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Lymph node metastasis of early oral tongue cancer after interstitial radiotherapy
Int. J. Radiation Oncology Biol. Phys., Vol. 58, No. 1, pp. 139 –146, 2004 Copyright © 2004 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/04/$–see front matter
doi:10.1016/S0360-3016(03)01459-7
CLINICAL INVESTIGATION
Head and Neck
LYMPH NODE METASTASIS OF EARLY ORAL TONGUE CANCER AFTER INTERSTITIAL RADIOTHERAPY † HIDEYA YAMAZAKI, M.D.,* TAKEHIRO INOUE, M.D,† KEN YOSHIDA, M.D.,† EIICHI TANAKA, M.D.,‡ YASUO YOSHIOKA, M.D.,† HIRONOBU NAKAMURA, M.D.,‡ SOUHEI FURUKAWA, D.D.S.,§ KIMISHIGE SHIMIZUTANI, D.D.S.,† NAOYA KAKIMOTO, D.D.S.,§ AND TOSHIHIKO INOUE, M.D.† Department of *Radiology, Toyonaka Municipal Hospital, Toyonaka City, Osaka, Japan; Departments of †Radiation Oncology, Osaka University Graduate School of Medicine and ‡Radiology, Osaka University Graduate School of Medicine, Osaka, Japan; § Department of Maxillo-Facial Radiology, Osaka University Graduate School of Dentistry, Suita, Osaka, Japan Purpose: To examine the prognostic factors for lymph node metastasis after brachytherapy for early (T1T2N0M0) oral tongue cancer. Methods and Materials: We reviewed the records of 571 patients (500 low dose rate and 71 high dose rate) treated at Osaka University Hospital between 1967 and 1999. Results: Patients with lymph node metastasis had tumor with an average diameter of 26 ⴞ 8 mm and a thickness of 9 ⴞ 5 mm; for patients without lymph node metastasis, the corresponding dimensions were 23 ⴞ 8 mm and 7.5 ⴞ 4 mm (p ⴝ 0.0004 and 0.001, respectively). After 5 years, the ulcerative (48%) and indurative/infiltrative (39%) types showed a higher ratio of nodal involvement than the exophytic (31%) and superficial (19%) types (p <0.0001). Multivariate analysis showed ulceration (p ⴝ 0.006) and a thickness of <6 mm (p ⴝ 0.04) to be statistically significant predisposing factors for lymph node metastasis. The lymph node control rate was 68% in 1967–1979, 71% in 1980 –1990, and 66% in 1990 –1999; the corresponding successful salvage rates for lymph node metastasis were 43%, 33%, and 58% (p ⴝ 0.04). Conclusion: The appearance of the tumor, especially the presence or absence of ulceration and the diameter and thickness, are useful prognostic indicators for lymph node metastasis. Although the rates of lymph node metastasis did not change, the salvage outcome for recurrence after interstitial radiotherapy has recently improved. © 2004 Elsevier Inc. Early tongue cancer, Brachytherapy, Lymph node metastasis.
INTRODUCTION
increase in lymph node metastasis, especially in the case of submental or submandibular lesions (6). We also examined the incidence of lymph node metastasis and assessed the outcome of salvage treatment in relation to the year of treatment to gain a better idea of the effect of modern diagnostic modalities (CT, ultrasonography, and MRI) and surgical advances. Because a more precise diagnosis can reduce false-negative findings of lymph node metastasis, a lower rate of lymph node metastasis after treatment and a better outcome for salvage surgery may result.
Although oral tongue carcinoma is a highly curable cancer when treated by radiotherapy (RT), especially interstitial brachytherapy (1– 4), lymph node metastasis occurs in 30 – 50% of cases even in patients with early-stage disease. Several prognostic factors for lymph node metastasis have been reported, including tumor thickness. However, an exact assessment of tumor thickness can only be achieved by postoperative pathologic examination. Because few reports have analyzed the prognostic factors for lymph node metastasis after interstitial RT, we examined the importance of thickness as detected by palpation. In addition, we examined the changes in the incidence of lymph node metastasis after treatment with conventional low-dose-rate (LDR) and the newly introduced high-dose-rate (HDR) brachytherapy. Because HDR brachytherapy uses catheter insertion mainly by the submental route and LDR brachytherapy from the oral side (5), some concern has been voiced about an
Between 1967 and 1999, 571 patients (369 males and 202 females) with previously untreated early mobile tongue cancer (T1-T2N0) were treated with RT at Osaka University Hospital. Patients treated with combined chemotherapy and 198 Au grain were excluded from the study. All tumors were histologically identified as squamous cell carcinoma. The
Reprint requests to: Hideya Yamazaki, M.D., Department of Radiation Oncology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871 Japan. Tel: ⫹81 6 6879 3482; Fax: ⫹81 6 6879 3489; E-mail: [email protected]
Supported by a grant from the Ministry of Health and Welfare of Japan. Received Nov 25, 2002, and in revised form Jun 30, 2003. Accepted for publication Jul 1, 2003.
METHODS AND MATERIALS
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Table 1. Patient and treatment characteristics Lymph node metastasis Characteristic Total (n) Gender (n) Male Female Stage T1 T2 T1N0M0 Br. Br. ⫹ EBRT T2N0M0 Br. Br. ⫹ EBRT Age (y) Largest diameter (mm) (n ⫽ 534) Thickness (mm) (n ⫽ 482) Treatment source 192 Ir 22 Ra 60 Co 137 Cs MicroSelectron–HDR Tumor type (n ⫽ 504) Superficial Exophytic Indurative Ulcerative
Yes
No
p
181 (32)
390 (68)
115 (31) 66 (33)
254 (69) 136 (67)
NS
54 (25) 127 (36)
160 (75) 230 (64)
0.01
50 (26) 4 (20)
144 (74) 16 (80)
NS
78 (38) 49 (32) 181 55 ⫾ 14
128 (62) 102 (68)
NS
55 ⫾ 13
NS
26 ⫾ 8
23 ⫾ 8
0.0004
9⫾5
7⫾4
0.001
98 (31) 62 (34) 0 1 20 (28)
218 (69) 121* (66) 2† 0 51 (72)
NS
31 (21) 29 (33) 48 (38) 57 (47)
118 (79) 62 (67) 93 (62) 66 (53)
0.0001
Abbreviations: Br ⫽ brachytherapy; EBRT ⫽ external beam radiotherapy; NS ⫽ not significant; HDR ⫽ high dose rate. Numbers in parentheses are percentages. Number of patients not always 571 because of missing data. * One patient was implanted with 226Ra and 192Ir. † One patient was implanted with 226Ra and 60Co.
