R ADIOTHERAPY 6 ONCOLOGY

ELSEVIER Radiotherapy and Oncology 39 (1996) 229-233

Prognostic factors of local control after radiotherapy in Tl glottic and supraglottic carcinoma of the larynx

Jesper Carl* a, Lisbeth J. Andersena, Mogens Pedersena, Ole Greisenb aDepartment of ecology, Aaborg Hospital, Section South, Hobrovej 18-22. DK-5XXXl Aalborg, Denmark

bDepartmenr of ENT. Aalborg hospital, Section South, Hobrovej 18-22, DK-WOO Aalborg, Denmark

Received 27 April 1995; revised 13 February 1996; accepted 20 February 1996

This study presents a retrospective analysis of a consecutive series of 161 patients treated with curatively intended radiotherapy for Tl supraglottic or glottic carcinoma from 1972 to 1990 at the Department of Oncology, Aalborg County Hospital, Denmark. All patients received radiotherapy given with 4-MV X-rays on lateral opposed fields. Intended dose was 60 Gy in 30 fractions. Multivariate analysis of recorded clinical parameters was applied to identify possible prognostic factors of local control. Tumor size, differentiation grade and sex were identified as significant independent prognostic parameters of local control. Five-year local control was 58% and 78% for supraglottic and glottic tumors, respectively. Applying salvage surgery the ultimate control rates were 82% and 97% for supraglottic and glottic tumors, respectively. Evaluation of treatment response 3-6 weeks following accomplish- ment of radiotherapy demonstrated that remaining tumor at the time of evaluation was an indicator of failure in local control.

Keywords: Radiotherapy; Neoplasms recurrence; Local prognosis; Laryngene neoplasms; Multivariate analysis

1. Introduction

High voltage radiotherapy is in Denmark the primary treatment of choice for squamous cell carcinoma of the larynx, irrespective of the clinical stage of tumour. The aim of this treatment is to obtain lasting tumour control with preservation of a good voice. Identification of prognostic parameters has the implication that prog- nostic unfavourable groups of patients can be identified and more aggressive treatment strategies applied.

According to other studies the local control rate of laryngeal carcinoma depends mainly on T-classification [1,2], tumour size [3-51, impaired vocal cord mobility [6-91, over-all treatment time [lO,l 11, and tumour regression during therapy [3,12,13]. This study presents a retrospective analysis of a consecutive series of pa- tients treated with curatively intended radiotherapy for Tl glottic and supraglottic carcinoma. Multivariate analysis of recorded clinical parameters has been ap-

+ Corresponding author.

plied to identify possible prognostic factors of local control.

2. Patients and methods

From 1972-1990 a total of 161 patients with histological verified invasive Tl squamous cell car- cinoma of the glottic or supraglottic larynx were treated at the Department of Oncology, Aalborg County Hospi- tal, Denmark. All patients underwent direct laryngoscopy with biopsy and tumours were histological graded as well, moderate or poorly differentiated. Tumours were staged according to the criteria of the UICC TNM classification of 1987. Tumor sizes were estimated from laryngoscopy and classified according to an estimated average diameter as small (C 5 mm), medi- um (5-10 mm), large (lo-30 mm) or very large (> 30 mm). All patients received radiotherapy given with a lin- ear accelerator (4 MV) on lateral opposed fields. Medi- an field size was 42 cm2 (range, 36-72 cm2). Fixation shells and individually designed altinium compen- sators for missing tissue were used. Dose was prescribed

0167-8MOM/.Sl5.00 0 1996 Elsevier Science Ireland Ltd. All rights reserved PII: SO167-8140(96)01738-9

230 C. Jesper et al. /Radiotherapy and Oncology 39 (1996) 229-233

to a reference point defined as 1 cm from the geometric field edge in the midplane. The reference point was assigned 95% of the target dose. Treatment was given daily for 5 days a week without breaks unless required by acute reactions, holidays or unforeseen events. Dose per fraction ranged between 1.5-2 Gy. Consequently dose has been recalculated to biological effective dose (BED*@) for an equivalent 2-Gy fractionation schedule using an alpha/beta ratio of 25 Gy and with no correc- tion for treatment time. Evaluation of response was made at the end of treatment, and at regular intervals for 10 years or until death, i.e. every 3-4 months for 3 years, every 6 months for 2 years and yearly for 5 years. Response evaluation was made by indirect laryngoscopy, and in cases where this technique was not sufficient by direct laryngoscopy 3-6 weeks after end of radiotherapy. Tumor size and response evaluation was performed by the same two persons during the whole period.

