Radiotherapy and Oncology. 13 ( 1988) IFI- I79

Elsevier 175

RTO 00504

Xavier Panis, Liliane Demange, ominique Froissart and Tan

Dc~plrrtnwt of R~tdiotharctpy, hstitrrt JecwGodirrcrt I BP 171, 51056 Reiuu Ccdcx. Frmce

(Rcccivcd 17 Scptcmbcr 1987. revision rcccivcd 24 February 19X8. accepted 29 April 1988)

Kq words: Mead and neck; Squamous cdl carcinoma: Fcmalc C:ISOS; Tobacco: Prognosis

--

Between 1970 and 198595 women presenting carcinomas of the oral cavity, pharynx or larynx, were treated at the Institut Jean-Godinot. Classification of these patients according to age shows a bimodal curve and the existence of two different populations. The main difference between groups appears to be the existence or not of tobacco intoxication. According to this criteria, the two groups of patients are statistically different in mean age (nonusers 16 years older than users, p < 0.01) and in the site of the primary, with an excess of carcinomas of the oral cavity in the nonusers group QI < 0.01). In contrast, no difference was found in the locoregional extension of the tumor (TNM), in the modalities and result of treatment or in the evolution

and survival of patients.

Ol67-8140/88/$03.50 0 1988 Elsevier Science Publishers B.V. (Biomedical Division)

introduction

It has been known for a long time that development

of squamous cell carcinomas of the upper aero- digestive tract (SCC-UADT) is widely influenced

by tobacco and alcohol exposure and it has been known for even longer that they occur essentially in men. Nevertheless, cases in women are tending to be more frequent, which gives some interest in

* Presented at the 6th annual meeting of ESTRO. Lisboa. Por-

tll@l, May 25528. 1987.

Addres.~.for correspondence: Dr. X. Panis. Dcpartmcnt of Radio-

therapy, Institut Jean-Godinot. BP 171. 51056 Reims Ccdex.

France.

studying the characteristics of this group of patients.

efinition of the stu ulation

Between 1970 and 1985, 158 women were treated at the Institut Jean-Godinot for SCC-UADT, rep: resenting 7% of the ihole population of patients seen for the same tumors over the same period of

time (2265 cases). Nasopharyngeal and sinusal tumors were exclud-

ed from the study in consideration of wide epide- miological differences. The ages of the 95 remaining

patients ranged from 26 to 88 years with an average of 61.4 years (S.D. 15.7).

176

Distribution of this population according to age (Fig. 1) shows a curve of a bimodal aspect, unusual in this type of tumor. The bimodal distribution is confirmed by the means of a Gaussian analysis, i.e.

- first normal distribution: 58% of patients with an average age of 52.1 years (S.D. 6.7)

- second normal distribution: 42% of patients with an average age of 78.0 years (S.D. 6.3).

Qf the various clinical data which were analyzed in order to find the characteristics which could sep- arate women into two distinct populations, use or not of tobacco appears to be the best in line with the theoretical findings. Therefore, according to this criteria we obtain a first group of 53 patients (55.8%) called tobacco users, with an average age of 54.0 y&ars (SD. 9.8) and a second group of 42 patients called tobacco nonusers (44.2%) with an average age of 70.3 years (S.D. 16.9). Difference in average ages between these two groups of patients (16 years) is statistically significant when using Stu- dent-Fisher r-test (p < 0.01) (Fig. 2). The question at this time is the consequence of this difference at the clinical level.

AS’ (years)

Fig. I. Gaussian analysis confirms the bimodal distribution of this population of patients according to age and then the exist-

ence of two distinct groups of women.

a 14-

12-

2-

ik

Essl Tobacco users cl Tobacco non users

Fig. 2. The differcncc in average age between the two groups of patients, as defined by tobacco use, is statistically significant 0,

< 0.01).

Analysis of the two groups of patients

The two groups of patients as defined by tobacco use were analyzed and compared according to their clinical, therapeutic and survival characteristics. Pretreatment data are listed in Table I, i.e. site of primary, T and N stages according to 1979 TNM classification (all the patients were MO), as were per- formance status on the Karnofsky scale and tumor histological differentiation.

