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High Dose Rate versus Low Dose Rate Interstitial Radiotherapy for Carcinoma of the Floor of Mouth
Int. J. Radiation Oncology Biol. Phys., Vol. 41, No. 1, pp. 53–58, 1998 Copyright © 1998 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/98 $19.00 1 .00
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Clinical Investigation HIGH DOSE RATE VERSUS LOW DOSE RATE INTERSTITIAL RADIOTHERAPY FOR CARCINOMA OF THE FLOOR OF MOUTH TAKEHIRO INOUE, M.D.,* TOSHIHIKO INOUE, M.D.,* HIDEYA YAMAZAKI, M.D.,* MASAHIKO KOIZUMI, M.D.,* KAZUFUMI KAGAWA, M.D.,* KEN YOSHIDA, M.D.,* HIROYA SHIOMI, M.D.,* ATSUSHI IMAI, M.D.,* KIMISHIGE SHIMIZUTANI, D.D.S.,† EICHII TANAKA, M.D.,† TAKAYUKI NOSE, M.D.,† TERUKI TESHIMA, M.D.,‡ SOUHEI FURUKAWA, D.D.S.,§ AND HAJIME FUCHIHATA, D.D.S.§
*Department of Radiation Oncology, Biomedical Research Center, †Department of Radiology, ‡Department of Medical Engineering, Osaka University Medical School, and §Department of Oral and Maxillofacial Radiology, Osaka University Dental School, Osaka, Japan Purpose: Patients with cancer of the floor of mouth are treated with radiation because of functional and cosmetic reasons. We evaluate the treatment results of high dose rate (HDR) and low dose rate (LDR) interstitial radiation for cancer of the floor of mouth. Methods and Materials: From January 1980 through March 1996, 41 patients with cancer of the floor of mouth were treated with LDR interstitial radiation using 198Au grains, and from April 1992 through March 1996 16 patients with HDR interstitial radiation. There were 26 T1 tumors, 30 T2 tumors, and 1 T3 tumor. For 21 patients treated with interstitial radiation alone, a total radiation dose of interstitial therapy was 60 Gy/10 fractions/6 –7 days in HDR and 85 Gy within 1 week in LDR. For 36 patients treated with a combination therapy, a total dose of 30 to 40 Gy of external radiation and a total dose of 48 Gy/8 fractions/5– 6 days in HDR or 65 Gy within 1 week in LDR were delivered. Results: Two- and 5-year local control rates of patients treated with HDR interstitial radiation were 94% and 94%, and those with LDR were 75% and 69%, respectively. Local control rate of patients treated with HDR brachytherapy was slightly higher than that with 198Au grains (p 5 0.113). For late complication, bone exposure or ulcer occurred in 6 of 16 (38%) patients treated with HDR and 13 of 41 (32%) patients treated with LDR. Conclusion: HDR fractionated interstitial brachytherapy can be an alternative to LDR brachytherapy for cancer of the floor of mouth and eliminate radiation exposure for the medical staff. © 1998 Elsevier Science Inc. Brachytherapy, Carcinoma of the floor of mouth, Dose rate.
INTRODUCTION
brachytherapy can eliminate radiation exposure for the medical staff. According to the randomized trial of comparison for local control rates of tongue carcinoma patients treated with HDR and low dose rate (LDR) interstitial radiation, local control rate and late complication of the HDR group were the same as those of the LDR group (4). In this paper, we evaluate the treatment results of HDR and LDR interstitial radiation for carcinoma of the floor of mouth.
Some patients with cancer of the floor of mouth are treated with radiation because of functional and cosmetic reasons. At the Osaka University Hospital, more than half of patients with cancer of the floor of mouth had been treated with interstitial radiotherapy (1). Before 1980, patients were mainly treated with 192Ir hair pins or Ra needles. For 192Ir hair pins or Ra needles, it is difficult to avoid the radiation for normal tissue of the tongue because of the long active length of these sources. From 1980, 198Au grains were available at our department. For 198Au grains, it is easy to implant under local anesthesia for patients with poor risk or aged patients (2). From July 1991, we carried out high dose rate (HDR) interstitial radiation for head and neck carcinomas (3). HDR
METHODS AND MATERIALS From January 1980 through March 1996, 41 patients with carcinoma of the floor of mouth were treated with LDR brachytherapy using 198Au grains. From 1992 to March 1996, 16 patients were treated with HDR 192Ir microsource.