Salvage on local recurrence was surgery by hemi or total laryngectomy. The endpoint was local control from start of treatment calculated by the Kaplan-Meier product limit method. In univariate analysis statistical significance was assessed by the log-rank test. Multi- variate analysis was made using the Cox proportional Hazard Method.

3.Result.9

Data on treatment characteristics of the 161 patients are shown in Table 1, together with the distribution of prognostic parameters of the patients included in the

Table I Characteristics of the 161 patients included in the analysis

Sex

Male 125 Female 36

Age Median (years (lower and upper quartiles)) 65 (58-72)

Site Supraglottic 27 Glottic 134

Grade Well 93 Moderately 58 Poorly IO

Tumor size Small 107 Medium 34 bv 20

Field area (cm’) Median (lower and upper quartiles) 42 (42-56)

Overall treatment time Median (lower and upper quartiles) 44 (41-47)

Biological effective dose (BEQ ,$ Median (Gy (lower and upper quartiles)) 60.00

(60.00-60.20)

Table 2 Fiveyear local control and significance of prognostic parameters tested by univariate log-rank analysis

Prognostic

!&7X

Female Male

Age $65 years >65 years

Site supraglottic Glottic

Local control

85% 72%

71% 79%

58% 78%

95% C.I.

73-97% 63-U%

60-82% 69-89%

37-78% 71-86%

P-value

OogrW

0.21

0.09

0.004

Well 81% 72-90% 0.01 Moderately 71% 58-84% Poorly 42% 8-76%

sii Small 85% 77-92% o.ooo2 Medium 58% 40-76% Large 49% 23-75%

Field area $42 cm2 77% 69-85% 0.22 >42 cm2 62% 50-74%

Treatment time s 44 days 75% 65-850/a 0.35 >44 days 75% 65-86%

Biological effective dose (BED2 *) s~cy 80% 72-88% 0.25 >mcY 67% 54-81%

study. Local recurrence occurred in 12 of 27 supraglottic and 28 of 134 glottic tumors following radiotherapy. Salvage surgery was successfully applied to control the cancer leading to 5-year ultimate local control of 82% and 97% for supraglottic and glottic tumors, respec- tively.

Risk of local failure stratified according to prognostic parameters in Table 1 is shown in Table 2. Only the prognostic factors site, grade and size were demonstrated by univariate log rank analysis to have significant influence of the 5-year local control. The 5- year local control for prognostic factors is shown for

Table 3 Final model by multivariate regression analysis on prognostic factors of local recurrence following radiation therapy Cbi2 = 29, dl: = 6, P=0.ooMJ4

Sex

Age Grade sii Field area Treatment time DOSC (BED2 oy)

Beta 95% C.I. exp@eta)

1.076 0.117-2.034 2.93 -0.015 -0.047-0.017 0.99

0.708 0.153-1.263 2.03 1.136 0.679-1.592 3.11

-O.&t2 -0.098-0.014 0.96 -0.219 -0.941-0.503 0.80

0.270 -0.442-0.983 1.31

C. Jesper et al. /Radiotherapy and Oncology 39 (1996) 229-233 231

Table 4 Evaluation of innuence of tumor response three to six weeks following accomplishment of radiotherapy on local control

Response at 60 Gy No. patients Local control S-year actuarial

Complete Incomplete

156 77% 5 o?h

each strata in Table 2. A significant correlation existed between several prognostic parameters in this study (data not shown).

Sex, grade and tumor size were the only prognostic parameters found to have significant influence on local control when a multivariate analysis was performed. The final model was stratified after site as the effect of size was significantly different in glottic and supraglottic tumors. The final regression model, including all pa- tients, is shown in Table 3. This model is used for calculating the recurrence free survival corrected for tumor size and sex shown in Fig. 1.