median patient age was 56 years (range 20 – 86; HDR group 55 ⫾ 14, LDR group 56 ⫾ 13, not statistically significant). The LDR group (1967–1996) comprised 311 male and 189 female patients. The HDR group (1991–1999) comprised 58 male and 13 female patients (p ⫽ 0.001). In the LDR group, 191 patients had T1 tumors and 310 had T2 tumors. In the HDR group, 23 patients had T1 tumors and 48 had T2 tumors (International Union Against Cancer TNM classification of 1987). Table 1 shows the patient characteristics by positive and negative lymph node status. All implantations were done under local anesthesia. A total of 171 patients (20 with T1, 151 with T2; HDR in 13, LDR in 158) underwent external beam RT (EBRT) using a 60Co teletherapy unit or linear accelerator. When the tumor was too large for implantation, the tumor appearance was the ulcerative/indurative type rather than the exophytic type with a larger tumor volume, or the tumor showed rapid progression, EBRT was administered first. In addition, when it took too long before implantation could be performed, we administered EBRT to
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prevent tumor progression. The patients received 2–3 Gy/ fraction for a median dose of 30 Gy (range 15–50) and were treated with a single lateral field that involved the primary site and the upper jugular lymph nodes. All 171 patients treated with EBRT also underwent interstitial needle implantation. For patients in the LDR group, the treatment sources consisted of an 192Ir hairpin for 317 patients, a 226 Ra needle for 181 patients, and 60Co and 137Cs for 1 patient each. 226Ra or 60Co was combined with 192Ir for 1 patient each. The needles were implanted with the PatersonParker system using a reference point 5 mm distant from the implant plane. The median dose for the LDR group treated with brachytherapy only was 70 Gy (range 61– 84) and with brachytherapy combined with EBRT was 70 Gy (range 50 –98). Patients in the HDR group received a total dose of 60 Gy in 10 fractions (range 42– 60, 6 Gy/fraction) for 1 week administered at a distant of 5 mm from the radioactive source. Two fractions were administered daily, and the interval between fractions was ⬎6 hours. Thirteen patients in the HDR group received an EBRT dose of 30 – 40 Gy (median 38) before implantation. The dose rates at the reference point for the LDR group ranged from 0.30 to 0.8 Gy/h, and for the HDR group from 1.0 to 3.4 Gy/min. Patients were followed for at least 13 months or until death, with a median follow-up time for the LDR group of 13 years (range 2–25) and for the HDR group of 3.8 years (range 1.1– 8). In principle, follow-up by physical examination was performed at at least 1-month intervals for the first 2 years and at 3– 6-month intervals thereafter. Examinations with imaging procedures such as CT, MRI, and/or ultrasonography were performed after 3, 6, 12, 18, and 24 months and at 1-year intervals thereafter or when local or lymph node recurrence was suspected. Chest radiographs were obtained once a year or when locoregional failure was suspected. To determine the rates of lymph node metastasis in terms of the year of treatment, we divided the patients into three groups: the early period until 1979 (n ⫽ 283), the first decade when modern modalities were used, 1980 –1990 (n ⫽ 168), and the next decade 1991–1999 (n ⫽ 120). Of the 181 patients with lymph node metastasis, the rN stage could be assessed in 158 and the distribution of lymph node metastasis in 154 patients. The tumor appearance was classified according to previously reported criteria (7): 91 were exophytic, 141 indurative/infiltrative, 149 superficial, and 123 were ulcerative. Tumors were classified as ulcerative if the initial physician had identified them as either indurative/infiltrative or ulcerative. We decided patients were lymph node positive when this was proved by pathologic examination or the lymph node continued to grow until the patient’s death. Nodal failure was not scored if the swollen node was diagnosed as negative by pathologic examination after surgical intervention. All 79 successfully salvaged patients and 82 patients classified as having failure underwent surgery. The 20 patients who were not surgically treated eventually died of the tumor, regardless of their treatment, because of progressive lymph node metastasis. These cases were, of course, not pathologically examined except by cytology. In
LN metastasis of tongue cancer after brachytherapy
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these cases, the location, number, and size of the lymph node metastases were assessed from data obtained from physical charts and imaging examinations. For statistical analysis, Student’s t test for normally distributed data and the Mann-Whitney U test for skewed data were used. Multiple data sets were analyzed by analysis of variance. The percentage was analyzed using the chi-square test. Local control, lymph node control, and survival data were estimated according to the Kaplan-Meier method and were examined for significance with a log–rank test. The Cox proportional hazard model was used for multivariate analysis. All analyses used the conventional p ⬍0.05 level of significance.
RESULTS Regional control Regional lymph node metastasis was seen in 181 patients (32%; Table 1). The regional control rate 1, 2, 3, and 5 years after treatment was 76%, 71%, 70%, and 68%, respectively. Therefore, most regional failures appeared during the first 2 years after treatment. Patients with Stage T2 had a 35% incidence of lymph node metastasis, and those with T1 had a 25% rate (p ⫽ 0.01). A comparison of the LDR and HDR groups showed that 158 patients (32%) in the LDR group received combined EBRT, but only 13 patients (18%) in the HDR group did so (p ⫽ 0.03). No statistically significant difference was noted in the incidence of lymph node metastasis between the LDR (161 of 500; 32%) and HDR (20 of 71; 28%) groups. Predisposing factors for lymph node metastasis were analyzed and are shown in Table 1. T stage (p ⫽ 0.01), longest diameter (p ⫽ 0.0004), thickness (p ⫽ 0.001), and tumor type (p ⫽ 0.0001) were identified as predisposing factors for lymph node metastasis. Patients with lymph node metastasis had a tumor diameter of 26 mm and thickness of 9 mm; the corresponding dimensions were 23 mm and 7 mm for patients without metastasis. We found that a smaller diameter correlated with a lower incidence of lymph node metastasis (p ⫽ 0.002; Fig. 1a). Patients with a tumor diameter of ⱕ10 mm, ⱕ20 mm, ⱕ30 mm, and ⬎30 mm had a 5-year lymph node control rate of 95%, 75%, 63%, and 59%, respectively. Only 1 patient with lymph node metastasis had a tumor with a diameter of ⱕ10 mm (1 of 19; 5%). Tumor diameter showed a strong correlation with thickness (correlation coefficient ⫽ 0.51, p ⬍0.0001). Lymph node metastasis was found in 26% (56 of 216) of tumors ⱕ5 mm in thickness and 39% (103 of 216) of tumors ⱖ6 mm in thickness (p ⫽ 0.001). Patients with a tumor thickness of ⱕ5 mm, ⱕ10 mm, and ⬎10 mm had a 5-year lymph node control rate of 74%, 62%, and 57%, respectively (Fig. 1b, p⫽ 0.002). Therefore, a smaller thickness and/or diameter were accompanied by a lower rate of lymph node metastasis. The tumor type also influenced nodal control (Fig. 1c). The ulcerative (48%) and indurative/infiltrative (39%) types had a higher rate of nodal involvement than did the exophytic (31%) and superficial (19%) types (p ⬍0.0001) at 5 years. The tumor type correlated strongly with the diameter (T stage) and thickness of the tumor (Table 2).
Fig. 1. Incidence of lymph node metastasis by (a) largest tumor diameter; (b) tumor thickness; and (c) tumor type. Dashed line indicates superficial; thick black line, exophytic; dotted line, indurative/infiltrative; and thin black line, ulcerative tumor type.
Multivariate analysis Multivariate analysis was performed to identify factors predicting for lymph node metastasis. Table 3 shows the results. Ulceration (tumor type) proved to be a determinant of lymph node metastasis. Compared with other tumor types
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Table 2. Characteristics by tumor type Characteristic
Superficial
Exophytic
Indurative/infiltrative
Ulcerative
Total (n) Gender (n) Male Female Stage T1 T2 T1N0M0 Br. Br. ⫹ EBRT T2N0M0 Br. Br. ⫹ EBRT Treatment source LDR MicroSelectron–HDR Irradiated dose (Gy) EBRT Br. Age (y) Largest diameter (mm) (n ⫽ 534) Thickness (mm) (n ⫽ 482)
149
91
141
123
96 (29) 53 (30)
54 (16) 37 (21)
96 (29) 45 (26)
84 (25) 39 (22)
NS
92 (50) 57 (18)
30 (16) 61 (19)
34 (18) 107 (34)
29 (16) 94 (29)
⬍0.001
86 (51) 6 (33)
24 (14) 6 (33)
28 (17) 6 (33)
29 (17) 0 (0)
0.01
39 (21) 18 (13)
33 (18) 28 (21)
63 (34) 44 (33)
49 (27) 45 (33)
NS
128 (29) 21 (37)
90 (20) 1 (2)
122 (27) 19 (33)
107 (24) 16 (28)
NS
27 ⫾ 6 68 ⫾ 7 55 ⫾ 13 20 ⫾ 8 5⫾2
28 ⫾ 6 70 ⫾ 5 57 ⫾ 13 24 ⫾ 7 9⫾5
30 ⫾ 5 68 ⫾ 7 55 ⫾ 14 25 ⫾ 7 9⫾4
p
29 ⫾ 4 68 ⫾ 8 52 ⫾ 15 28 ⫾ 8 10 ⫾ 5
NS NS* NS (p ⫽ 0.07) ⬍0.0001 ⬍0.0001
Abbreviations: LDR ⫽ low dose rate; other abbreviations as in Table 1. Numbers in parentheses are percentages. * p ⫽ 0.02, superficial vs. exophytic type.