Reprint requests to: Takehiro Inoue, M.D., Department of Radiation Oncology, Biomedical Research Center, Osaka University Medical School, 2-2 Yamadaoka, Suita, Osaka 565, Japan. Acknowledgment—This study was supported in part by the Grantin-Aid for Cancer Research from the Ministry of Health and
Welfare (7-33, 9-27) and by the Grant-in-Aid for Scientific Research (A) from the Ministry of Education, Science, Sports and Culture (06304032) of the Japanese Government. Accepted for publication 24 November 1997. 53
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Table 1. Characteristics
No. cases Age Sex
Range Median Male Female
T1 T2 T3 N0 N1 N2
LDR
HDR
41 38–83 62 36 5 22 19 0 38 3 0
16 32–80 60 16 0 4 11 1 14 1 1
88% 12% 54% 46% 0% 93% 7% 0%
100% 0% 25% 69% 6% 88% 6% 6%
We compared the treatment results of patients treated with LDR brachytherapy using 198Au grains and HDR brachytherapy using 192Ir microsource. Table 1 shows the age and sex distribution and TN classification of 41 patients treated with LDR brachytherapy and 16 patients with HDR brachytherapy. The median ages of LDR and HDR groups were 62 (range, 38 – 83) and 60 (range, 32– 80) years old. There were 36 male patients and 5 female patients in the LDR group; all patients were male in the HDR group. There are no statistically significant differences in age or sex distributions between the two groups. Of 41 patients of the LDR group, 22 (54%) were classified as T1 and 19 (46%) as T2, and of 16 patients of the HDR group, 4 (25%) were classified as T1, 11 (69%) as T2, and one (6%) as T3 (p 5 0.0569). Thirty-eight patients (93%) were classified as N0 and 3 (7%) as N1 in the LDR group, and 14 (88%) were classified as N0, one (6%) each as N1 and N2 in the HDR group (not significant). The radiation methods for individual patients were decided by more than two doctors in charge who had more than 10 years’ experience of the brachytherapy. Table 2 shows the tumor size and treatment method for carcinoma of the floor of mouth. For the LDR group, 15 patients were treated with interstitial radiation alone, 11 patients with a combination of external radiation and interstitial radiation, and 15 patients with concurrent chemotherapy during external radiation and interstitial radiation. We used 45 mg of
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peplomycin (range, 25– 60 mg) or 60 mg of bleomycin (range, 45–135) as the concurrent chemotherapy. The corresponding figures for the HDR group were 6, 8, and 2 patients for each treatment, respectively. Twenty-one of 43 patients (49%) with a tumor of 30 mm or less were treated with interstitial radiation alone; all 14 patients with a tumor more than 30 mm or with nodal metastasis were treated with a combined treatment of external and interstitial radiation with or without concurrent chemotherapy (p 5 0.003). For the patients treated with interstitial radiation alone, the median dose of the LDR group was 85 Gy (range, 58 –132 Gy) within 1 week. In the HDR group, all patients were treated with a total dose of 60 Gy/10 fractions/7 days (Table 3). For the patients treated with a combination of 30 – 40 Gy of external radiation and interstitial radiation, the median dose of LDR brachytherapy was 65 Gy (range, 42–129 Gy) within 1 week. In the HDR group, all patients were treated with 48 Gy/8 fractions/6 days after the external radiation. The median interval between external radiation and LDR brachytherapy was 28 days (range, 5–76 days), and that for the HDR group was 20 days (1–29 days). Method of HDR interstitial radiotherapy was reported in previous papers (3, 4). Before the insertion of guide tubes for carcinoma of the floor of mouth, an individualized template was made because of the parallel implantation and ideal arrangement of applicators (Fig. 1). The pattern of the implantation of applicators such as triangles or squares was decided according to the size and location of the tumors. Eight patients were treated with double-plane implantation, and eight patients with volume implant. Applicators for the 192 Ir microsource were inserted from the mouth floor to the skin surface of the submental or submandibular region through the above mentioned template. In some patients with tongue invasion, applicators were inserted from the dorsal surface of the tongue to the skin surface. Dwell lengths of the 192Ir microsource were 10 to 35 mm with 2.5-mm steps. HDR interstitial radiation was carried out twice a day using microSelectron-HDR (Nucletron-Oldelft, The Netherlands). Time interval between two treatments was more than 6 hours (3, 4). Reference point of dose calculation of
Table 2. Tumor size and treatment method LDR Tumor size (mm) N0 ¶ 20 ¶ 30 ¶ 40 . 40 N1–2 Total
HDR
Int. alone
Ext. 1 Int.
Ext. 1 Che. 1 Int.
Total
Int. alone
Ext. 1 Int.
Ext. 1 Che. 1 Int.
Total
11 4 0 0
8 2 1 0
3 4 5 0
22 10 6 0
2 4 0 0
0 4 1 1
1 0 1 0
3 8 2 1
0 15
0 11
3 15
3 41
0 6
2 8
0 2
2 16
Int. 5 interstitial radiation; Ext. 5 external radiation; Che. 5 chemotherapy.
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Table 3. Radiation dose Interstitial radiation HDR†
LDR* External radiation
No. patients
Median dose
(Min.–Max.)
No. patients
Dose
0 30–40 Gy
15 26
85 Gy/7 d 65 Gy/7d
(58–132) (42–129)
6 10
60 Gy/10 Fr/7 d 48 Gy/8 Fr/6 d
* Dose delivered within 1 week. 0.83 3 permanent dose of † All patients were treated with 60 Gy or 48 Gy.
198
interstitial radiation was 5 mm from the source. Dose rate at the reference point changed according to the activity of the 192 Ir microsource. Average dose rates (single fraction dose/ overall treatment time in the first fraction) at the reference point ranged from 0.79 to 6.86 Gy/min (median: 2.5 Gy/min). Forty-one patients of the LDR group were followed at least 27 months or until their deaths. The maximum follow-up period was 136 months and the median was 65 months in the LDR group. One patient in the HDR group was lost to follow-up at 11 months after treatment because of the Hanshin Earthquake in January 1995. Fifteen patients of the HDR group were followed at least 19 months or until their deaths. The maximum was 61 months and the median follow-up period was 30 months in the HDR group. Student’s t test and chi-square test were used for the comparison of patients’ characteristics. Local control rates and cause-specific survival rates were calculated with the Kaplan–Meier method. Statistical significance was tested by means of log rank test. RESULTS Of 16 patients treated with HDR interstitial radiation, one died with nodal metastasis without local recurrence 7 months after radiation (Table 4). Two patients died with secondary esophageal or rectal cancer. Another patient died
Au.
with cerebral infarction 19 months after radiation. One patient was lost to follow-up at 11 months after treatment. The remaining nine are alive with no evidence of disease. Only one T3 tumor recurred 6 months after a combination therapy of 32 Gy of external radiation and 48 Gy/8 fractions of HDR interstitial radiation. This patient was treated with surgery for local recurrence, and died with rectal carcinoma 20 months after radiation as mentioned above. All 13 patients with T1 and T2 tumors were locally controlled. Of 41 patients treated with LDR, 12 developed local recurrence. Seven patients died with local tumor and two with nodal metastases. Two patients died with lung cancer, one with esophageal cancer, and one with another oral cancer. Two- and 5-year local control rates of patients treated with HDR interstitial radiation were 94% (Fig. 2). On the other hand, two- and 5-year local control rates of patients treated with 198Au grains were 75% (T1, 81%; T2, 67%) and 69% (T1, 76%; T2, 60%), respectively. This difference was not statistically significant (p 5 0.1130). Two- and 5-year cause-specific survival rates of patients treated with HDR interstitial radiation were 94% (Fig. 3). On the other hand, 2- and 5-year local control rates of patients treated with 198Au grains were 82% (T1, 91%; T2, 72%) and 76% (T1, 85%; T2, 67%), respectively. This difference was not statistically significant (p 5 0.2891). Table 5 shows local control of carcinoma of the floor of mouth according to the tumor size. For the LDR group, 17 of 22 tumors (77%) not more than 20 mm and 10 of 12 (83%) not more than 30 mm were locally controlled, and only 2 of 7 tumors (29%) more than 30 mm were controlled with radiation (p 5 0.0253). For the HDR group, all tumors not more than 40 mm were locally controlled. Table 6 shows local control according to the treatment Table 4. Treatment results LDR
Fig. 1. Individualized template for carcinoma of the floor of mouth.
