The influence of some factors on local control of early glottic cancer

Clinical Oncology(1991) 3:330-334 © 1991 The Royal College of Radiologists

Clinical Oncology

Original Article The Influence of Some Factors on Local Control of Early Glottic Cancer J. Krawczyk, V. Svoboda and L. Foster Department of Radiotherapy and Oncology, St Mary's Hospital, Portsmouth, UK

Abstract. A total of 135 patients with TINoM0 and T2NoM0 carcinoma of the vocal cord were treated during a 20-year period at St Mary's Hospital in Portsmouth by local radiotherapy. A total of 122 patients were available for local control analysis. The local control of T1 tumours was 80.5%, and for T2, 51.1%, total TI+T2 local control was 69.7% (P<0.001). The only other factor in univariate analysis, which influenced the results was the overall treatment time. In the group of patients treated by an overall time of 45 days or less, the local control was 83.7%. For longer time it was 62% (P<0.02). Multivariate analysis confirmed these findings but brought out the importance of vocal cord mobility as the best discriminating factor between localcontrol and failure, followed by overall treatment time. Keywords: Glottic cancer; Radiotherapy; TI-2NoMo; Overall treatment time; Vocal cord mobility

INTRODUCTION

Radiotherapy is a main modality in the treatment of early vocal cord carcinoma (Kim et al., 1978; Olszewski et al., 1985; Perez and Brady, 1987; Sinha, 1987; Mendenhall et al., 1988; Lusinchi et al., 1989; Van Acht et al., 1989). The lack of lymphatic drainage and the accessibility to inspection makes an early glottic tumour very suitable for analysis of local treatment results. However, some factors, such as the overall treatment time, are rarely analysed in papers reporting on radiotherapy of laryngeal carcinoma (Maciejewski et al., 1983; Correspondence and offprint requests to: Dr V. Svoboda, Department of Radiotherapy and Oncology,St Mary's Hospital, Portsmouth, Hampshire, UK.

Mendenhall et al., 1984; Kaercher et al., 1987; Overgaard et al., 1988; Van Acht et al., 1989), and have never been described for T1 and TzNoM0 vocal cord lesions. The purpose of this retrospective analysis is to find the relationship between the dose, time, fractionation and stage of the disease and the likelihood of local control. This analysis was possible because during the last 20 years this department has used several types of fractionation, but with similar treatment volumes and techniques.

MATERIAL AND METHODS

Patient Characteristics A total of 135 patients with TINoM0 and T2NoM0 squamous cell carcinoma of the true vocal cord were seen in the Department of Radiotherapy at St Mary's Hospital, Portsmouth, between 1 January 1966 and 31 December 1985. Of these 135 patients 115 (85%) were men and 20 (15%) women. The mean age of the patients was 64 years (range 33-87 years). Patients were followed-up until death or until 31 October 1989. Thirteen patients were excluded from the analysis of primary disease control because they had died without local recurrence but with intercurrent disease (two patients), unknown causes (nine patients), or had laryngectomy prior to radiotherapy (one patient) less than 3 years from the initial treatment. We also excluded from this analysis one patient who died with mediastinal node metastases after 48 months, there being no adequate information about possible local recurrence. However, all these patients were included in the analysis of survival. Twelve patients were followed up for less than 5 years. These patients were included in all statistics up to 4 years from first day of treatment.

Factors Influencing Local Control of Early Glottic Cancer

Staging The tumours were staged according to the UICC classification criteria. All patients had both direct and indirect laryngoscopy. Laryngeal tomograms were performed in 64% of the patients (47% in Tt tumours, and 90% with T2 tumours) and soft tissue lateral films were taken in 31% of patients. There were 83 patients with TINoM0 tumours and 52 with T2NoMo t u m o u r s .

Treatment All patients were treated either with a cobalt-60 teletherapy unit or 4 MeV linear accelerator in the supine position with parallel opposed lateral fields (in 74% of patients), or an anterolateral wedged pair (26%). The whole larynx was treated, but no attempt was made to treat the lymphatic drainage areas. Field sizes ranged from 4x4 to 8×6 cm, but the most common for both T1 and T2 tumours were 6x4, 6x5 and 5x5 cm. The mean values for both stages were 29 c m 2. Ten patients were treated with accelerated fractionation (three fractions per day, dose per fraction from 162 cGy to 212 cGy, minimum interval between the sessions being 3 h, overall time 1118 days). One patient was treated with six large fractions over 18 days, a total dose of 30 Gy. All the remaining patients received daily treatments to a total tumour dose which varied between 7020 cGy and 5500 cGy. The dose per fraction was between 226 and 150 cGy. The overall time ranged between 34 and 66 days.

Statistics All the factors potentially influencing local control were analysed in univariate fashion followed by multivariate analysis to assess variables which may best predict local control (Fisher, 1936).

RESULTS

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83.3% for the whole group of 135 patients, 79.9% and 96.1% for 83 patients with T1 disease, and 52.9% and 63.2% for 52 patients with stage T2 disease. This includes 29 patients who underwent salvage surgery (13 patients with T1, 16 with T2 tumour). The 5-year actuarial survival after salvage surgery was 55.5% for stage T1 and 54.3% for T2.