without ulceration, the existence of an ulcer was associated with a relative ratio of 1.64 (p ⫽ 0.006), and a tumor thickness of ⱕ5 mm was associated with a lower metastatic rate, with a relative ratio of 1.48 (p ⫽ 0.04). Patients with Stage T2 tumor or one with a larger diameter appeared to have a greater rate of lymph node metastasis, with a relative risk of 1.48 (p ⫽ 0.06, not significant). Distribution and number of involved lymph node areas The number of involved lymph node areas after EBRT and brachytherapy or brachytherapy alone is shown in Table 4. The ipsilateral upper jugular (47%, n ⫽ 105), submandibular (24%, n ⫽ 54), and middle jugular (14%, n ⫽ 32) nodes were the major sites for metastasis of oral tongue cancer after brachytherapy, accounting for 85% of all such metastases. For patients treated with a different protocol,
upper jugular lymph node involvement was seen in 45% of the LDR group and in 56% of the HDR group. The submaxillary nodes accounted for 24% of the metastases of the LDR group and 16% of the HDR group; the corresponding rates for the submental nodes were 8% and 0%. The assessment of the patients treated solely with brachytherapy revealed similar results. Therefore, there appeared to be no increase as a result of seeding in the submental or submandibular approach using HDR brachytherapy. Lymph node metastasis and salvage Table 5 shows the salvage outcomes for lymph node metastasis by T stage and rN stage after EBRT and brachytherapy or brachytherapy alone. One-half of the lymph node metastases that were Stage rN2b or less could be salvaged if locally controlled. Between 1967 and 1979, the regional
Table 3. Results of multivariate Cox hazard model Variable
Strata
Odds ratio
95% Confidence interval
p
Gender Age (y) Time of treatment T stage (diameter) Tumor type Treatment Dose rate Thickness (mm)
Male vs. female ⱕ59 vs. ⱖ60 ⱕ1979 vs. ⱖ1980 T1 vs. T2 Ulcer (yes vs. no) EBRT ⫹ Br. vs. Br. HDR vs. LDR ⱕ5 vs. ⱖ6
0.99 1.07 0.97 1.48 1.64 1.34 1.28 1.48
0.70–1.40 0.78–1.49 0.68–1.39 0.98–2.24 1.16–2.33 0.92–1.95 0.70–2.33 1.01–2.19
0.94 0.66 0.89 0.06 0.006 0.13 0.43 0.04
Abbreviations as in Tables 1 and 2.
LN metastasis of tongue cancer after brachytherapy
Table 4. Distribution and number of involved lymph node areas Ipsilateral lymph node (n) LDR group EBRT ⫹ Br. or Br. alone Retroauricular Submental Submandibular Upper jugular Middle jugular Lower jugular Supraclavicle Br. only Retroauricular Submental Submandibular Upper jugular Middle jugular Lower jugular Supraclavicle
2 (1) 15 (8) 50 (24) 89 (45) 27 (14) 13 (7) 2 (1) 2 (1) 13 (10) 32 (24) 61 (45) 19 (14) 9 (7) 0 (0)
HDR group
4 (16) 14 (56) 5 (20) 2 (8)
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Table 5. Salvage outcome of lymph node metastasis according to T and rN stage
Contralateral lymph node (n) LDR group
2 (22) 2 (22) 2 (22) 2 (22) 1 (12)
HDR group
Ultimate control T stage
Local failure
EBRT ⫹ Br. or Br. alone T1
No
1 (100) Yes
T2 2 (9) 13 (59) 5 (23) 2 (9)
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2 (50) 1 (25) 1 (25)
No
1 (50) 1 (50) Yes
Abbreviations as in Tables 1 and 2. Numbers in parentheses are percentages.
control rate for early tongue cancer was 68% 5 years after treatment; the corresponding rate for lymph node control was 71% in 1980 –1990 and 66% in 1991–1999 (Table 6). The failure patterns and salvage success rates are shown in Table 6. The lymph node control rate was 68% in 1967–1979, 71% in 1980 –1990, and 66% in 1990 –1999; the corresponding rates for lymph node metastasis were 43% (38 of 89), 33% (16 of 49), and 58% (25of 43; p ⫽ 0.04). In the case of lymph node metastasis alone, the ultimate control rate was 48% (28 of 59) in 1967–1979, 43% (10 of 23) in 1980 –1989, and 88% (22 of 30) in 1990 –1999 (p ⫽ 0.001). When local and/or nodal failure was detected, surgical intervention was used first, with or without adjuvant chemotherapy and/or RT. If the patient’s condition did not allow for surgery, or if the patient refused to undergo surgery, RT and/or chemotherapy were used. Six patients declined any additional treatment even though lymph node metastasis was noted. The salvage success rates for local recurrence also improved with time. In 1990 – 1999, 75% of patients were salvaged compared with 43% in 1967–1980 and 63% in 1980 –1989 (p ⫽ 0.11, not significant). However, the salvage rate for patients with both lymph node and local failure or advanced lymph node metastasis (rN2c or rN3) did not improve during these periods. The cause-specific survival rates showed minor improvement from 74% in 1967–1979 to 84% in 1990 –1999 (p ⫽ 0.14, not significant). The patient record included 9 cases of rN2c. Four cases had failure in both local control and lymph nodes, and all cases had concurrent bilateral lymph node metastasis. One primary tongue cancer with rN2c lymph node metastasis
Br. only T1
No
Yes
T2
No
Yes
rN stage
Yes
No
%
N1 N2a N2b N2c Unknown N1 N2a N2b Unknown N1 N2a N2b N2c N3 Unknown N1 N2a N2b N2c N3 Unknown
9 1 6
9 1 7 1 4 2 3 2 12 3 13 3 2 1 13 6 11 2 1 6
50 50 46 0 100 43 0 0 50 54 57 52 25 0 88 38 25 8 50 0 14
9 1 6 1
47 50 50 0
4 1 2 2 7 3 8 1 1 1 6 3 6 1 1 6
43 0 0 50 56 40 60 50 0 75 40 40 14 50 0 0
N1 N2a N2b N2c Unknown N1 N2a N2b Unknown N1 N2a N2b N2c N3 Unknown N1 N2a N2b N2c N3 Unknown
4 3 2 14 4 14 1 7 8 2 1 2 1 8 1 6 4 3 2 9 2 12 1 3 4 2 1 1
Abbreviations as in Table 1.
was located on the ventral surface, but the other primary tumors were located in the lateral border. Although eight of these patients underwent salvage surgery with or without postoperative RT and chemotherapy, only three could be salvaged. DISCUSSION Oral tongue cancer located anterior to the circumvallate papillae has a vital impact, not only on speech, but also on
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Table 6. Local and regional control, and cause-specific survival rates and successful salvage rates for lymph node metastasis and/or local recurrence according to time of treatment
Local control rate (%) Lymph node control rate (%) Cause-specific survival rate (%) Lymph node metastasis alone Local recurrence alone Both N stage of patient with lymph node metastasis alone N1 N2a N2b N2c N3
1967–1979
1980–1989
1990–1999
p
78 68 74 28/59 (48) 15/35 (43) 10/30 (34)
75 71 75 10/23 (43) 10/16 (63) 6/26 (23)
82 66 84 22/30 (88) 9/12 (75) 3/13 (23)
NS NS NS (p ⫽ 0.14) 0.001 NS (p ⫽ 0.11) NS
11/26 (42) 4/7 (57) 8/19 (42) 0/1 (0) 0/1 (0)
3/6 (50) 0/1 (0) 4/10 (40) 1/3 (33) 0/1 (0)
9/12 (75) 1/1 (100) 8/11 (73) 0/1 (0) —
NS NS NS NS NS
Abbreviation: NS ⫽ not significant. Data presented as number of patients salvaged/total with lymph node metastasis, with the percentage in parentheses, unless noted otherwise. Number of patients not always 571 because of missing data.