No. cases Local recurrence Death with primary tumor Death with regional node Death with double cancer Bone exposure and/or ulcer
41 12 7 2 4 13
HDR 29% 17% 5% 10% 32%
16 1 0 1 2 6
6% 0% 6% 13% 38%
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Table 5. Local control by tumor size LDR
HDR
Tumor size (mm)
No. patients
Local control
%
No. patients
Local control
%
¶ 20 ¶ 30 ¶ 40 . 40 Total
22 12 7 — 41
17 10 2 — 29
77 83 29 — 71
4 9 2 1 16
4 9 2 0 15
100 100 100 0 94
¶ 30 versus . 30 in LDR; p 5 0.0253.
Fig. 2. Local control rates of patients treated with HDR brachytherapy using 192Ir microsource and LDR brachytherapy using 198 Au grains.
method and interval between external and interstitial radiation. For the LDR group, 13 of 15 tumors (87%) treated with interstitial radiation alone were locally controlled, and 16 of 26 tumors (62%) treated with a combination of external and interstitial radiation with or without chemotherapy were also locally controlled. Twenty-six tumors treated with a combination of external and interstitial radiation were divided into two groups according to interval between external and interstitial radiation. Twelve of 15 tumors (80%) with interval not more than 28 days were controlled, and only 4 of 11 tumors (36%) with interval more than 28 days were locally controlled (p 5 0.0641). For the HDR group, all 6 tumors treated with interstitial radiation alone were locally controlled, and 9 of 10 patients treated with a combination of external and interstitial radiation were controlled. As for grades 2 and 3 of objective score for late complication according to Late Effects Normal Tissues (LENT) Subjective Objective Management and Analytic (SOMA) Tables (5), bone exposure or ulcer of the mucosa of the floor of mouth occurred in 6 of 16 (38%) patients in the HDR group, and 13 of 41 (32%) patients in the LDR group (Table 7). The median
delay between brachytherapy and complication in the HDR group was 9 months (range, 2–20 months), and that in the LDR group was 17 months (range, 5–38 months). One of 19 patients with complication received surgery for bone exposure, and another 18 patients were treated with non-narcotic medication and/or antibiotics. In the HDR group, 3 of 5 patients with gingival invasion and 3 of 11 without gingival invasion showed late complication. Among 11 patients without gingival invasion, 6 were treated with dwell length of 10 or 15 mm and 5 patients with dwell length of 20 to 35 mm. No late complication occurred in the patients treated with dwell length of 10 or 15 mm. Three of the 5 patients treated with dwell length of 20 to 35 mm developed late complication. In the LDR group, 3 of 6 patients with gingival invasion showed late complication, and 10 of 35 patients without gingival invasion showed late complication. For the LDR group, late complication occurred in 3 of 15 patients (20%) treated with interstitial radiation alone, and in 10 of 26 patients (38%) with a combination therapy of external and interstitial radiation (p 5 0.3815). For the HDR group, late complication occurred in 3 of 6 patients treated with interstitial radiation alone, and in 3 of 10 patients treated with a combination therapy of external and interstitial radiation (p 5 0.7897). Table 8 shows bone exposure and/or soft tissue ulcer by tumor size of patients without lower gum invasion. For the HDR group, bone exposure and/or soft tissue ulcer occurred in 3 of 9 tumors not more than 30 mm. There were only 2 tumors more than 30 mm without gum invasion, and one of them had local recurrence and Table 6. Local control by treatment method and interval between external and interstitial radiation LDR Interval (days)
Fig. 3. Cause-specific survival rates of patients treated with HDR brachytherapy using 192Ir microsource and LDR brachytherapy using 198Au grains.
Interstitial alone Ext. 1 Int. ¶ 28 Ä 29 Total
No. Local patients control
HDR %
No. Local patients control
%
15
13
87
6
6
100
15 11 41
12 4 29
80 36 71
8 2 16
7 2 15
88 100 94
¶ 28 versus Ä 29 in LDR; p 5 0.0641.
HDR brachytherapy for mouth floor cancer
Table 7. Bone exposure and/or ulcer by dwell length Source HDR
LDR
Lower gum invasion 1 2
Dwell length (mm)
No. patients
Bone exposure and/or ulcer
5 6 5 16 6 35 41
3 0 3 6 (38%) 3 10 13 (32%)
¶ 15 Ä 20
Total 1 2 Total
another tumor was controlled without complication. For the LDR group, late complication occurred in 4 of 20 tumors (20%) not more than 20 mm, and in 6 of 15 tumors (40%) more than 20 mm (p 5 0.3586). DISCUSSION Local control rates of carcinoma of the floor of mouth treated with radiation in Osaka University Hospital were reported by Ikeda et al in 1985 (1). In this paper, local control rates of T1, T2, and T3 carcinoma of the mouth floor were reported as 80%, 56%, and 17%, respectively. More than half of the patients were treated with interstitial radiation. Forty patients were treated with Ra needles or 192Ir hair pins and six patients with Rn seeds and 198Au grains. However, from January 1985 through April 1993, 26 patients were treated with 198Au grains and only three patients with Ra needles, 137Cs needles, and 192Ir hair pins. Shimizutani et al reported the results of 45 patients with carcinoma of the oral cavity treated with 198Au grains in Osaka University Hospital (2). Local control rate for patients with T1 and T2 oral cancers including the carcinoma of the floor of mouth were 80% and 59%, respectively. Matsumoto et al (6) reported the local control rates of T1, T2a (¶3 cm), and T2b (.3 cm) lesions treated with 198Au grains as 89%, 76%, and 56%. Our results also showed lower local control rates in tumors more than 3 cm. Shimizutani et al reported a lower local control rate in the patients with longer interval between external and interstitial radiation. For the patients with carcinoma of the floor of mouth, a longer interval resulted in a lower control rate (p 5 0.0641). In recent years, we mainly used 198Au grains for LDR brachytherapy because of small irradiated volume of normal tissue. According to the present study, local control rates of HDR brachytherapy were better than those of 198Au grains. Delclos et al stated that gold grain implants were more subject to cold spots than radium or iridium implants (7). It is difficult to get the homogeneous dose distribution with 198 Au grains because of the technical problem. Another demerit of 198Au grain is the expulsion or dislocation of gold grains during high activity of the radioisotope. This problem also resulted in the dose inhomogeneity. For HDR brachytherapy, it is easy to implant the applicators in ideal arrangement using template. Even for the irregular arrange-