The Pearson chi-square test was used for statis- tical comparison. A statistically significant differ- ence between groups was found on the primary site @ < 0.01) where there appears to be an excess of carcinomas of the oral cavity in the tobacco non- user group of patients. In contrast, none of the other characteristics were significantly different.

Treatment type and modalities (Table II), results of curative trea:meDts. occurrence and site of re- currence (Table III), status of patients at the time of analysis and causes of death (Table IV) were also compared without showing any difference between the two groups of patients.

Survival curves were obtained using the Kaplan- Meier actuarial method (Rothman’s confidence in-

177

TABLE I

Pretreatment characteristics of patients.

Characteristic Tobacco Tobacco

users nonusers

(I? = 53) jr? = 42)

Sire y f‘ pritmrry

Oral cavity 12

Oropharynx 21

Hypopharynx IO

Supraglottic larynx 5

Glottic larynx 3

Unknown (cervical nodes) 2

T-src~gc

TO 3

TI (Y

I.2 15

T3 20

T4 IO

IV-SrnqqJ

N, 23

N, 7

N2 5

NJ 18

Perjbrnitrncc~ sIuIus Kurnf$sk~ rctngc

80-100 41

50-70 11

<50 I

Turnor djflhwtriulirw

Well 40

Moderately 4

Poorly 2

Unknown 7

29

7

4

0

0

2

2 4

IO

15

II

23

6

0

13

26

15

I

2x

I

7

6

TABLE II

Treatment characteristics of patients.

____~_~___ -- ______ ._ ___

Characieris~ics Tobacco Tobacco users nonusers

(/I = 53) (II = 42) ~_^______I .

TI*~(> of trwiom t No treatment I I Palliative 5 7 Curative 47 34

Moriulilii~s if nwittwjt

Chemothcripy alone 3 0 Chcmothcrapy + ra&&erilpy 6 3 Surgery illOllC 1 7

Surgery t r;ldiothcrapy 6 3 RaJi0thilpy illOlIC 36 32

-_I_

TABLE III

Results of curative treatment.

-__I_

Tobacco

users

Tobacco

nonusers

Response to trcatmcnt

(6 months minimum interval) Recurrence ---___

Complele Partial T N T,N

36147 (0.76) 1 i/47 (0.24) 5 2 2

20/34 (0.59) 14/34 (0.41) 3 2 0

DifTerence between groups is not statistically significant.

- Tobacco users . ..-.. Tobacco non users

Months

Fig. 3. Using log-rank test, no difference has been found in the

survival of the two groups of patients.

TABLE IV

Status of patients at time of analysis: causes of death.

_. __--

status CdUSCS Of death _l_-_

NED DCD T M OC ID UK -”

Tobacco users 16 37 26 I -- 5 -i

Tobacco nonusers 8 34 27 2 I I 3 ___.__--_ . _l__-__ ___.

NED = alive with no cvidcncc of discasc; DCD = dcccascd: T

= locoregional disease; M = distant metastasis only; OC =

other c.mccr; ID = intercurrent discasc; UK = unknown WJSC.

178

- Tobacco users .. Tobacco ncm users

Months

Fig, 4. Even limited to patients with oral carcinoma, the com-

prison of survival did no! show uny dilfcrcncc bctwccn groups of puticnts.

terval at 95%) and compared with a two-sided sum- mary chi-square (log-rank) test. The first couple of curves (Fig, 3) were obtained from the whole group of patients: the second couple (Fig. 4) were restric- ted to patients with carcinoma of the oral cavity, assuming that this previously detected difference between groups of women could result in a differ- ence in survival. However, no statistically signifi- cant difference was found either in the whole popu- lation or in patients with tumor of the oral cavity.

Bkmssion

Our population of women represents 7% of the whole population presenting SCC-UADT. There- fore, the evolution of this rate over the 16 year study period needs to be analysed in detail. Indeed, comparison of the two intervals 1970-1977 and 1978-1985 shows an increase from 5.25 to 8%. Re- garding the site of the primary, this enlargement of the relative number of cases in women appears es- sentially in oral and pharyngo-laryngeal tumors classically related to tobacco use, where the rate in- crease from 2.75 to 5% over the periods 1970-1977 and 1978-1985 respectively. By contrast, tumors of cavum and facial sinuses remain quite stable, i.e. 2.5 and 3% over the same periods of time.