the coordination of chewing and swallowing. RT, considered to be a minimally invasive treatment procedure, has the advantage of preserving the shape and functions of the tongue. To limit unwanted RT, the method of LDR brachytherapy was changed from 226Ra to 192Ir. This so-called LDR brachytherapy has come into wide use and become the gold standard in brachytherapy (1– 4). We initiated HDR brachytherapy using a remote afterloading technique that eliminated radiation exposure except to the patient (5, 8). A 5-year local control rate of 81% was obtained with this type of brachytherapy, equal to that obtained with LDR brachytherapy. Several other authors have recently reported similar results (9, 10). The incidence of regional metastasis of N0 early tongue cancer is reported to be about 20 –50%, and ⬎90% of such cases occur within 18 –24 months after treatment. Lymph node metastasis normally already exists outside the local lesion when brachytherapy is performed so that several reports have cited the usefulness of elective neck dissection or RT (11, 12). At our institute, also, EBRT (30 Gy in 10 fractions within 2 weeks) was added before implantation to reduce lymph node metastasis; however, no therapeutic benefits were obtained. On the contrary, the rate of complications increased (13). Although several studies have reported on the reduction of lymph node metastasis after prophylactic RT or elective neck dissection, few survival benefits were obtained. Beenken et al. (16) reported that prospective randomized clinical trials failed to demonstrate survival benefits for patients undergoing elective treatment, because the log–rank test required at least 290 patients to detect a 5% survival difference (with p ⬍0.05 and a power of 0.82), a larger number than ever enrolled in a trial held at a single institution. Therefore, it is believed that prophylactic neck treatment should be limited to patients who are unavailable for regular follow-up or to patients with a higher risk of cervical lymph node metastasis. Thus, we
adopted a wait-and-see policy, performing neither prophylactic neck RT nor prophylactic surgical excision. A multiinstitutional prospective trial for prophylactic treatment is anticipated for high-risk patients who present with a relatively large ulcerative tumor with a thickness of ⬎5 mm or with a poorly differentiated tumor. We found no difference in the distribution of lymph node metastasis between the HDR and LDR groups. Although caution should be taken with regard to tumor seeding by insertion (6), seeding to submental/submandibular lesions does not appear to be a clinical problem in HDR brachytherapy. The first-echelon nodes are subdigastric (45% in LDR and 56% in HDR) and submandibular (24% in LDR and 16% in HDR), which concurs with the previously reported results of Lindberg (17) for patients with oral tongue cancer on admission, with an incidence of metastasis of 60% for subdigastric and 23% for submandibular nodes. This means that little effect can be expected from brachytherapy, with or without EBRT, on lymph node metastasis distribution. Byer et al. (18) also reported metastasis rates of 73% and 18% for these lymph nodes after elective neck dissection in 48 patients with carcinoma of the oral tongue and a clinically negative neck. Mid-jugular involvement was seen in 14% of the patients in the LDR group and 20% of those in the HDR group, similar to the rates reported by Lindberg (11%) and Byer et al. (18%) for mid-jugular lesions. Modern imaging modalities, such as ultrasonography, CT, and MRI are now being used to evaluate local and lymph node status, resulting in the detection of smaller lymph nodes than would normally be found by physical examination alone. However, contrary to our expectations, the rate of lymph node metastasis did not decline in the past decade despite modern imaging analysis. We used a nodal size ⬎10 mm in the short-axis diameter or the presence of central lucency as the criteria for nodal metastasis. Shingai
LN metastasis of tongue cancer after brachytherapy
et al. (19), using the same criteria, reported that CT provided an accuracy of ⬎90%, a sensitivity of nearly 90%, and a specificity of 100%. However, a large number of malignant nodes with a diameter of ⬍10 mm were identified, and extranodal spread was also found to have occurred in a substantial percentage of these smaller nodes. Because the present radiologic criteria for assessing cervical lymph node status are based largely on size, these findings indicate major limitations in the current capability of detecting metastatic disease (20). Furthermore, because our data are limited as a result of their retrospective nature, additional investigations are needed to establish concrete results regarding the applicability of modern imaging procedures. We found that the salvage rates have recently increased. One reason for this may be new developments in surgery, such as reconstruction techniques, but additional analysis was not possible because of the variety of techniques used in salvage surgery held in many hospitals. In contrast, the salvage rates for both local and lymph node failure did not improve. Stage rN2c (bilateral or contralateral) and rN3 (ⱖ6 cm) tumors are also difficult to treat successfully. Therefore, metastasis should be detected as soon as possible and followed closely. Piedbois et al. (21) reported a successful salvage rate of 62% (13 of 21) after therapeutic neck dissection and 47% (9 of 19) after elective treatment, and Lydiatt et al. (22) reported corresponding rates of 41% and 40%. Although it is difficult to compare our data with their salvage rates, because their salvage results were not always divided according to local control and rN stage, our 88% salvage rate obtained in the 1990s for patients with lymph node metastasis only is no less than that reported in other centers. One concern is the short follow-up time for patients
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treated between 1990 and 1999. Longer follow-up periods are needed because late recurrence, not only locally, but also as lymph node lesions, may occur even after 2 years without evidence of disease, including recurrence after salvage treatment. Multivariate analysis indicated that ulceration and thickness followed by T stage are significant indicators of lymph node metastasis (p ⫽ 0.06). This is natural because ulceration may indicate deeper invasion and correlated with tumor thickness, which has already been confirmed by pathologic studies as an important predisposing factor for lymph node metastasis (23, 24). Although the problems in determining the exact thickness of a tumor by palpation only are several, we can safely assume that thin tumors with a thickness of ⬍5 mm have a lower incidence of lymph node metastasis. In addition, cases with smaller tumors ⱕ10 mm in diameter (1 of 19; 5%), had only one lymph node metastasis, and ulceration increased the risk of such metastasis, an indicator that closely correlated with the tumor thickness. Therefore, not only thickness, but also the diameter and type of tumor, especially if ulcerative, may be helpful information for predicting lymph node metastasis of T1-T2 tumors. CONCLUSION The appearance of the tumor, especially the presence or absence of ulceration and diameter and thickness, are useful prognostic indicators for lymph node metastasis. Although the rates of lymph node metastasis did not change, the salvage outcome for recurrence after interstitial RT has recently improved.
REFERENCES 1. Pernot M, Malissard L, Hoffstetter S, et al. The study of tumoral, radiobiological, and general health factors that influence results and complications in a series of 448 oral tongue carcinomas treated exclusively by irradiation. Int J Radiat Oncol Biol Phys 1994;29:673–679. 2. Mazeron JJ, Crook JM, Benck V, et al. Iridium 192 implantation of T1 and T2 carcinomas of the mobile tongue. Int J Radiat Oncol Biol Phys 1990;19:1369–1376. 3. Fein DA, Mendenhall WM, Parsons JT, et al. Carcinoma of the oral tongue: A comparison of results and complications of treatment with radiotherapy and/or surgery. Head Neck 1994; 16:358–365. 4. Shibuya H, Hoshina BM, Takeda M, et al. Brachytherapy for stage I and II oral tongue cancer: An analysis of past cases focusing on local control and complications. Int J Radiat Oncol Biol Phys 1993;26:51–58. 5. Inoue TA, Inoue TO, Teshima T, et al. Phase III trial of high and low dose rate interstitial radiotherapy for early oral tongue cancer. Int J Radiat Oncol Biol Phys 1996;36:1201–1204. 6. Nishimura T, Nozue M, Kaneko M, et al. Tumor seeding to the neck through percutaneous applicators of interstitial highdose-rate brachytherapy for cancer of the tongue: A case report. Nippon Acta Radiol 1997;57:281–282. 7. Yoshioka Y, Yoshida K, Shimizutani K, et al. Proposal of a new grading system for evaluation of tongue hemiatrophy as
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a late effect of brachytherapy for oral tongue cancer. Radiother Oncol 2001;61:87–92. Yamazaki H, Inoue T, Yoshida K, et al. Influence of age on the results of brachytherapy for early tongue cancer. Int J Radiat Oncol Biol Phys 2001;49:931–936. Leung TW, Wong VYW, Woug CM, et al. High dose rate brachytherapy for carcinoma of the oral tongue. Int J Radiat Oncol Biol Phys 1997;39:1113–1120. Klein M, Langfold A, Koch K, et al. Treatment of squamous cell carcinoma of the floor of the mouth and tongue by interstitial high-dose rate irradiation using iridium-192. Int J Maxillofac Surg 1998;27:45–48. Leborgne F, Leborgne JH, Barlocci LA, et al. Elective neck irradiation in the treatment of cancer of the oral tongue. Int J Radiat Oncol Biol Phys 1987;13:1149–1153. Dias FL, Kligerman J, Matos de Sa G, et al. Elective neck dissection versus observation in stage I squamous cell carcinomas of the tongue and floor of the mouth. Otolaryngol Head Neck Surg 2001;125:23–29. Hori S, Inoue T, Shigematsu Y. Analysis of neck lymph node metastasis in TxN0 tongue cancer. Gann no Rinsho 1977;23: 507–510 (in Japanese). Meoz R, Fletcher G, Lindberg R. Anatomical converge in elective irradiation of the neck for squamous cell carcinoma of the oral tongue. Int J Radiat Oncol Biol Phys 1982;8:1881– 1885.
