24_04_2014_Overall Treatment Time Tongue Carcinoma

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doi:10.1016/S0360-3016(03)00507-8

CLINICAL INVESTIGATION Head and Neck

EFFECT OF TREATMENT TIME ON OUTCOME OF RADIOTHERAPY FORORAL TONGUE CARCINOMA

YOICHIRO HOSOKAWA, D.D.S., PH.D.,* HIROKI SHIRATO, M.D., PH.D.,

TAKASHI NISHIOKA, M.D., PH.D., KAZUHIKO TSUCHIYA, M.D., PH.D., TA-CHEN CHANG, M.D.,

KENJI KAGEI, M.D., PH.D., KEIICHI OHOMORI, D.D.S., PH.D., KEN-ICHI OBINATA, D.D.S., PH.D.,

MASAYUKI KANEKO, D.D.S., PH.D.,* KAZUO MIYASAKA, M.D., PH.D., ANDMOTOYASU NAKAMURA, D.D.S., PH.D.

*Department of Dental Radiology, Health Sciences University of Hokkaido, Tobetsu, Japan; Department of Radiology, HokkaidoUniversity School of Medicine, Sapporo, Hokkaido, Japan; Department of Dental Radiology, Hokkaido University School of

Dentistry, Sapporo, Hokkaido, Japan

Purpose: To investigate the importance of total treatment time on the outcome of external beam radiotherapy(EBRT) followed by internal brachytherapy for the treatment of oral tongue carcinoma.Methods and Materials: Ninety-four patients with T1T2N0 squamous cell carcinoma of the oral tongue weretreated using 3540 Gy EBRT followed by 3540 Gy interstitial 137Cs brachytherapy between 1985 and 1995.The interval between the end of EBRT and the start of interstitial treatment varied for numerous unavoidablereasons, with a mean of 25.3 days and standard deviation of 3.5 days. The median follow-up period was 59.1months (range 6146).Results: The actuarial survival rate of all cases was 78.4% at 5 years. The 5-year local control rate for those withT1 and T2 was 92.8% and 62.7%, respectively (p< 0.05). The local control rate of the primary tumor in patientswith a total treatment time >43 days was statistically lower than that of patients with a total treatment time 43 days or not), and location of disease (posterior or not). Regression analysis for 5-year local control as afunction of treatment duration showed a 2% loss of local control per day of treatment extension >30 days (r 0.94, p < 0.01).Conclusion: The total treatment time was associated with the local control rate in the RT of oral tonguecarcinoma. The loss in local control was estimated to be 2.0% per additional day in our series for oral tonguecarcinoma. 2003 Elsevier Inc.

Oral tongue carcinoma, Radiotherapy, Total treatment time.

INTRODUCTION

The total treatment time is now recognized as an important

prognostic factor influencing local control of head-and-neck

carcinomas treated by external beam radiotherapy (EBRT)

(16).Increases in radiation time are reported to result in a

decrease in local control ranging from 1.5% to 1.7% per

additional day of treatment (6). In the case of combined

EBRT and brachytherapy, however, the influence of the

time factor on local control is less clear. That EBRT fol-

lowed by brachytherapy is effective has been well estab-

lished, but a period of several weeks without RT is often

required between the two treatments owing to cutaneous

and/or mucosal reactions after EBRT. Few studies have

evaluated the time factor in this treatment combination for

head-and-neck carcinomas(35).

Accordingly, the aim of this study was to determine the

effect of total treatment time on local control of head-and-

neck cancer in combination treatment with EBRT and

brachytherapy.

METHODS AND MATERIALS

This retrospective study was carried out on all patients

with T1T2N0 oral tongue carcinoma who received EBRT

followed by brachytherapy to the primary tumor at Hok-

kaido University Medical Hospital between 1985 and 1995.

All patients had histopathologically proven squamous cell

carcinoma. They were previously untreated and did not have

distant metastasis as evaluated by clinical examination, lab-

oratory tests, and chest radiography. Patients with 6

months of follow-up were excluded.

Reprint requests to: Yoichiro Hosokawa, D.D.S., Ph.D., Depart-

ment of Dental Radiology, Health Sciences University of Hok-kaido, Kanazawa 1757, Tobetsu, Hokkaido, Japan. Tel: 01332-3-

1211; Fax: 01332-3-1410; E-mail: [email protected]

Received Sep 6, 2002, and in revised form Apr 3, 2003. Ac-cepted for publication Apr 7, 2003.

Int. J. Radiation Oncology Biol. Phys., Vol. 57, No. 1, pp. 7178, 2003Copyright 2003 Elsevier Inc.