Local Tumour Control As we were interested mainly in local control, only the 122 patients who were suitable for such assessment were then analysed. There were 37 local failures (residual disease or recurrence) in this group (30.3%). The mean time of local recurrence was 17.5 months, with five recurrences (13.5%) after more than three years. The local control rates with the minimum followup of three years, are presented according to the stage, total dose, dose per fraction, histology and the overall treatment time in Tables 1-5 respectively. There is no difference in local control between stage Tla and Tlb (79.6% and 82.6% respectively). For the group of T1 tumours, local control was achieved in 80.5% and for stage T2 tumours it was 51.1%. (Table 1). The difference is statistically significant (P<0.001). If we look at the total dose (Table 2), the only statistically significant difference is between the doses of ~<60 Gy and all the larger doses. In the first group, there were seven local failures in 42 patients (16.7 % ). In the second group, there were 30 local failures in 80 patients (37.5%), P<0.02. There is no statistically significant difference in the local failure according to the dose per fraction (Table 3). In the group treated by 180 cGy or less, there were 35.6% local failures. In the group treated by larger doses per fraction, the Table 1. Local control by stage of the disease

Local control Local failure

Tla

Tlb

T2

43 (79.6%) 11 (20.4%)

19 (82.6%) 4 (17.4%)

23 (51.5%) 22 (48.9%)

Table 2. Local control by total tumour dose

~<60 Gy

Survival Out of 135 patients 90 were alive five years after the first day of treatment. Five-year survival without evidence of recurrence was achieved in 63 out of 83 patients (76%) in stage T1, and in 27 out of 52 patients (52%) in stage T2. The 5-year actuarial survival and the ageadjusted survival were respectively 69.5% and

61-64 Gy 65-68 Gy >69 Gy

Local control 35 (83.3%) 4 (50%) Local failure 7 (16.7%) 4 (50%)

5 (71.4%) 41 (63.1%) 2 (28.6%) 24 (36.9%)

Table 3. Local control by dose per fraction

Local control Local failure

~<180 cGy

181-200 cGy

>200 cGy

38 (64.4%) 21 (35.6%)

35 (74.5%) 12 (25.5%)

12 (75%) 4 (25%)

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figure was 25.4% ( P > 0 . 2 ) . No relation was found between the degree of differentiation and the local control (Table 4). Local control was, however, related to the overall t r e a t m e n t time (Table 5) being i m p r o v e d for shorter overall time. The t u m o u r was locally controlled in 36 out of 43 patients (83.7%) if the overall time was 45 or fewer days, and in 49 out of 79 patients (62%) treated in m o r e than 45 days (P<0.02). The differences in local control for stages T1 and T2 are shown in Tables 6 and 7.

Table 8. Field size and local control Stage

T1

T2

Table 4. Local control and tumour differentiation Differentiation Good

Moderate Poor

Not given Other a

Local control 28 (70%) 29 (69%) 5 (50%) 19 (76%) 4 (80%) Local failure 12 (30%) 13 (31%) 5 (50%) 6 (24%) 1 (20%) a 4 carcinoma in situ, 1 verrucous carcinoma

Table 5. Local control by overall treatment time in days

Local control Local failure

~<40

41-45

46-50

51-60

i>61

17 3

19 4

4 4

38 24

7 2

Table 6. Local control by overall treatment time for T1 tumours

Time >45 days Time ~<45days P>0.1

Control

Failure

% control

32 30

11 4

74.4 88.2

No significant difference.

Table 7. Local control by overall treatment time for T2 tumours

Time >45 days Time <~45days P>0.2

Control

Failure

% control

17 6

19 3

47.2 66.7

No significant difference.

To exclude other factors which could contribute to these results we have also checked the influence of the field size, t r e a t m e n t technique and, for the T2 tumours, vocal cord mobility. Local control was achieved in 63/91 patients (69%) treated by parallel o p p o s e d fields, and 22/31 (71%) patients treated by anterolateral oblique fields. T h e r e was therefore no significant difference between these two techniques. Table 8 presents the relationship between the

TI+T2

Fieldsize (cm2)

Number of patients Total

Analysed

<20 20-25 26-30 31-35 36--40 >40 23-25 26-30 31-35 36-40 >40 <25 25-30 31-35 36-40 >40