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15. Vanderbrouck C, Sancho-Garnier H, Chassegne D, et al. Elective versus therapeutic radical neck dissection in epidermoid carcinoma of the oral cavity: Result of randomized clinical trial. Cancer 1980;46:386–390. 16. Beenken S, Krontiras H, Maddox W, et al. T1 and T2 squamous cell carcinoma of the oral tongue: Prognostic factors and the role of elective lymph node dissection. Head Neck 1999; 21:124–130. 17. Lindberg R. Distribution of cervical lymph node metastasis from squamous cell carcinoma of the respiratory and digestive tracts. Cancer 1972;29:1446–1449. 18. Byer RM, Wold PF, Ballantyne AJ. Rationale for elective neck dissection. Head Neck Surg 1988;10:160–167. 19. Shingai S, Suzuki I, Nakajima T, et al. Computed tomography evaluation of lymph node metastasis in head and neck carcinoma. J Craniomaxillofac Surg 1995;23:233–237.
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20. Don DM, Anzai Y, Lufkin RB, et al. Evaluation of cervical lymph node metastasis in squamous cell carcinoma of the head and neck. Laryngoscope 1995;105:669–674. 21. Piedbois P, Mazeron JJ, Haddad E, et al. Stage I-II squamous cell carcinoma of the oral cavity treated by iridium-192: Is elective neck dissection indicated. Radiother Oncol 1881;21: 100–106. 22. Lydiatt D, Robbins T, Byers R, et al. Treatment of stage I and II oral tongue cancer. Head Neck 1993;15:308–312. 23. Fukano H, Matsuura H, Hasegawa Y, et al. Depth of invasion as a predictive factor for cervical lymph node metastasis in tongue carcinoma. Head Neck 1997;19:205–210. 24. Yuen AP, Lam KY, Wei WI, et al. A comparison of the prognostic significance of tumor diameter, length, width, thickness, area, volume, and clinicopathological features of oral tongue carcinoma. Am J Surg 2000;180:139–143.
doi:10.1016/S0360-3016(03)01459-7
CLINICAL INVESTIGATION
Head and Neck
LYMPH NODE METASTASIS OF EARLY ORAL TONGUE CANCER AFTER INTERSTITIAL RADIOTHERAPY † HIDEYA YAMAZAKI, M.D.,* TAKEHIRO INOUE, M.D,† KEN YOSHIDA, M.D.,† EIICHI TANAKA, M.D.,‡ YASUO YOSHIOKA, M.D.,† HIRONOBU NAKAMURA, M.D.,‡ SOUHEI FURUKAWA, D.D.S.,§ KIMISHIGE SHIMIZUTANI, D.D.S.,† NAOYA KAKIMOTO, D.D.S.,§ AND TOSHIHIKO INOUE, M.D.† Department of *Radiology, Toyonaka Municipal Hospital, Toyonaka City, Osaka, Japan; Departments of †Radiation Oncology, Osaka University Graduate School of Medicine and ‡Radiology, Osaka University Graduate School of Medicine, Osaka, Japan; § Department of Maxillo-Facial Radiology, Osaka University Graduate School of Dentistry, Suita, Osaka, Japan Purpose: To examine the prognostic factors for lymph node metastasis after brachytherapy for early (T1T2N0M0) oral tongue cancer. Methods and Materials: We reviewed the records of 571 patients (500 low dose rate and 71 high dose rate) treated at Osaka University Hospital between 1967 and 1999. Results: Patients with lymph node metastasis had tumor with an average diameter of 26 ⴞ 8 mm and a thickness of 9 ⴞ 5 mm; for patients without lymph node metastasis, the corresponding dimensions were 23 ⴞ 8 mm and 7.5 ⴞ 4 mm (p ⴝ 0.0004 and 0.001, respectively). After 5 years, the ulcerative (48%) and indurative/infiltrative (39%) types showed a higher ratio of nodal involvement than the exophytic (31%) and superficial (19%) types (p <0.0001). Multivariate analysis showed ulceration (p ⴝ 0.006) and a thickness of <6 mm (p ⴝ 0.04) to be statistically significant predisposing factors for lymph node metastasis. The lymph node control rate was 68% in 1967–1979, 71% in 1980 –1990, and 66% in 1990 –1999; the corresponding successful salvage rates for lymph node metastasis were 43%, 33%, and 58% (p ⴝ 0.04). Conclusion: The appearance of the tumor, especially the presence or absence of ulceration and the diameter and thickness, are useful prognostic indicators for lymph node metastasis. Although the rates of lymph node metastasis did not change, the salvage outcome for recurrence after interstitial radiotherapy has recently improved. © 2004 Elsevier Inc. Early tongue cancer, Brachytherapy, Lymph node metastasis.
INTRODUCTION
increase in lymph node metastasis, especially in the case of submental or submandibular lesions (6). We also examined the incidence of lymph node metastasis and assessed the outcome of salvage treatment in relation to the year of treatment to gain a better idea of the effect of modern diagnostic modalities (CT, ultrasonography, and MRI) and surgical advances. Because a more precise diagnosis can reduce false-negative findings of lymph node metastasis, a lower rate of lymph node metastasis after treatment and a better outcome for salvage surgery may result.
Although oral tongue carcinoma is a highly curable cancer when treated by radiotherapy (RT), especially interstitial brachytherapy (1– 4), lymph node metastasis occurs in 30 – 50% of cases even in patients with early-stage disease. Several prognostic factors for lymph node metastasis have been reported, including tumor thickness. However, an exact assessment of tumor thickness can only be achieved by postoperative pathologic examination. Because few reports have analyzed the prognostic factors for lymph node metastasis after interstitial RT, we examined the importance of thickness as detected by palpation. In addition, we examined the changes in the incidence of lymph node metastasis after treatment with conventional low-dose-rate (LDR) and the newly introduced high-dose-rate (HDR) brachytherapy. Because HDR brachytherapy uses catheter insertion mainly by the submental route and LDR brachytherapy from the oral side (5), some concern has been voiced about an
Between 1967 and 1999, 571 patients (369 males and 202 females) with previously untreated early mobile tongue cancer (T1-T2N0) were treated with RT at Osaka University Hospital. Patients treated with combined chemotherapy and 198 Au grain were excluded from the study. All tumors were histologically identified as squamous cell carcinoma. The
Reprint requests to: Hideya Yamazaki, M.D., Department of Radiation Oncology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871 Japan. Tel: ⫹81 6 6879 3482; Fax: ⫹81 6 6879 3489; E-mail: [email protected]
Supported by a grant from the Ministry of Health and Welfare of Japan. Received Nov 25, 2002, and in revised form Jun 30, 2003. Accepted for publication Jul 1, 2003.