The tumor response, evaluated 3-6 weeks after radiotherapy, turned out to be a predictor of local con- trol. The results in Table 4 show that in none of the pa- tients with persisting tumor, the local tumor was controlled by radiotherapy. In the group of the remain- ing patients who presented a complete regression of the primary tumor however, more than 20% experienced a local recurrence after curatively intended radiotherapy.

1

0.8

0

1 ‘, ’

L IL. c)

0 1 2 3 4 5

Time in years

Fig. 1. The figure demonstrate local control after definitive radiotherapy as estimated by the final prognostic model described in the text. (a) Estimated local control for the most favourable case: a fe- male with a primary grade well small size (less than 5 mm in diameter) laryngeal tumor. (b) Estimated local control for an intermediate case: a male with a primary moderately grade medium sixe (S-10 mm) laryngeal tumor. (c) Estimated local control for the most adverse case: a male with a primary poorly grade large size (lo-30 mm) laryngeal tumor.

4. -aa

The present study is a retrospective analysis perform- ed on 161 patients treated with definitive radiotherapy of Tl laryngeal carcinoma in order to identify factors prognostic for local control.

Five-year local control rates following definitive radiotherapy of Tl glottic laryngeal carcinoma are reported in the range of 80-93% [6,8,14-161, which is consistent with the confidence interval of the correspon- ding local control rate in the present study. Local con- trol rates similar to the ones observed in this study has been reported by others using analogous treatment regimes [12] including another Danish centre who reported a 5-year local control rate of 76% for Tl glottic tumors [17]. Applying salvage surgery the ultimate 5- year control glottic tumors is reported in the range 90%-98% [3,6,14,16-191 in close agreement with the result in the present study.

Five-year local control rates following definitive radiotherapy of Tl supraglottic laryngeal carcinoma are reported in the range of 69%-84% [6,20-221, which again does not significantly differ from the confidence interval of 37%-78% of local control in the present study.

From a radiobiological viewpoint the probability of local control depends on the number of clonogenic cells, their radiosensitivity and the biologically effective dose delivered [23]. Several studies has identified tumor size as a prognostic factor of local control (3-51. Correspon- dingly increasing tumor diameter was found to be a sig- nificant adverse prognostic factor of local control in the present study. Parameters as vocal cord immobilization and aryepiglottic extension identified as adverse prog- nostic parameters in other studies [6-91 may in reality be alternative measures of tumor size, thus confounding this factor.

In the present study the multivariate analysis demonstrated sex and grade to be independent prog- nostic factors, as shown in other studies [4,24]. The age of female patients was significant lower than for male patients, and eventhough the multivariate analysis in the present study demonstrated sex to be more important than age, the result should be taken with caution due to a low female to male ratio in the study. Correspondingly other studies has reported age as a independently prog- nostic parameter [2,25].

The multivariate analysis in the present study did not demonstrate any significant influence of given radiation dose or treatment time on local control rate. The failure to demonstrate any dose response relation was partially due to the fact that the major part of doses applied was in a narrow range, actually less than two Gy, leading to a consequently small expected rise in local control judg- ed on the steepness of clinical dose response curves [26]. Furthermore the correlations between dose, treatment

232 C. Jesper et al. /Radiotherapy and Oncology 39 (19%) 229-233

time and tumor size, may have confounded any dose or treatment time influence on local control in tumor size as the predominant prognostic factor.

An evaluation of treatment response, three to six weeks following accomplishment of radiotherapy, demonstrated that remaining tumor at the time of evalu- ation was an indicator of failure in local control in ac- cordance with other studies [3,12,13]. In the present study this observation was of little practical clinical value as 23% of the patients, despite presenting a com- plete regression of the tumor, experienced a local re- currence.

Local control rates following radiotherapy in the present study were not significantly different from what is reported elsewhere, however the confidence intervals of local control rates overlapped in the lower range of the intervals reported in the literature. This indicates the need for intensification of treatment in order of increas- ed dose and shortened treatment time for patients with adverse prognostic factors identified in the present study. Furthermore estimates of tumor size could be replaced by more accurate objective measures of tumor size as by CT imaging as reported recently [27].

In conclusion, the present study demonstrated tumor size, grade and sex as significant independent prognostic parameters of local control in 161 patients treated with definitive radiotherapy of Tl laryngeal carcinoma.

Acknowledgements

This study was supported by the Danish Cancer Society.

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