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ments of applicators, we can get the homogeneous dose distribution using dose optimization of a stepping source dosimetry system (4). Mazeron et al (8) reported the local control rates of T1N0 and T2N0 carcinoma of the floor of mouth treated with 192Ir hair pins as 93.5% and 74.5%, respectively. Grades 1, 2, and 3 complications of soft tissue were also reported as 15 of 95 (16%), 8 of 95 (8%), and 8 of 95 (8%), respectively. Ikeda et al (1) reported that 22 of 46 (48%) patients showed bone exposure, and these complications occurred in the patients treated with Ra needles or 192Ir hair pins. Shimizutani et al (2) reported that bone exposure occurred in 8 of 26 (31%) patients treated with 198Au grains. According to the present data, 6 of 16 (38%) patients in the HDR group and 13 of 41 (32%) patients in the LDR group showed bone exposure and/or ulcer. There were no significant differences between complication rates of the patients treated with HDR and LDR interstitial radiation. For the HDR group, there were three patients with bone exposures of mandible in five with lower gum invasion, and for the LDR group 3 of 6 patients with lower gum invasion showed bone exposure. In these patients, lower gum was included in the treatment volume. It was difficult to avoid bone exposure of the mandible for these patients with gingival invasion. For the patients without lower gum invasion, dwell length of the stepping source was the important factor for bone exposure in the HDR interstitial radiation. Careful follow-up for bone exposure or ulcer in patients treated with dwell length of 20 mm or more is needed. Matsumoto et al (6) reported lower local control rate (55%) in patients with lower gum invasion than that in patients without gum invasion (82%). Our results suggested a high complication rate in patients with lower gum invasion. Tumors with lower gum invasion treated with interstitial radiation have lower local control and higher complication rates. Hicks et al (9) reported high local control rate (87%) of surgical treatment, regardless of T stage, in patients with negative margins. In our hospital, patients with lower gum invasion were mainly treated with surgery, and interstitial radiation is applied for the patients who refused surgical treatment. According to the phase III trial for early tongue carcinoma treated with HDR and LDR interstitial radiation, Table 8. Bone exposure and/or ulcer by tumor size of patients without lower gum invasion Tumor size (mm) HDR
¶ ¶ ¶ .
LDR
¶ 20 ¶ 30 ¶ 40
20 30 40 40
No. patients
Bone exposure and/or ulcer
4 5 1 1 11 20 10 5 35
1 2 0 0 3 (27%) 4 4 2 10 (29%)
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HDR interstitial radiation had almost the same local control rate and the same complication compared with LDR interstitial radiation (4). We found the same result in a retrospective study for carcinoma of the floor of mouth. HDR brachytherapy for carcinoma of the floor of mouth had slightly higher local control (p 5 0.1130) and the same complication compared with LDR brachythe-
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rapy. HDR fractionated interstitial radiation may become an alternative to LDR interstitial radiation for carcinoma of the floor of mouth. However, in this retrospective study, follow-up periods in patients treated with HDR brachytherapy were short compared with the LDR group, and longer follow-up is needed for local control and complication.
REFERENCES 1. Ikeda, H.; Nishiyama, K.; Masaki, N.; Shigematsu, Y.; Inoue, Ta.; Nakamura, M.; Kubo, K.; Fuchihata, H.; Shimizutani, K.; Kawasaki, Y.; Tanaka, Y. Squamous cell carcinoma of the floor of the mouth treated by radiotherapy. Nippon Acta Radiol. 45:877– 893; 1985 (in Japanese). 2. Shimizutani, K.; Koseki, Y.; Inoue, To.; Teshima, T.; Furukawa, S.; Kubo, K.; Fuchihata, H.; Masaki, N.; Ikeda, H.; Tanaka, Y. Application of 198Au grain for carcinoma of oral cavity. Strahlenther. Onkol. 171:29 –34; 1995. 3. Teshima, T.; Inoue, T.; Ikeda, H.; Murayama, S.; Furukawa, S.; Shimizutani K. Phase I/II study of high dose rate interstitial radiotherapy for head and neck cancer. Strahlenther. Onkol. 168:617– 621; 1992. 4. Inoue, Ta.; Inoue, To.; Teshima, T.; Murayama, S.; Shimizutani, K.; Fuchihata, H.; Furukawa, S. Phase III clinical trial of high and low dose rate interstitial radiotherapy for early tongue cancer. Int. J. Radiat. Oncol. Biol. Phys. 36:1201–1204; 1996.
5. LENT SOMA Tables. Radiother. Oncol. 35:17– 60; 1995. 6. Matsumoto, S.; Takeda, M.; Shibuya, H.; Suzuki, S. T1 and T2 Squamous cell carcinoms of the floor of the mouth: Results of brachytherapy mainly using 198Au grains. Int. J. Radiat. Oncol. Biol. Phys. 34:833– 841; 1996. 7. Delclos, L.; Lindberg, R. D.; Fletcher, G. H. Squamous cell carcinoma of the oral tongue and floor of mouth. Am. J. Roentgenol. 126:223–228; 1976. 8. Mazeron, J. J.; Grimard, L.; Raynal, M.; Haddad, E., Piedbois, P.; Martin, M.; Marinello, G.; Nair, R. C.; Le Bourgeois, J. P.; Pierquin, B. Iridium-192 curietherapy for T1 and T2 epidermoid carcinomas of the floor of the mouth. Int. J. Radiat. Oncol. Biol. Phys. 18:1299 –1306; 1990. 9. Hicks, W. L.; Loree, T. R.; Garcia, R. I.; Maamoun, S.; Marshall, D.; Orner, J. B.; Bakamjian, V. Y.; Shedd, D. P. Squamous cell carcinoma of the floor of mouth: A 20-year review. Head Neck 19:400 – 405; 1997.