Printed in the USA. All rights reserved0360-3016/03/$see front matter

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cally lower than that of patients with a total treatment time

of43 days (p 0.05;Fig. 5).

The T stage and the location of the primary tumor in each

group are shown in Table 3. Patients who had a total

treatment time 43 days had more T2 tumors than patients

who had a total treatment time of43 days (p 0.05). The

results of the present examination of the actuarial local

control rate in 64 patients with T2 tumors indicated that this

rate was statistically lower in patients whose total treatment

time was 43 days (p 0.05; Fig. 6). No statistically

significant differences were found in the rate of lesions

located in the posterior portion of the tongue and in the

average total dose between these two groups.

Twenty-two patients had an adverse reaction to RT: 11

cases of transient tongue ulcer that healed within several

months, 5 cases of persistent tongue ulcer that did not elicit

severe complaints, 4 cases of severe tongue ulcer that re-

quired surgery, and 2 cases of osteoradionecrosis of the

mandible. No statistically significant differences were noted

in the rate of late adverse effects among any subgroups with

regard to age, gender, T stage, N stage, dose, total treatment

period, or treatment year (Table 3).

A correlation was found between the total treatment time

and the interval from the end of EBRT to the start of

brachytherapy (0.69, p 0.01) in the correlation analysis

(Table 4). Thus, the interval from the end of EBRT to the

start of brachytherapy was not included as an explanatory

variable in the multivariate analysis. The correlation analy-

sis showed that the correlation coefficient between total

treatment time and T stage was not so great (0.2875).

Multivariate analysis revealed that, in all cases, the local

control rate was significantly related to T stage (T2 or not),

total treatment time, and location of disease (posterior or

not; Table 5).

Table 1. Results of radiation dose and treatment time

Average EBRT dose (Gy) 35.4 (SD 2.61)Average brachytherapy dose (Gy) 39.7 (SD 4.41)Average dose rate at 5 mm from implant (Gy/h) 0.43 (SD 0.08)Total treatment time (d) 2969Average total treatment time (d) 43.3 (SD 5.92)Average duration from start to end of EBRT (d) 25.3 (SD 3.54)Average interval between EBRT and brachytherapy (d) 14.6 (SD 5.49)

Average duration of brachytherapy (h) 92.2 (SD 19.5)Distribution of patients above and below mean duration (n)Above (43 d) 41Below (43 d) 53

Reasons for long interval* between EBRT and brachytherapy (n)Public holidays 2Availability of room for brachytherapy 1Poor health status 1Refusal of patient to undergo implantation 1Severe reaction of external irradiation 3

5-year actuarial survival rate (%)All (n 94) 78.4Local recurrence (n 22) 66.2No local recurrence (n 72) 81.5

* More than 1 SD greater than the mean (21 d).Abbreviations: EBRT external beam radiotherapy; SD standard deviation.

Fig. 1. Regional control rates of patients with local failure andthose with local control.

73Effect of treatment time of RT for tongue carcinoma Y. HOSOKAWA et al.


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Figure 7shows a plot of the 5-year local control rate as a

function of treatment duration for all patients. Patients were

grouped into subgroups according to total treatment time,

and the Kaplan-Meier 5-year local control rate was calcu-

lated for each group. A linear regression line was thenfitted

to these data points. This line demonstrated a 2% loss of

local control per day of treatment extension 30 days. A

strong correlation was found between the total treatment

time and local control rate (r 0.94, p 0.01).

DISCUSSION

The management of carcinoma of the tongue in its early

stages by brachytherapy with or without EBRT has been

used in many cancer centers (10 19). It was previously

suggested that local control correlated well with overall

survival(5, 14, 15). Our results were consistent with these

results, suggesting the importance of local control. The

patients with carcinoma at the posterior third of the oral

tongue in our series had lower local control rates. Hintz et

al.(20)concluded that patients showing involvement of the

base of the tongue were technically more demanding than

those with tumors of the oral tongue. Our results may have

been due to the technical difficulty of implantation in the

posterior location compared with that for tumors at the

anterior or middle part of the tongue.

The 5-year local control rate after RT for early tongue

carcinoma has been reported to be about 90% for T1 and

6592% for T2(16 19).Our treatment results also showed

a significant difference in the local control rate between

patients with T1 and those with T2 lesions. Our multivariate

analysis indicated that prolongation of the overall treatment

time is also an independent significant factor for local

control. The correlation analysis showed that the correlation

coefficient between the total treatment time and the T stage

was not so great (0.2875). However, when we divided the

patients into two groups at 43 days, the proportion of those

with T2 was greater in the group with a total treatment time

Table 2. Cause of death according to local control status

Cause

Local recurrence (n)

No Yes

Local failure 0 2Regional LN metastasis 4 3Distant metastasis 2 1Other disease 6 2Unknown 1 3Total 13 (n 72) 11 (n 22)

Fig. 2. Local control rates of T1 and T2.