METHODS AND MATERIALS
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Table 1. Patient and treatment characteristics Lymph node metastasis Characteristic Total (n) Gender (n) Male Female Stage T1 T2 T1N0M0 Br. Br. ⫹ EBRT T2N0M0 Br. Br. ⫹ EBRT Age (y) Largest diameter (mm) (n ⫽ 534) Thickness (mm) (n ⫽ 482) Treatment source 192 Ir 22 Ra 60 Co 137 Cs MicroSelectron–HDR Tumor type (n ⫽ 504) Superficial Exophytic Indurative Ulcerative
Yes
No
p
181 (32)
390 (68)
115 (31) 66 (33)
254 (69) 136 (67)
NS
54 (25) 127 (36)
160 (75) 230 (64)
0.01
50 (26) 4 (20)
144 (74) 16 (80)
NS
78 (38) 49 (32) 181 55 ⫾ 14
128 (62) 102 (68)
NS
55 ⫾ 13
NS
26 ⫾ 8
23 ⫾ 8
0.0004
9⫾5
7⫾4
0.001
98 (31) 62 (34) 0 1 20 (28)
218 (69) 121* (66) 2† 0 51 (72)
NS
31 (21) 29 (33) 48 (38) 57 (47)
118 (79) 62 (67) 93 (62) 66 (53)
0.0001
Abbreviations: Br ⫽ brachytherapy; EBRT ⫽ external beam radiotherapy; NS ⫽ not significant; HDR ⫽ high dose rate. Numbers in parentheses are percentages. Number of patients not always 571 because of missing data. * One patient was implanted with 226Ra and 192Ir. † One patient was implanted with 226Ra and 60Co.
median patient age was 56 years (range 20 – 86; HDR group 55 ⫾ 14, LDR group 56 ⫾ 13, not statistically significant). The LDR group (1967–1996) comprised 311 male and 189 female patients. The HDR group (1991–1999) comprised 58 male and 13 female patients (p ⫽ 0.001). In the LDR group, 191 patients had T1 tumors and 310 had T2 tumors. In the HDR group, 23 patients had T1 tumors and 48 had T2 tumors (International Union Against Cancer TNM classification of 1987). Table 1 shows the patient characteristics by positive and negative lymph node status. All implantations were done under local anesthesia. A total of 171 patients (20 with T1, 151 with T2; HDR in 13, LDR in 158) underwent external beam RT (EBRT) using a 60Co teletherapy unit or linear accelerator. When the tumor was too large for implantation, the tumor appearance was the ulcerative/indurative type rather than the exophytic type with a larger tumor volume, or the tumor showed rapid progression, EBRT was administered first. In addition, when it took too long before implantation could be performed, we administered EBRT to
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prevent tumor progression. The patients received 2–3 Gy/ fraction for a median dose of 30 Gy (range 15–50) and were treated with a single lateral field that involved the primary site and the upper jugular lymph nodes. All 171 patients treated with EBRT also underwent interstitial needle implantation. For patients in the LDR group, the treatment sources consisted of an 192Ir hairpin for 317 patients, a 226 Ra needle for 181 patients, and 60Co and 137Cs for 1 patient each. 226Ra or 60Co was combined with 192Ir for 1 patient each. The needles were implanted with the PatersonParker system using a reference point 5 mm distant from the implant plane. The median dose for the LDR group treated with brachytherapy only was 70 Gy (range 61– 84) and with brachytherapy combined with EBRT was 70 Gy (range 50 –98). Patients in the HDR group received a total dose of 60 Gy in 10 fractions (range 42– 60, 6 Gy/fraction) for 1 week administered at a distant of 5 mm from the radioactive source. Two fractions were administered daily, and the interval between fractions was ⬎6 hours. Thirteen patients in the HDR group received an EBRT dose of 30 – 40 Gy (median 38) before implantation. The dose rates at the reference point for the LDR group ranged from 0.30 to 0.8 Gy/h, and for the HDR group from 1.0 to 3.4 Gy/min. Patients were followed for at least 13 months or until death, with a median follow-up time for the LDR group of 13 years (range 2–25) and for the HDR group of 3.8 years (range 1.1– 8). In principle, follow-up by physical examination was performed at at least 1-month intervals for the first 2 years and at 3– 6-month intervals thereafter. Examinations with imaging procedures such as CT, MRI, and/or ultrasonography were performed after 3, 6, 12, 18, and 24 months and at 1-year intervals thereafter or when local or lymph node recurrence was suspected. Chest radiographs were obtained once a year or when locoregional failure was suspected. To determine the rates of lymph node metastasis in terms of the year of treatment, we divided the patients into three groups: the early period until 1979 (n ⫽ 283), the first decade when modern modalities were used, 1980 –1990 (n ⫽ 168), and the next decade 1991–1999 (n ⫽ 120). Of the 181 patients with lymph node metastasis, the rN stage could be assessed in 158 and the distribution of lymph node metastasis in 154 patients. The tumor appearance was classified according to previously reported criteria (7): 91 were exophytic, 141 indurative/infiltrative, 149 superficial, and 123 were ulcerative. Tumors were classified as ulcerative if the initial physician had identified them as either indurative/infiltrative or ulcerative. We decided patients were lymph node positive when this was proved by pathologic examination or the lymph node continued to grow until the patient’s death. Nodal failure was not scored if the swollen node was diagnosed as negative by pathologic examination after surgical intervention. All 79 successfully salvaged patients and 82 patients classified as having failure underwent surgery. The 20 patients who were not surgically treated eventually died of the tumor, regardless of their treatment, because of progressive lymph node metastasis. These cases were, of course, not pathologically examined except by cytology. In
LN metastasis of tongue cancer after brachytherapy
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141
these cases, the location, number, and size of the lymph node metastases were assessed from data obtained from physical charts and imaging examinations. For statistical analysis, Student’s t test for normally distributed data and the Mann-Whitney U test for skewed data were used. Multiple data sets were analyzed by analysis of variance. The percentage was analyzed using the chi-square test. Local control, lymph node control, and survival data were estimated according to the Kaplan-Meier method and were examined for significance with a log–rank test. The Cox proportional hazard model was used for multivariate analysis. All analyses used the conventional p ⬍0.05 level of significance.
RESULTS Regional control Regional lymph node metastasis was seen in 181 patients (32%; Table 1). The regional control rate 1, 2, 3, and 5 years after treatment was 76%, 71%, 70%, and 68%, respectively. Therefore, most regional failures appeared during the first 2 years after treatment. Patients with Stage T2 had a 35% incidence of lymph node metastasis, and those with T1 had a 25% rate (p ⫽ 0.01). A comparison of the LDR and HDR groups showed that 158 patients (32%) in the LDR group received combined EBRT, but only 13 patients (18%) in the HDR group did so (p ⫽ 0.03). No statistically significant difference was noted in the incidence of lymph node metastasis between the LDR (161 of 500; 32%) and HDR (20 of 71; 28%) groups. Predisposing factors for lymph node metastasis were analyzed and are shown in Table 1. T stage (p ⫽ 0.01), longest diameter (p ⫽ 0.0004), thickness (p ⫽ 0.001), and tumor type (p ⫽ 0.0001) were identified as predisposing factors for lymph node metastasis. Patients with lymph node metastasis had a tumor diameter of 26 mm and thickness of 9 mm; the corresponding dimensions were 23 mm and 7 mm for patients without metastasis. We found that a smaller diameter correlated with a lower incidence of lymph node metastasis (p ⫽ 0.002; Fig. 1a). Patients with a tumor diameter of ⱕ10 mm, ⱕ20 mm, ⱕ30 mm, and ⬎30 mm had a 5-year lymph node control rate of 95%, 75%, 63%, and 59%, respectively. Only 1 patient with lymph node metastasis had a tumor with a diameter of ⱕ10 mm (1 of 19; 5%). Tumor diameter showed a strong correlation with thickness (correlation coefficient ⫽ 0.51, p ⬍0.0001). Lymph node metastasis was found in 26% (56 of 216) of tumors ⱕ5 mm in thickness and 39% (103 of 216) of tumors ⱖ6 mm in thickness (p ⫽ 0.001). Patients with a tumor thickness of ⱕ5 mm, ⱕ10 mm, and ⬎10 mm had a 5-year lymph node control rate of 74%, 62%, and 57%, respectively (Fig. 1b, p⫽ 0.002). Therefore, a smaller thickness and/or diameter were accompanied by a lower rate of lymph node metastasis. The tumor type also influenced nodal control (Fig. 1c). The ulcerative (48%) and indurative/infiltrative (39%) types had a higher rate of nodal involvement than did the exophytic (31%) and superficial (19%) types (p ⬍0.0001) at 5 years. The tumor type correlated strongly with the diameter (T stage) and thickness of the tumor (Table 2).
Fig. 1. Incidence of lymph node metastasis by (a) largest tumor diameter; (b) tumor thickness; and (c) tumor type. Dashed line indicates superficial; thick black line, exophytic; dotted line, indurative/infiltrative; and thin black line, ulcerative tumor type.