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Clinical Investigation HIGH DOSE RATE VERSUS LOW DOSE RATE INTERSTITIAL RADIOTHERAPY FOR CARCINOMA OF THE FLOOR OF MOUTH TAKEHIRO INOUE, M.D.,* TOSHIHIKO INOUE, M.D.,* HIDEYA YAMAZAKI, M.D.,* MASAHIKO KOIZUMI, M.D.,* KAZUFUMI KAGAWA, M.D.,* KEN YOSHIDA, M.D.,* HIROYA SHIOMI, M.D.,* ATSUSHI IMAI, M.D.,* KIMISHIGE SHIMIZUTANI, D.D.S.,† EICHII TANAKA, M.D.,† TAKAYUKI NOSE, M.D.,† TERUKI TESHIMA, M.D.,‡ SOUHEI FURUKAWA, D.D.S.,§ AND HAJIME FUCHIHATA, D.D.S.§
*Department of Radiation Oncology, Biomedical Research Center, †Department of Radiology, ‡Department of Medical Engineering, Osaka University Medical School, and §Department of Oral and Maxillofacial Radiology, Osaka University Dental School, Osaka, Japan Purpose: Patients with cancer of the floor of mouth are treated with radiation because of functional and cosmetic reasons. We evaluate the treatment results of high dose rate (HDR) and low dose rate (LDR) interstitial radiation for cancer of the floor of mouth. Methods and Materials: From January 1980 through March 1996, 41 patients with cancer of the floor of mouth were treated with LDR interstitial radiation using 198Au grains, and from April 1992 through March 1996 16 patients with HDR interstitial radiation. There were 26 T1 tumors, 30 T2 tumors, and 1 T3 tumor. For 21 patients treated with interstitial radiation alone, a total radiation dose of interstitial therapy was 60 Gy/10 fractions/6 –7 days in HDR and 85 Gy within 1 week in LDR. For 36 patients treated with a combination therapy, a total dose of 30 to 40 Gy of external radiation and a total dose of 48 Gy/8 fractions/5– 6 days in HDR or 65 Gy within 1 week in LDR were delivered. Results: Two- and 5-year local control rates of patients treated with HDR interstitial radiation were 94% and 94%, and those with LDR were 75% and 69%, respectively. Local control rate of patients treated with HDR brachytherapy was slightly higher than that with 198Au grains (p 5 0.113). For late complication, bone exposure or ulcer occurred in 6 of 16 (38%) patients treated with HDR and 13 of 41 (32%) patients treated with LDR. Conclusion: HDR fractionated interstitial brachytherapy can be an alternative to LDR brachytherapy for cancer of the floor of mouth and eliminate radiation exposure for the medical staff. © 1998 Elsevier Science Inc. Brachytherapy, Carcinoma of the floor of mouth, Dose rate.
INTRODUCTION
brachytherapy can eliminate radiation exposure for the medical staff. According to the randomized trial of comparison for local control rates of tongue carcinoma patients treated with HDR and low dose rate (LDR) interstitial radiation, local control rate and late complication of the HDR group were the same as those of the LDR group (4). In this paper, we evaluate the treatment results of HDR and LDR interstitial radiation for carcinoma of the floor of mouth.
Some patients with cancer of the floor of mouth are treated with radiation because of functional and cosmetic reasons. At the Osaka University Hospital, more than half of patients with cancer of the floor of mouth had been treated with interstitial radiotherapy (1). Before 1980, patients were mainly treated with 192Ir hair pins or Ra needles. For 192Ir hair pins or Ra needles, it is difficult to avoid the radiation for normal tissue of the tongue because of the long active length of these sources. From 1980, 198Au grains were available at our department. For 198Au grains, it is easy to implant under local anesthesia for patients with poor risk or aged patients (2). From July 1991, we carried out high dose rate (HDR) interstitial radiation for head and neck carcinomas (3). HDR
METHODS AND MATERIALS From January 1980 through March 1996, 41 patients with carcinoma of the floor of mouth were treated with LDR brachytherapy using 198Au grains. From 1992 to March 1996, 16 patients were treated with HDR 192Ir microsource.
Reprint requests to: Takehiro Inoue, M.D., Department of Radiation Oncology, Biomedical Research Center, Osaka University Medical School, 2-2 Yamadaoka, Suita, Osaka 565, Japan. Acknowledgment—This study was supported in part by the Grantin-Aid for Cancer Research from the Ministry of Health and
Welfare (7-33, 9-27) and by the Grant-in-Aid for Scientific Research (A) from the Ministry of Education, Science, Sports and Culture (06304032) of the Japanese Government. Accepted for publication 24 November 1997. 53
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Table 1. Characteristics
No. cases Age Sex
Range Median Male Female
T1 T2 T3 N0 N1 N2
LDR
HDR
41 38–83 62 36 5 22 19 0 38 3 0
16 32–80 60 16 0 4 11 1 14 1 1
88% 12% 54% 46% 0% 93% 7% 0%
100% 0% 25% 69% 6% 88% 6% 6%
We compared the treatment results of patients treated with LDR brachytherapy using 198Au grains and HDR brachytherapy using 192Ir microsource. Table 1 shows the age and sex distribution and TN classification of 41 patients treated with LDR brachytherapy and 16 patients with HDR brachytherapy. The median ages of LDR and HDR groups were 62 (range, 38 – 83) and 60 (range, 32– 80) years old. There were 36 male patients and 5 female patients in the LDR group; all patients were male in the HDR group. There are no statistically significant differences in age or sex distributions between the two groups. Of 41 patients of the LDR group, 22 (54%) were classified as T1 and 19 (46%) as T2, and of 16 patients of the HDR group, 4 (25%) were classified as T1, 11 (69%) as T2, and one (6%) as T3 (p 5 0.0569). Thirty-eight patients (93%) were classified as N0 and 3 (7%) as N1 in the LDR group, and 14 (88%) were classified as N0, one (6%) each as N1 and N2 in the HDR group (not significant). The radiation methods for individual patients were decided by more than two doctors in charge who had more than 10 years’ experience of the brachytherapy. Table 2 shows the tumor size and treatment method for carcinoma of the floor of mouth. For the LDR group, 15 patients were treated with interstitial radiation alone, 11 patients with a combination of external radiation and interstitial radiation, and 15 patients with concurrent chemotherapy during external radiation and interstitial radiation. We used 45 mg of
