% to 90%.1–5 In our hospital, the LC rate for low-dose-rate interstitial brachytherapy of early mobile tongue cancer was 84%, while that for high-doserate interstitial brachytherapy was 87%.8 The LC rate for the T1 and T2 patients in the present study who were treated with direct electron beam radiation using an IOC for early tongue cancer was inferior to that of interstitial brachytherapy. These findings contrast with the results reported by Wang,11 but they correlate with the results reported by Akine.19 However, the LC rate for patients who received BED of more than 90.9 Gy10 or BEDcorr of more than 77.5 Gy10 using the IOC technique was nearly equivalent to that of interstitial brachytherapy. However, since the placement of the IOC in the patient requires meticulous technique and skill, we believe that interstitial brachytherapy is a more reliable treatment for tongue cancer than the IOC technique. In addition, T3 tongue cancers were not controlled by the IOC technique, but are well-controlled by interstitial brachytherapy.18 We therefore suggest that the main radiation therapy for mobile tongue cancer should remain interstitial brachytherapy. However, the IOC technique has been shown to still be suitable for elderly patients or others with high anesthesia risks, especially those with early-stage disease. Yamazaki et al. reported that age and dental factors, including prosthesis irritation, are potentially important prognostic factors for local control of early stage oral tongue cancer by brachytherapy.20 This is also considered to be applicable for the IOC technique. In this study, the median age of patients was 73 years old, and 19 of the 30 patients were older than 65. In addition, 10 of the 30 patients were inoperable cases due to the presence of systemic disease or because of their advanced age. Therefore, if age is important prognostic
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factor for the radiotherapy of tongue cancer, the population of this study is disadvantaged in terms of local control. The complications of external beam radiation therapy for tongue cancer include xerostomia, mucositis, diminished taste acuity, osteonecrosis and so on.21 Recently, the sparing of the parotid glands with intensity modulated radiation therapy has significantly reduced the incidence of xerostomia.22,23 The main complication of direct electron beam radiation using an IOC for tongue cancer observed in our study was the development of soft tissue ulcers. Although we thought that the BED3 or BEDcorr3 might have had an impact on complications, there were no significant correlations between these factors and the complication rate or type in this study. As the placement of the IOC in the patient requires meticulous technique and skill, it is very difficult to reproduce the day-to-day geometric concentration of the electron beam. As a result, soft tissue ulcers were still experienced even by patients with a small BED3 or BEDcorr3, while they were not experienced by other patients with a large BED3 or BEDcorr3. The one patient who developed osteoradionecrosis in the mandible had been treated by external beam radiation for lymph node metastasis after initial treatment using an IOC. We assumed that the osteoradionecrosis had been caused by this external beam radiation for the neck lymph node metastasis, but this is still open for interpretation. The incidence of regional metastasis of N0 early tongue cancer has been reported to be about 30%.24,25 When the depth of invasion of the primary tumor of the tongue exceeded 4 mm, occult metastasis in the cervical lymph nodes occurred in from 37.5% to 45% of patients.26,27 The incidence of occult regional metastasis was about 38% in the present study. This result was similar to the findings of the previous reports about early tongue cancer patients. In conclusion, direct electron beam radiotherapy using an IOC for tongue cancer was therefore found to be an acceptable treatment, especially for patients with a high anesthesia risks. While this treatment is not recommended for patients with advanced disease, those with T1 or T2 disease should experience a significant benefit from this treatment regimen. The optimum BED10 and BEDcorr10 values for early tongue cancer treated using the IOC technique were at least 90.9 Gy10 for BED10 and at least 77.5 Gy10 for BEDcorr10. Further studies in a larger number of patients are needed to confirm the efficacy and complication rates associate with this treatment. Conflict of interest statement None declared. Acknowledgment The authors would like to thank the late Professor Takehiro Inoue for his valuable guidance. References 1. Mazeron JJ, Crook JM, Benck V, Marinello G, Martin M, Raynal M, et al. Iridium 192 implantation of T1 and T2 carcinomas of the mobile tongue. Int J Radiat Oncol Biol Phys 1990;19(6):1369–76. 2. Pernot M, Malissard L, Aletti P, Hoffstetter S, Forcard JJ, Bey P. Iridium-192 brachytherapy in the management of 147 T2N0 oral tongue carcinomas treated with irradiation alone: comparison of two treatment techniques. Radiother Oncol 1992;23(4):223–8.