Multivariate analysis Multivariate analysis was performed to identify factors predicting for lymph node metastasis. Table 3 shows the results. Ulceration (tumor type) proved to be a determinant of lymph node metastasis. Compared with other tumor types
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Table 2. Characteristics by tumor type Characteristic
Superficial
Exophytic
Indurative/infiltrative
Ulcerative
Total (n) Gender (n) Male Female Stage T1 T2 T1N0M0 Br. Br. ⫹ EBRT T2N0M0 Br. Br. ⫹ EBRT Treatment source LDR MicroSelectron–HDR Irradiated dose (Gy) EBRT Br. Age (y) Largest diameter (mm) (n ⫽ 534) Thickness (mm) (n ⫽ 482)
149
91
141
123
96 (29) 53 (30)
54 (16) 37 (21)
96 (29) 45 (26)
84 (25) 39 (22)
NS
92 (50) 57 (18)
30 (16) 61 (19)
34 (18) 107 (34)
29 (16) 94 (29)
⬍0.001
86 (51) 6 (33)
24 (14) 6 (33)
28 (17) 6 (33)
29 (17) 0 (0)
0.01
39 (21) 18 (13)
33 (18) 28 (21)
63 (34) 44 (33)
49 (27) 45 (33)
NS
128 (29) 21 (37)
90 (20) 1 (2)
122 (27) 19 (33)
107 (24) 16 (28)
NS
27 ⫾ 6 68 ⫾ 7 55 ⫾ 13 20 ⫾ 8 5⫾2
28 ⫾ 6 70 ⫾ 5 57 ⫾ 13 24 ⫾ 7 9⫾5
30 ⫾ 5 68 ⫾ 7 55 ⫾ 14 25 ⫾ 7 9⫾4
p
29 ⫾ 4 68 ⫾ 8 52 ⫾ 15 28 ⫾ 8 10 ⫾ 5
NS NS* NS (p ⫽ 0.07) ⬍0.0001 ⬍0.0001
Abbreviations: LDR ⫽ low dose rate; other abbreviations as in Table 1. Numbers in parentheses are percentages. * p ⫽ 0.02, superficial vs. exophytic type.
without ulceration, the existence of an ulcer was associated with a relative ratio of 1.64 (p ⫽ 0.006), and a tumor thickness of ⱕ5 mm was associated with a lower metastatic rate, with a relative ratio of 1.48 (p ⫽ 0.04). Patients with Stage T2 tumor or one with a larger diameter appeared to have a greater rate of lymph node metastasis, with a relative risk of 1.48 (p ⫽ 0.06, not significant). Distribution and number of involved lymph node areas The number of involved lymph node areas after EBRT and brachytherapy or brachytherapy alone is shown in Table 4. The ipsilateral upper jugular (47%, n ⫽ 105), submandibular (24%, n ⫽ 54), and middle jugular (14%, n ⫽ 32) nodes were the major sites for metastasis of oral tongue cancer after brachytherapy, accounting for 85% of all such metastases. For patients treated with a different protocol,
upper jugular lymph node involvement was seen in 45% of the LDR group and in 56% of the HDR group. The submaxillary nodes accounted for 24% of the metastases of the LDR group and 16% of the HDR group; the corresponding rates for the submental nodes were 8% and 0%. The assessment of the patients treated solely with brachytherapy revealed similar results. Therefore, there appeared to be no increase as a result of seeding in the submental or submandibular approach using HDR brachytherapy. Lymph node metastasis and salvage Table 5 shows the salvage outcomes for lymph node metastasis by T stage and rN stage after EBRT and brachytherapy or brachytherapy alone. One-half of the lymph node metastases that were Stage rN2b or less could be salvaged if locally controlled. Between 1967 and 1979, the regional
Table 3. Results of multivariate Cox hazard model Variable
Strata
Odds ratio
95% Confidence interval
p
Gender Age (y) Time of treatment T stage (diameter) Tumor type Treatment Dose rate Thickness (mm)
Male vs. female ⱕ59 vs. ⱖ60 ⱕ1979 vs. ⱖ1980 T1 vs. T2 Ulcer (yes vs. no) EBRT ⫹ Br. vs. Br. HDR vs. LDR ⱕ5 vs. ⱖ6
0.99 1.07 0.97 1.48 1.64 1.34 1.28 1.48
0.70–1.40 0.78–1.49 0.68–1.39 0.98–2.24 1.16–2.33 0.92–1.95 0.70–2.33 1.01–2.19
0.94 0.66 0.89 0.06 0.006 0.13 0.43 0.04
Abbreviations as in Tables 1 and 2.
LN metastasis of tongue cancer after brachytherapy
Table 4. Distribution and number of involved lymph node areas Ipsilateral lymph node (n) LDR group EBRT ⫹ Br. or Br. alone Retroauricular Submental Submandibular Upper jugular Middle jugular Lower jugular Supraclavicle Br. only Retroauricular Submental Submandibular Upper jugular Middle jugular Lower jugular Supraclavicle
2 (1) 15 (8) 50 (24) 89 (45) 27 (14) 13 (7) 2 (1) 2 (1) 13 (10) 32 (24) 61 (45) 19 (14) 9 (7) 0 (0)
HDR group
4 (16) 14 (56) 5 (20) 2 (8)
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Table 5. Salvage outcome of lymph node metastasis according to T and rN stage
Contralateral lymph node (n) LDR group
2 (22) 2 (22) 2 (22) 2 (22) 1 (12)
HDR group
Ultimate control T stage
Local failure
EBRT ⫹ Br. or Br. alone T1
No
1 (100) Yes
T2 2 (9) 13 (59) 5 (23) 2 (9)
● H. YAMAZAKI et al.
2 (50) 1 (25) 1 (25)
No
1 (50) 1 (50) Yes
Abbreviations as in Tables 1 and 2. Numbers in parentheses are percentages.
control rate for early tongue cancer was 68% 5 years after treatment; the corresponding rate for lymph node control was 71% in 1980 –1990 and 66% in 1991–1999 (Table 6). The failure patterns and salvage success rates are shown in Table 6. The lymph node control rate was 68% in 1967–1979, 71% in 1980 –1990, and 66% in 1990 –1999; the corresponding rates for lymph node metastasis were 43% (38 of 89), 33% (16 of 49), and 58% (25of 43; p ⫽ 0.04). In the case of lymph node metastasis alone, the ultimate control rate was 48% (28 of 59) in 1967–1979, 43% (10 of 23) in 1980 –1989, and 88% (22 of 30) in 1990 –1999 (p ⫽ 0.001). When local and/or nodal failure was detected, surgical intervention was used first, with or without adjuvant chemotherapy and/or RT. If the patient’s condition did not allow for surgery, or if the patient refused to undergo surgery, RT and/or chemotherapy were used. Six patients declined any additional treatment even though lymph node metastasis was noted. The salvage success rates for local recurrence also improved with time. In 1990 – 1999, 75% of patients were salvaged compared with 43% in 1967–1980 and 63% in 1980 –1989 (p ⫽ 0.11, not significant). However, the salvage rate for patients with both lymph node and local failure or advanced lymph node metastasis (rN2c or rN3) did not improve during these periods. The cause-specific survival rates showed minor improvement from 74% in 1967–1979 to 84% in 1990 –1999 (p ⫽ 0.14, not significant). The patient record included 9 cases of rN2c. Four cases had failure in both local control and lymph nodes, and all cases had concurrent bilateral lymph node metastasis. One primary tongue cancer with rN2c lymph node metastasis
Br. only T1
No
Yes
T2
No
Yes
rN stage
Yes
No
%
N1 N2a N2b N2c Unknown N1 N2a N2b Unknown N1 N2a N2b N2c N3 Unknown N1 N2a N2b N2c N3 Unknown
9 1 6
9 1 7 1 4 2 3 2 12 3 13 3 2 1 13 6 11 2 1 6
50 50 46 0 100 43 0 0 50 54 57 52 25 0 88 38 25 8 50 0 14
9 1 6 1
47 50 50 0
4 1 2 2 7 3 8 1 1 1 6 3 6 1 1 6
43 0 0 50 56 40 60 50 0 75 40 40 14 50 0 0
N1 N2a N2b N2c Unknown N1 N2a N2b Unknown N1 N2a N2b N2c N3 Unknown N1 N2a N2b N2c N3 Unknown
4 3 2 14 4 14 1 7 8 2 1 2 1 8 1 6 4 3 2 9 2 12 1 3 4 2 1 1
Abbreviations as in Table 1.