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peplomycin (range, 25– 60 mg) or 60 mg of bleomycin (range, 45–135) as the concurrent chemotherapy. The corresponding figures for the HDR group were 6, 8, and 2 patients for each treatment, respectively. Twenty-one of 43 patients (49%) with a tumor of 30 mm or less were treated with interstitial radiation alone; all 14 patients with a tumor more than 30 mm or with nodal metastasis were treated with a combined treatment of external and interstitial radiation with or without concurrent chemotherapy (p 5 0.003). For the patients treated with interstitial radiation alone, the median dose of the LDR group was 85 Gy (range, 58 –132 Gy) within 1 week. In the HDR group, all patients were treated with a total dose of 60 Gy/10 fractions/7 days (Table 3). For the patients treated with a combination of 30 – 40 Gy of external radiation and interstitial radiation, the median dose of LDR brachytherapy was 65 Gy (range, 42–129 Gy) within 1 week. In the HDR group, all patients were treated with 48 Gy/8 fractions/6 days after the external radiation. The median interval between external radiation and LDR brachytherapy was 28 days (range, 5–76 days), and that for the HDR group was 20 days (1–29 days). Method of HDR interstitial radiotherapy was reported in previous papers (3, 4). Before the insertion of guide tubes for carcinoma of the floor of mouth, an individualized template was made because of the parallel implantation and ideal arrangement of applicators (Fig. 1). The pattern of the implantation of applicators such as triangles or squares was decided according to the size and location of the tumors. Eight patients were treated with double-plane implantation, and eight patients with volume implant. Applicators for the 192 Ir microsource were inserted from the mouth floor to the skin surface of the submental or submandibular region through the above mentioned template. In some patients with tongue invasion, applicators were inserted from the dorsal surface of the tongue to the skin surface. Dwell lengths of the 192Ir microsource were 10 to 35 mm with 2.5-mm steps. HDR interstitial radiation was carried out twice a day using microSelectron-HDR (Nucletron-Oldelft, The Netherlands). Time interval between two treatments was more than 6 hours (3, 4). Reference point of dose calculation of
Table 2. Tumor size and treatment method LDR Tumor size (mm) N0 ¶ 20 ¶ 30 ¶ 40 . 40 N1–2 Total
HDR
Int. alone
Ext. 1 Int.
Ext. 1 Che. 1 Int.
Total
Int. alone
Ext. 1 Int.
Ext. 1 Che. 1 Int.
Total
11 4 0 0
8 2 1 0
3 4 5 0
22 10 6 0
2 4 0 0
0 4 1 1
1 0 1 0
3 8 2 1
0 15
0 11
3 15
3 41
0 6
2 8
0 2
2 16
Int. 5 interstitial radiation; Ext. 5 external radiation; Che. 5 chemotherapy.
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Table 3. Radiation dose Interstitial radiation HDR†
LDR* External radiation
No. patients
Median dose
(Min.–Max.)
No. patients
Dose
0 30–40 Gy
15 26
85 Gy/7 d 65 Gy/7d
(58–132) (42–129)
6 10
60 Gy/10 Fr/7 d 48 Gy/8 Fr/6 d
* Dose delivered within 1 week. 0.83 3 permanent dose of † All patients were treated with 60 Gy or 48 Gy.
198
interstitial radiation was 5 mm from the source. Dose rate at the reference point changed according to the activity of the 192 Ir microsource. Average dose rates (single fraction dose/ overall treatment time in the first fraction) at the reference point ranged from 0.79 to 6.86 Gy/min (median: 2.5 Gy/min). Forty-one patients of the LDR group were followed at least 27 months or until their deaths. The maximum follow-up period was 136 months and the median was 65 months in the LDR group. One patient in the HDR group was lost to follow-up at 11 months after treatment because of the Hanshin Earthquake in January 1995. Fifteen patients of the HDR group were followed at least 19 months or until their deaths. The maximum was 61 months and the median follow-up period was 30 months in the HDR group. Student’s t test and chi-square test were used for the comparison of patients’ characteristics. Local control rates and cause-specific survival rates were calculated with the Kaplan–Meier method. Statistical significance was tested by means of log rank test. RESULTS Of 16 patients treated with HDR interstitial radiation, one died with nodal metastasis without local recurrence 7 months after radiation (Table 4). Two patients died with secondary esophageal or rectal cancer. Another patient died
Au.
with cerebral infarction 19 months after radiation. One patient was lost to follow-up at 11 months after treatment. The remaining nine are alive with no evidence of disease. Only one T3 tumor recurred 6 months after a combination therapy of 32 Gy of external radiation and 48 Gy/8 fractions of HDR interstitial radiation. This patient was treated with surgery for local recurrence, and died with rectal carcinoma 20 months after radiation as mentioned above. All 13 patients with T1 and T2 tumors were locally controlled. Of 41 patients treated with LDR, 12 developed local recurrence. Seven patients died with local tumor and two with nodal metastases. Two patients died with lung cancer, one with esophageal cancer, and one with another oral cancer. Two- and 5-year local control rates of patients treated with HDR interstitial radiation were 94% (Fig. 2). On the other hand, two- and 5-year local control rates of patients treated with 198Au grains were 75% (T1, 81%; T2, 67%) and 69% (T1, 76%; T2, 60%), respectively. This difference was not statistically significant (p 5 0.1130). Two- and 5-year cause-specific survival rates of patients treated with HDR interstitial radiation were 94% (Fig. 3). On the other hand, 2- and 5-year local control rates of patients treated with 198Au grains were 82% (T1, 91%; T2, 72%) and 76% (T1, 85%; T2, 67%), respectively. This difference was not statistically significant (p 5 0.2891). Table 5 shows local control of carcinoma of the floor of mouth according to the tumor size. For the LDR group, 17 of 22 tumors (77%) not more than 20 mm and 10 of 12 (83%) not more than 30 mm were locally controlled, and only 2 of 7 tumors (29%) more than 30 mm were controlled with radiation (p 5 0.0253). For the HDR group, all tumors not more than 40 mm were locally controlled. Table 6 shows local control according to the treatment Table 4. Treatment results LDR
Fig. 1. Individualized template for carcinoma of the floor of mouth.