1 37 19 11 11 4 17 17 14 2 2

1 33 17 11 11 4 16 14 13 0 2

Local control (%) 0 82 (27/33) 82 (14/17) 82 (9/11) 91 (10/11) 50( 2/ 4) 44 (7/16) 64 (9/14) 54 (7/13) 0 ( 0/ 2) 68 (34/50) 74 (23/31) 67 (16/24) 91 (10/11) 33 ( 2/ 6)

field sizes and the local control rate for stage T1, stage T2 and for the whole group. Again, we found no significant influence of field size on local control. In 42 out of 45 patients with T2 tumours we were able to check the vocal cord mobility. R e d u c e d mobility was associated with p o o r e r prognosis, as only 39.1% of the patients (9/23) had local control. T 2 tumours with full mobility were controlled locally in 68.4% (13/19 patients) (P=0.056). It is possible, that the better results for patients with shorter overall t r e a t m e n t time could be related to uneven distribution of this prognostic factor. In fact, m o r e patients with reduced vocal cord mobility were treated in shorter overall time (6/9, 66.7%), than in longer overall time (17/33, 51.5%). Better results were nevertheless obtained in patients treated faster despite their group being prognostically less favourable. T h e multivariate procedure of stepwise discriminant analysis was then applied to the data to seek that combination of explanatory variables or prognostic factors which might best predict local control. This procedure requires influential variables to be sequentially tested for inclusion into a regression-like model. The significance of each prognostic factor is adjusted for those already present in the model, thereby reducing the confounding effect of correlated variables. O f the eight prognostic factors (total dose, overall t r e a t m e n t time, dose per fraction, histology, vocal cord mobility, treatment field size, t r e a t m e n t technique), vocal cord mobility was that variable which best discriminated between local control and failure (P<0.001) followed by overall t r e a t m e n t time of 45 days or less and m o r e than 45 days (P=0.035). O t h e r variables were not significant.

Factors Influencing Local Control of Early Glottic Cancer

DISCUSSION

Our material is relatively homogeneous because only early tumours of similar site and histology were assessed. Both lymphatic and haematogenous spread is rare (Kim et al., 1978; Woodhouse et al., 1981; Mittal et al., 1983; Perez and Brady, 1987; Lusinchi et al., 1989). The treatment techniques were similar and the differences between them did not influence the results, so that the only treatmentrelated variables were the total dose, dose per fraction, and overall treatment time. We did not find any connection between the degree of histological differentiation and the probability of local control. Similar results are reported by Lusinchi et al. (1989) and Van Acht et al. (1989). However, Olszewski et al. (1985) found differently. The dose per fraction in our material did not influence the local control. This finding was confirmed by Maciejewski et al. (1983) and Lusinchi et al. (1989), but not by Schwaibold et al. (1988). In the latter paper, however, there is not sufficient information about the overall treatment time; it is possible, that the poorer results achieved in the group of patients treated by 180 cGy per fraction were due to a longer overall treatment time. In our material, two factors in the univariate analysis influenced the local control, namely the stage of the disease, and the overall treatment time. In the multivariate analysis, stage of the disease is less significant than vocal cord mobility. The duration of treatment (~<45 days vs >45 days) was the only other variable introduced into the model (P=0.035) with short treatment times having a beneficial effect. However, considering the duration of treatment as a continuous rather than a dichotomous variable resulted in a reduction of its level of significance (P=0.155). The remaining six variables, when adjusted for mobility and treatment duration, offered no significant additional information regarding prognosis. Our local control results in T 1 tumours are comparable with the results of other centres (Woodhouse et al., 1981; Mittal et al., 1983; Olszewski et al., 1985; Missailidou et al., 1986; Sinha, 1987; Schwaibold et al., 1988; Lusinchi et al., 1989; Van Acht et al., 1989) and only slightly worse than the results of Kim et al. (1978) and Mendenhall et al. (1988). Our results of T2 tumour therapy on the other hand are worse than is usually reported (Kim et al., 1978; Harwood and DeBoer, 1980; Missailidou et al., 1986; Karim et al., 1987; Sinha, 1987; Howell-Burke et al., 1988; Mendenhall etal., 1988). However our results are remarkably similar to those from San Francisco (Woodhouse et al., 1981) where local control for T2 tumours was 52%. They used a

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dose of 180 cGy per fraction, indicating a long overall treatment time. Surprisingly, in our material, total doses of 60 Gy or less are associated with better results than larger doses. The only explanation seems to be the fact that the majority (81%) of these patients were treated with a short overall time thus reducing the repopulation of the clonogenic cells during the course. Such a conclusion is supported by some results of treatment of more advanced or differently located laryngeal carcinoma (Maciejewski et al., 1983; Mendenhall et al., 1984; Kaercher et al., 1987; Overgaard et al., 1988; Van Acht et al., 1989). We are probably looking at the expression of a general rule in head and neck cancer as illustrated by Withers et al. (1988); namely, that the longer the overall treatment time, the worse the results.

CONCLUSIONS 1. Vocal cord mobility as a prognostic factor is more informative than the tumour stage. 2. The only other variable influencing prognosis is overall treatment time with shorter treatment times having a beneficial effect. Acknowledgements. Dr J. Krawczyk holds a grant from the Cancer Research Campaign. The authors wish to express their gratitude for this generous support, and also for the help of Mrs F. Morris, who assisted with the statistical evaluation and did the language correction. We are also indebted to Mr B. Higgins of the School of Mathematical Studies at Portsmouth Polytechnic for multivariate analysis of our data.

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Received for publication October 1990 Accepted February 1991