3. Shibuya H, Hoshina M, Takeda M, Matsumoto S, Suzuki S, Okada N. Brachytherapy for stage I & II oral tongue cancer: an analysis of past cases focusing on control and complications. Int J Radiat Oncol Biol Phys 1993;26(1):51–8. 4. Fein DA, Mendenhall WM, Parsons JT, McCarty PJ, Stringer SP, Million RR, et al. Carcinoma of the oral tongue: a comparison of results and complications of treatment with radiotherapy and/or surgery. Head Neck 1994;16(4):358–65. 5. Matsuura K, Hirokawa Y, Fujita M, Akagi Y, Ito K. Treatment results of stage I and II oral tongue cancer with interstitial brachytherapy: maximum tumor thickness is prognostic of nodal metastasis. Int J Radiat Oncol Biol Phys 1998;40(3):535–9. 6. Lau HY, Hay JH, Flores AD, Threlfall WJ. Seven fractions of twice daily high doserate brachytherapy for node-negative carcinoma of the mobile tongue results in loss of therapeutic ratio. Radiother Oncol 1996;39(1):15–8. 7. Leung TW, Wong VY, Wong CM, Tung SY, Lui CM, Leung LC, et al. High dose rate brachytherapy for carcinoma of the oral tongue. Int J Radiat Oncol Biol Phys 1997;39(5):1113–20. 8. Inoue T, Yoshida K, Yoshioka Y, Shimamoto S, Tanaka E, Yamazaki H, et al. Phase III trial of high- vs low-dose-rate interstitial radiotherapy for early mobile tongue cancer. Int J Radiat Oncol Biol Phys 2001;51(1):171–5. 9. Fayos JV, Lampe I. Peroral irradiation of carcinoma of the oral tongue. Radiology 1969;93(2):387–94. 10. Wang CC, Doppke KP, Biggs PJ. Intra-oral cone radiation therapy for selected carcinomas of the oral cavity. Int J Radiat Oncol Biol Phys 1983;9(8):1185–9. 11. Wang CC. Radiotherapeutic management and results of T1N0, T2N0 carcinoma of the oral tongue: evaluation of boost techniques. Int J Radiat Oncol Biol Phys 1989;17(2):287–91. 12. Hall EJ, Giaccia AJ. Time, dose and fractionation in radiotherapy. In: Hall EJ, Giaccia AJ, editors. Radiobiology for the radiologist. Philadelphia: Lippincott Williams and Wilkins; 2006. p. 378–97. 13. Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer statistics, 2011. CA Cancer J Clin 2001;51(1):15–36. 14. Franceschi D, Gupta R, Spiro RH, Shah JP. Improved survival in the treatment of squamous carcinoma of the oral tongue. Am J Surg 1993;166(4):360–5. 15. Haddadin KJ, Soutar DS, Oliver RJ, Webster MH, Robertson AG, MacDonald DG. Improved survival for patients with clinically T1/T2, no tongue tumors undergoing a prophylactic neck dissection. Head Neck 1999;21(6):517–25. 16. Yoshimura R, Shibuya H, Miura M, Watanabe H, Ayukawa F, Hayashi K, et al. Quality of life of oral cancer patients after low-dose-rate interstitial brachytherapy. Int J Radiat Oncol Biol Phys 2009;73(3):772–8. 17. Yamazaki H, Inoue T, Yoshida K, Tanaka E, Yoshioka Y, Nakamura H, et al. Lymph node metastasis of early oral tongue cancer after interstitial radiotherapy. Int J Radiat Oncol Biol Phys 2004;58(1):139–46. 18. Kakimoto N, Inoue T, Inoue T, Murakami S, Furukawa S, Yoshida K, et al. Results of low- and high-dose-rate interstitial brachytherapy for T3 mobile tongue cancer. Radiother Oncol 2003;68(2):123–8. 19. Akine Y, Tokita N, Ogino T, Tsukiyama I, Egawa S, Saikawa M, et al. Stage I–II carcinoma of the anterior two-thirds of the tongue treated with different modalities: a retrospective analysis of 244 patients. Radiother Oncol 1991;21(1):24–8. 20. Yamazaki H, Inoue T, Yoshida K, Kotsuma T, Yoshioka Y, Koizumi M, et al. Assessment of influence of smoking, drinking, leukoplakia and dental irritation on local control of early oral tongue carcinoma treated with brachytherapy: age and dental factors are potential prognostic factors. Tumori 2009;95(4):461–6. 21. Cooper JS. The oral cavity. In: Cox JD, Ang KK, editors. Radiation oncology rationale technique results. Louis: St. Mosby; 2003. p. 219–54. 22. Stock M, Dorr W, Stromberger C, Mock U, Koizar S, Potter R, et al. Investigations on parotid gland recovery after imrt in head and neck tumor patients. Strahlenther Onkol 2010;186(12):665–71. 23. Nutting CM, Morden JP, Harrington KJ, Urbano TG, Bhide SA, Clark C, et al. Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer (parsport): a phase 3 multicentre randomised controlled trial. Lancet Oncol 2011;12(2):127–36. 24. Prince S, Bailey BM. Squamous carcinoma of the tongue: review. Br J Oral Maxillofac Surg 1999;37(3):164–74. 25. Keski-Santti H, Atula T, Tornwall J, Koivunen P, Makitie A. Elective neck treatment versus observation in patients with T1/T2 N0 squamous cell carcinoma of oral tongue. Oral Oncol 2006;42(1):96–101. 26. Kurokawa H, Yamashita Y, Takeda S, Zhang M, Fukuyama H, Takahashi T. Risk factors for late cervical lymph node metastases in patients with stage I or II carcinoma of the tongue. Head Neck 2002;24(8):731–6. 27. Okamoto M, Nishimine M, Kishi M, Kirita T, Sugimura M, Nakamura M, et al. Prediction of delayed neck metastasis in patients with stage i/ii squamous cell carcinoma of the tongue. J Oral Pathol Med 2002;31(4):227–33.