No. cases Local recurrence Death with primary tumor Death with regional node Death with double cancer Bone exposure and/or ulcer
41 12 7 2 4 13
HDR 29% 17% 5% 10% 32%
16 1 0 1 2 6
6% 0% 6% 13% 38%
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Table 5. Local control by tumor size LDR
HDR
Tumor size (mm)
No. patients
Local control
%
No. patients
Local control
%
¶ 20 ¶ 30 ¶ 40 . 40 Total
22 12 7 — 41
17 10 2 — 29
77 83 29 — 71
4 9 2 1 16
4 9 2 0 15
100 100 100 0 94
¶ 30 versus . 30 in LDR; p 5 0.0253.
Fig. 2. Local control rates of patients treated with HDR brachytherapy using 192Ir microsource and LDR brachytherapy using 198 Au grains.
method and interval between external and interstitial radiation. For the LDR group, 13 of 15 tumors (87%) treated with interstitial radiation alone were locally controlled, and 16 of 26 tumors (62%) treated with a combination of external and interstitial radiation with or without chemotherapy were also locally controlled. Twenty-six tumors treated with a combination of external and interstitial radiation were divided into two groups according to interval between external and interstitial radiation. Twelve of 15 tumors (80%) with interval not more than 28 days were controlled, and only 4 of 11 tumors (36%) with interval more than 28 days were locally controlled (p 5 0.0641). For the HDR group, all 6 tumors treated with interstitial radiation alone were locally controlled, and 9 of 10 patients treated with a combination of external and interstitial radiation were controlled. As for grades 2 and 3 of objective score for late complication according to Late Effects Normal Tissues (LENT) Subjective Objective Management and Analytic (SOMA) Tables (5), bone exposure or ulcer of the mucosa of the floor of mouth occurred in 6 of 16 (38%) patients in the HDR group, and 13 of 41 (32%) patients in the LDR group (Table 7). The median
delay between brachytherapy and complication in the HDR group was 9 months (range, 2–20 months), and that in the LDR group was 17 months (range, 5–38 months). One of 19 patients with complication received surgery for bone exposure, and another 18 patients were treated with non-narcotic medication and/or antibiotics. In the HDR group, 3 of 5 patients with gingival invasion and 3 of 11 without gingival invasion showed late complication. Among 11 patients without gingival invasion, 6 were treated with dwell length of 10 or 15 mm and 5 patients with dwell length of 20 to 35 mm. No late complication occurred in the patients treated with dwell length of 10 or 15 mm. Three of the 5 patients treated with dwell length of 20 to 35 mm developed late complication. In the LDR group, 3 of 6 patients with gingival invasion showed late complication, and 10 of 35 patients without gingival invasion showed late complication. For the LDR group, late complication occurred in 3 of 15 patients (20%) treated with interstitial radiation alone, and in 10 of 26 patients (38%) with a combination therapy of external and interstitial radiation (p 5 0.3815). For the HDR group, late complication occurred in 3 of 6 patients treated with interstitial radiation alone, and in 3 of 10 patients treated with a combination therapy of external and interstitial radiation (p 5 0.7897). Table 8 shows bone exposure and/or soft tissue ulcer by tumor size of patients without lower gum invasion. For the HDR group, bone exposure and/or soft tissue ulcer occurred in 3 of 9 tumors not more than 30 mm. There were only 2 tumors more than 30 mm without gum invasion, and one of them had local recurrence and Table 6. Local control by treatment method and interval between external and interstitial radiation LDR Interval (days)
Fig. 3. Cause-specific survival rates of patients treated with HDR brachytherapy using 192Ir microsource and LDR brachytherapy using 198Au grains.
Interstitial alone Ext. 1 Int. ¶ 28 Ä 29 Total
No. Local patients control
HDR %
No. Local patients control
%
15
13
87
6
6
100
15 11 41
12 4 29
80 36 71
8 2 16
7 2 15
88 100 94
¶ 28 versus Ä 29 in LDR; p 5 0.0641.
HDR brachytherapy for mouth floor cancer
Table 7. Bone exposure and/or ulcer by dwell length Source HDR
LDR
Lower gum invasion 1 2
Dwell length (mm)
No. patients
Bone exposure and/or ulcer
5 6 5 16 6 35 41
3 0 3 6 (38%) 3 10 13 (32%)
¶ 15 Ä 20
Total 1 2 Total
another tumor was controlled without complication. For the LDR group, late complication occurred in 4 of 20 tumors (20%) not more than 20 mm, and in 6 of 15 tumors (40%) more than 20 mm (p 5 0.3586). DISCUSSION Local control rates of carcinoma of the floor of mouth treated with radiation in Osaka University Hospital were reported by Ikeda et al in 1985 (1). In this paper, local control rates of T1, T2, and T3 carcinoma of the mouth floor were reported as 80%, 56%, and 17%, respectively. More than half of the patients were treated with interstitial radiation. Forty patients were treated with Ra needles or 192Ir hair pins and six patients with Rn seeds and 198Au grains. However, from January 1985 through April 1993, 26 patients were treated with 198Au grains and only three patients with Ra needles, 137Cs needles, and 192Ir hair pins. Shimizutani et al reported the results of 45 patients with carcinoma of the oral cavity treated with 198Au grains in Osaka University Hospital (2). Local control rate for patients with T1 and T2 oral cancers including the carcinoma of the floor of mouth were 80% and 59%, respectively. Matsumoto et al (6) reported the local control rates of T1, T2a (¶3 cm), and T2b (.3 cm) lesions treated with 198Au grains as 89%, 76%, and 56%. Our results also showed lower local control rates in tumors more than 3 cm. Shimizutani et al reported a lower local control rate in the patients with longer interval between external and interstitial radiation. For the patients with carcinoma of the floor of mouth, a longer interval resulted in a lower control rate (p 5 0.0641). In recent years, we mainly used 198Au grains for LDR brachytherapy because of small irradiated volume of normal tissue. According to the present study, local control rates of HDR brachytherapy were better than those of 198Au grains. Delclos et al stated that gold grain implants were more subject to cold spots than radium or iridium implants (7). It is difficult to get the homogeneous dose distribution with 198 Au grains because of the technical problem. Another demerit of 198Au grain is the expulsion or dislocation of gold grains during high activity of the radioisotope. This problem also resulted in the dose inhomogeneity. For HDR brachytherapy, it is easy to implant the applicators in ideal arrangement using template. Even for the irregular arrange-