was located on the ventral surface, but the other primary tumors were located in the lateral border. Although eight of these patients underwent salvage surgery with or without postoperative RT and chemotherapy, only three could be salvaged. DISCUSSION Oral tongue cancer located anterior to the circumvallate papillae has a vital impact, not only on speech, but also on
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Table 6. Local and regional control, and cause-specific survival rates and successful salvage rates for lymph node metastasis and/or local recurrence according to time of treatment
Local control rate (%) Lymph node control rate (%) Cause-specific survival rate (%) Lymph node metastasis alone Local recurrence alone Both N stage of patient with lymph node metastasis alone N1 N2a N2b N2c N3
1967–1979
1980–1989
1990–1999
p
78 68 74 28/59 (48) 15/35 (43) 10/30 (34)
75 71 75 10/23 (43) 10/16 (63) 6/26 (23)
82 66 84 22/30 (88) 9/12 (75) 3/13 (23)
NS NS NS (p ⫽ 0.14) 0.001 NS (p ⫽ 0.11) NS
11/26 (42) 4/7 (57) 8/19 (42) 0/1 (0) 0/1 (0)
3/6 (50) 0/1 (0) 4/10 (40) 1/3 (33) 0/1 (0)
9/12 (75) 1/1 (100) 8/11 (73) 0/1 (0) —
NS NS NS NS NS
Abbreviation: NS ⫽ not significant. Data presented as number of patients salvaged/total with lymph node metastasis, with the percentage in parentheses, unless noted otherwise. Number of patients not always 571 because of missing data.
the coordination of chewing and swallowing. RT, considered to be a minimally invasive treatment procedure, has the advantage of preserving the shape and functions of the tongue. To limit unwanted RT, the method of LDR brachytherapy was changed from 226Ra to 192Ir. This so-called LDR brachytherapy has come into wide use and become the gold standard in brachytherapy (1– 4). We initiated HDR brachytherapy using a remote afterloading technique that eliminated radiation exposure except to the patient (5, 8). A 5-year local control rate of 81% was obtained with this type of brachytherapy, equal to that obtained with LDR brachytherapy. Several other authors have recently reported similar results (9, 10). The incidence of regional metastasis of N0 early tongue cancer is reported to be about 20 –50%, and ⬎90% of such cases occur within 18 –24 months after treatment. Lymph node metastasis normally already exists outside the local lesion when brachytherapy is performed so that several reports have cited the usefulness of elective neck dissection or RT (11, 12). At our institute, also, EBRT (30 Gy in 10 fractions within 2 weeks) was added before implantation to reduce lymph node metastasis; however, no therapeutic benefits were obtained. On the contrary, the rate of complications increased (13). Although several studies have reported on the reduction of lymph node metastasis after prophylactic RT or elective neck dissection, few survival benefits were obtained. Beenken et al. (16) reported that prospective randomized clinical trials failed to demonstrate survival benefits for patients undergoing elective treatment, because the log–rank test required at least 290 patients to detect a 5% survival difference (with p ⬍0.05 and a power of 0.82), a larger number than ever enrolled in a trial held at a single institution. Therefore, it is believed that prophylactic neck treatment should be limited to patients who are unavailable for regular follow-up or to patients with a higher risk of cervical lymph node metastasis. Thus, we
adopted a wait-and-see policy, performing neither prophylactic neck RT nor prophylactic surgical excision. A multiinstitutional prospective trial for prophylactic treatment is anticipated for high-risk patients who present with a relatively large ulcerative tumor with a thickness of ⬎5 mm or with a poorly differentiated tumor. We found no difference in the distribution of lymph node metastasis between the HDR and LDR groups. Although caution should be taken with regard to tumor seeding by insertion (6), seeding to submental/submandibular lesions does not appear to be a clinical problem in HDR brachytherapy. The first-echelon nodes are subdigastric (45% in LDR and 56% in HDR) and submandibular (24% in LDR and 16% in HDR), which concurs with the previously reported results of Lindberg (17) for patients with oral tongue cancer on admission, with an incidence of metastasis of 60% for subdigastric and 23% for submandibular nodes. This means that little effect can be expected from brachytherapy, with or without EBRT, on lymph node metastasis distribution. Byer et al. (18) also reported metastasis rates of 73% and 18% for these lymph nodes after elective neck dissection in 48 patients with carcinoma of the oral tongue and a clinically negative neck. Mid-jugular involvement was seen in 14% of the patients in the LDR group and 20% of those in the HDR group, similar to the rates reported by Lindberg (11%) and Byer et al. (18%) for mid-jugular lesions. Modern imaging modalities, such as ultrasonography, CT, and MRI are now being used to evaluate local and lymph node status, resulting in the detection of smaller lymph nodes than would normally be found by physical examination alone. However, contrary to our expectations, the rate of lymph node metastasis did not decline in the past decade despite modern imaging analysis. We used a nodal size ⬎10 mm in the short-axis diameter or the presence of central lucency as the criteria for nodal metastasis. Shingai
LN metastasis of tongue cancer after brachytherapy
et al. (19), using the same criteria, reported that CT provided an accuracy of ⬎90%, a sensitivity of nearly 90%, and a specificity of 100%. However, a large number of malignant nodes with a diameter of ⬍10 mm were identified, and extranodal spread was also found to have occurred in a substantial percentage of these smaller nodes. Because the present radiologic criteria for assessing cervical lymph node status are based largely on size, these findings indicate major limitations in the current capability of detecting metastatic disease (20). Furthermore, because our data are limited as a result of their retrospective nature, additional investigations are needed to establish concrete results regarding the applicability of modern imaging procedures. We found that the salvage rates have recently increased. One reason for this may be new developments in surgery, such as reconstruction techniques, but additional analysis was not possible because of the variety of techniques used in salvage surgery held in many hospitals. In contrast, the salvage rates for both local and lymph node failure did not improve. Stage rN2c (bilateral or contralateral) and rN3 (ⱖ6 cm) tumors are also difficult to treat successfully. Therefore, metastasis should be detected as soon as possible and followed closely. Piedbois et al. (21) reported a successful salvage rate of 62% (13 of 21) after therapeutic neck dissection and 47% (9 of 19) after elective treatment, and Lydiatt et al. (22) reported corresponding rates of 41% and 40%. Although it is difficult to compare our data with their salvage rates, because their salvage results were not always divided according to local control and rN stage, our 88% salvage rate obtained in the 1990s for patients with lymph node metastasis only is no less than that reported in other centers. One concern is the short follow-up time for patients
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treated between 1990 and 1999. Longer follow-up periods are needed because late recurrence, not only locally, but also as lymph node lesions, may occur even after 2 years without evidence of disease, including recurrence after salvage treatment. Multivariate analysis indicated that ulceration and thickness followed by T stage are significant indicators of lymph node metastasis (p ⫽ 0.06). This is natural because ulceration may indicate deeper invasion and correlated with tumor thickness, which has already been confirmed by pathologic studies as an important predisposing factor for lymph node metastasis (23, 24). Although the problems in determining the exact thickness of a tumor by palpation only are several, we can safely assume that thin tumors with a thickness of ⬍5 mm have a lower incidence of lymph node metastasis. In addition, cases with smaller tumors ⱕ10 mm in diameter (1 of 19; 5%), had only one lymph node metastasis, and ulceration increased the risk of such metastasis, an indicator that closely correlated with the tumor thickness. Therefore, not only thickness, but also the diameter and type of tumor, especially if ulcerative, may be helpful information for predicting lymph node metastasis of T1-T2 tumors. CONCLUSION The appearance of the tumor, especially the presence or absence of ulceration and diameter and thickness, are useful prognostic indicators for lymph node metastasis. Although the rates of lymph node metastasis did not change, the salvage outcome for recurrence after interstitial RT has recently improved.
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