Fig. 3. Local control rates according to tumor location.

74 I. J. Radiation Oncology Biology Physics Volume 57, Number 1, 2003


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and-neck carcinomas, it has been reported that the total

duration of RT and the delay between EBRT and brachy-

therapy were significant prognostic factors for local control

and overall survival of soft palate and tonsil carcinomas(7).

In our results for oral tongue carcinoma, the local control

rate for those with a total treatment time 43 days was

statistically lower than that for those with a total treatment

time of43 days. Thisfinding is consistent with the results

of Mendenhallet al.(8),who reported that local control was

achieved in 16 (76%) of 21 cases with a total treatment time

of 40 days and in 5 (36%) of 14 cases with a total

treatment time of 40 days. Our results for T2 tumors

suggest that the total treatment time of combined EBRT and

brachytherapy might be a biologically important factor for

local control in tongue carcinomas independent of tumor

size and tumor location. The loss in local control was

estimated to be 2.0% per additional day in our series for oraltongue carcinoma. This rate is roughly in accordance with

the estimation of 1.51.7% by Hendry et al. (6) and that of

2.4% derived from the results of Bataini et al. (21) for

oropharyngeal carcinomas. Although these results were not

based on prospective randomized trials, the strong correla-

tion between the total treatment time and local control rate

(r 0.94,p 0.01) suggests that total treatment time is one

of the most important prognostic factors. Accelerated re-

population of tumor cells may take place in patients with

oral tongue carcinoma as it does in those with head-and-

neck carcinoma(24).

We were unable to avoid a delay in the interval betweenEBRT and brachytherapy. The strong correlation between

the overall treatment time and the interval between EBRT

and brachytherapy made it impossible to determine which

was the more important prognostic factor. The longer treat-

ment time might have been the reason for the lower local

control rate of combined treatment compared with that of

brachytherapy alone in a past series (25). It would not be

profitable to add an EBRT dose to compensate for the delay

in the start of brachytherapy, because this would increase

late adverse reactions(19, 25).On the basis of these results

and those of previous studies, we are now treating T1-T2

Fig. 6. Local control rate according to total treatment time forpatients with T2 tumor.

Table 4. Partial correlation coefficients

T stage Location TTT Total dose Year Age Gender Interval

T stage 1.0000 0.2488 0.2875 0.1356 0.0461 0.0021 0.1221 0.1918Location 0.2488 1.0000 0.0629 0.0622 0.1385 0.0816 0.2158 0.0622TTT 0.2875 0.0629 1.0000 0.1395 0.2337 0.0924 0.0904 0.6944Total dose 0.1356 0.0622 0.1395 1.0000 0.1655 0.0357 0.0816 0.0003Year 0.0461 0.1385 0.2337 0.1655 1.0000 0.0404 0.2754 0.1538Age 0.0021 0.0816 0.0924 0.0357 0.0404 1.0000 0.0447 0.1929Gender 0.1221 0.2158 0.0904 0.0816 0.2754 0.0447 1.0000 0.0340Interval 0.1918 0.0622 0.6944 0.0003 0.1538 0.1929 0.0340 1.0000

Abbreviation: TTT total treatment time.

Table 5. Results of multivariate analysis on possible prognosticfactors (Cox regression model)

FactorRelative

risk p

T stage (T2 or not) 5.723 0.011Disease location (posterior or not) 4.617 0.039Total treatment time 4.214 0.048

Total dose 2.125 0.141Treatment year 1.284 0.272Age 0.298 0.573Gender (male or not) 0.006 0.946



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oral tongue carcinoma with brachytherapy alone, at 60 70

Gy in 1 week, to reduce the total treatment time for primary

tongue tumors. We are using low-dose-rate continuous RT

for T1 and small T2 tumors with single plane 137Cs implan-

tation and starting high-dose-rate twice-daily RT with 129Ir

for larger T2 tumors to optimize the dose distribution in

space.

CONCLUSION

The local control rate of T1T2 oral tongue carcinoma

was better in cases of T1 than in T2 carcinoma; better in

cases of carcinoma located in the anterior or middle of

the tongue than in those located posteriorly; and better in

cases with shorter than in those with longer treatment

times. A treatment time of43 days was associated with

a poor local control rate in patients with T2 primary

tumors. The results indicate that both the total treatment

time and the interval between EBRT and brachytherapy

are biologically important prognostic factors for localcontrol.

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24_04_2014_Overall Treatment Time Tongue Carcinoma