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ments of applicators, we can get the homogeneous dose distribution using dose optimization of a stepping source dosimetry system (4). Mazeron et al (8) reported the local control rates of T1N0 and T2N0 carcinoma of the floor of mouth treated with 192Ir hair pins as 93.5% and 74.5%, respectively. Grades 1, 2, and 3 complications of soft tissue were also reported as 15 of 95 (16%), 8 of 95 (8%), and 8 of 95 (8%), respectively. Ikeda et al (1) reported that 22 of 46 (48%) patients showed bone exposure, and these complications occurred in the patients treated with Ra needles or 192Ir hair pins. Shimizutani et al (2) reported that bone exposure occurred in 8 of 26 (31%) patients treated with 198Au grains. According to the present data, 6 of 16 (38%) patients in the HDR group and 13 of 41 (32%) patients in the LDR group showed bone exposure and/or ulcer. There were no significant differences between complication rates of the patients treated with HDR and LDR interstitial radiation. For the HDR group, there were three patients with bone exposures of mandible in five with lower gum invasion, and for the LDR group 3 of 6 patients with lower gum invasion showed bone exposure. In these patients, lower gum was included in the treatment volume. It was difficult to avoid bone exposure of the mandible for these patients with gingival invasion. For the patients without lower gum invasion, dwell length of the stepping source was the important factor for bone exposure in the HDR interstitial radiation. Careful follow-up for bone exposure or ulcer in patients treated with dwell length of 20 mm or more is needed. Matsumoto et al (6) reported lower local control rate (55%) in patients with lower gum invasion than that in patients without gum invasion (82%). Our results suggested a high complication rate in patients with lower gum invasion. Tumors with lower gum invasion treated with interstitial radiation have lower local control and higher complication rates. Hicks et al (9) reported high local control rate (87%) of surgical treatment, regardless of T stage, in patients with negative margins. In our hospital, patients with lower gum invasion were mainly treated with surgery, and interstitial radiation is applied for the patients who refused surgical treatment. According to the phase III trial for early tongue carcinoma treated with HDR and LDR interstitial radiation, Table 8. Bone exposure and/or ulcer by tumor size of patients without lower gum invasion Tumor size (mm) HDR
¶ ¶ ¶ .
LDR
¶ 20 ¶ 30 ¶ 40
20 30 40 40
No. patients
Bone exposure and/or ulcer
4 5 1 1 11 20 10 5 35
1 2 0 0 3 (27%) 4 4 2 10 (29%)
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HDR interstitial radiation had almost the same local control rate and the same complication compared with LDR interstitial radiation (4). We found the same result in a retrospective study for carcinoma of the floor of mouth. HDR brachytherapy for carcinoma of the floor of mouth had slightly higher local control (p 5 0.1130) and the same complication compared with LDR brachythe-
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rapy. HDR fractionated interstitial radiation may become an alternative to LDR interstitial radiation for carcinoma of the floor of mouth. However, in this retrospective study, follow-up periods in patients treated with HDR brachytherapy were short compared with the LDR group, and longer follow-up is needed for local control and complication.
REFERENCES 1. Ikeda, H.; Nishiyama, K.; Masaki, N.; Shigematsu, Y.; Inoue, Ta.; Nakamura, M.; Kubo, K.; Fuchihata, H.; Shimizutani, K.; Kawasaki, Y.; Tanaka, Y. Squamous cell carcinoma of the floor of the mouth treated by radiotherapy. Nippon Acta Radiol. 45:877– 893; 1985 (in Japanese). 2. Shimizutani, K.; Koseki, Y.; Inoue, To.; Teshima, T.; Furukawa, S.; Kubo, K.; Fuchihata, H.; Masaki, N.; Ikeda, H.; Tanaka, Y. Application of 198Au grain for carcinoma of oral cavity. Strahlenther. Onkol. 171:29 –34; 1995. 3. Teshima, T.; Inoue, T.; Ikeda, H.; Murayama, S.; Furukawa, S.; Shimizutani K. Phase I/II study of high dose rate interstitial radiotherapy for head and neck cancer. Strahlenther. Onkol. 168:617– 621; 1992. 4. Inoue, Ta.; Inoue, To.; Teshima, T.; Murayama, S.; Shimizutani, K.; Fuchihata, H.; Furukawa, S. Phase III clinical trial of high and low dose rate interstitial radiotherapy for early tongue cancer. Int. J. Radiat. Oncol. Biol. Phys. 36:1201–1204; 1996.
5. LENT SOMA Tables. Radiother. Oncol. 35:17– 60; 1995. 6. Matsumoto, S.; Takeda, M.; Shibuya, H.; Suzuki, S. T1 and T2 Squamous cell carcinoms of the floor of the mouth: Results of brachytherapy mainly using 198Au grains. Int. J. Radiat. Oncol. Biol. Phys. 34:833– 841; 1996. 7. Delclos, L.; Lindberg, R. D.; Fletcher, G. H. Squamous cell carcinoma of the oral tongue and floor of mouth. Am. J. Roentgenol. 126:223–228; 1976. 8. Mazeron, J. J.; Grimard, L.; Raynal, M.; Haddad, E., Piedbois, P.; Martin, M.; Marinello, G.; Nair, R. C.; Le Bourgeois, J. P.; Pierquin, B. Iridium-192 curietherapy for T1 and T2 epidermoid carcinomas of the floor of the mouth. Int. J. Radiat. Oncol. Biol. Phys. 18:1299 –1306; 1990. 9. Hicks, W. L.; Loree, T. R.; Garcia, R. I.; Maamoun, S.; Marshall, D.; Orner, J. B.; Bakamjian, V. Y.; Shedd, D. P. Squamous cell carcinoma of the floor of mouth: A 20-year review. Head Neck 19:400 – 405; 1997.