If we now consider the 55.8% global rate of to- bacco users in our studied population, we find a similar increase, from 36.5% over the 1970-1977 period to 61.5% over that of 1978-1985. The ex-

tension of the female population with SCC-UADT appears in our series essentially in tobacco-related tumors and corresponds to an increase in the per- centage of patients who smoke. Therefore, there is no evidence to assume that this increase is the consequence of modifications in our own recruit- ment of patients or in the behavior of the general population of women regarding tobacco.

Existence of a twofold population related to to- bacco use in women with head and neck carcinoma has been previously reported by Daly et al. [3] in 95 patients (nonusers II years older than users) and by ourselves in a smaller series of 34 patients (non- users 15 years older than users).

In the current study, observation of a bimodal distribution according to age in women with SCC-UADT has been also related to tobacco use and the two groups of patients have been com- pared. Therefore, two remarks can be made regard- ing this heterogeneity:

(I) In Fig. 2; age distribution of nonusers and users, few patients out of the middle-aged group and 3 out of the 4 younger patients appear as having never smoked. If we except a hypohesis of incorrect information we can admit the existence of a third group of patients hidden to statistical analysis by its smallness. Then, women with SCC-UADT could be separated into three distinct groups according to age and tobacco use, the youngest and the oldest having never smoked. (2) The number of women who smoke increased progressively in our series during the 1970-1977 and 1978-1985 intervals of time. This constant in- crease is probably going to erase the multimodal distribution of this population in the near future by overshadowing the nonsmoker groups of patients. This is suggested by the study of the equivalent population of men where we found 98.5% of smok- ers. In this population, the average age is 58.0 years (SD. 11) similar to the 54.0 years average in the group of women who smoke.

Detailed comparative analysis of clinical, thera- peutic and survival data find the site of tumor as the only difference between the two groups of patients as defined by tobacco intoxication, with an

excess of oral carcinomas in the nonuser group. Even limited to these cases, the study does not show any difference in patients’ prognosis. No compari- son has been made with the male population due to lack of available data for valuable statistical analysis.

Tobacco, smoked or chewed, all the more when associated with alcohol, is a well-known carcino- genic agent of the upper aero-digestive tract

[5,10,14]. Its responsibility in head and neck carcin- ogenesis is once again confirmed in our study when considering the decrease in the average age of ap- pearance of these tumors in the smoker group of patients (54.0 years) in comparison with that of

nonsmokers (70.3 years). So what about this part of our population with

carcinoma but without a previous history of tobac- co intoxication? Only supposition can be made through data from litterature with regard to the origin of these tumors [1,2,4&l.

_ a viral agent such as human papillomavirus [I 1,151 or herpes simplex virus [ 11,121

- a genetic link as suggested by the association of head and neck carcinoma with genetic dis- eases such as Fanconi’s anemia [7.9], xeroder- ma pigmentosum or bilateral retinoblastoma

c131*

The following hypothesis could be advanced: a double speed carcinogenesis in head and neck car- cinomas, rapid in exceptional cases, occurring in the young and perhaps related to genetic disorders. Though slow in the majority of patients, it may eventually be of viral origin and be accelerated by exposure to tobacco and alcohol acting as cocar- cinogens.

1

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6

7

8

9

IO

II

I2

13

I4

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adon, E. Prcvcntion ofcanccr of the oral cavity and phar- ynx. CA 37: 49--Q. 1981.

Binnie, W.H.. Rankin, K.W.. Mackenzie. I.C. Etiology of oral squamous cell carcinoma. J. Oral. Pathol. 12: I l-29. 1983.

Dalcy, N.J.. David. J.M. and Combes. P.F. Epith~liomas

epidermoides des voies acrodigestives supbricures chez la

femme. Ann. Oto. Laryngol. 99: 397401. 1982.

Decker. J. and Goldstein. J.C. Current concepts in otoldr-

yngology: risk factors in head and neck cancer, N. Engl. J. Radiat. 306: lI5l--I 154, 1982.

Flamant. R.. Lassere, O., Lazar. P., Leguerinais, J.. Denoix.

P. and Schwartz. D. DilTercnccs in sex ratio according to

cancer site and possible relationship with USC of tobacco and

al&ol. Rcvicw OT 65000 CiiSCS. J. Natl. C’anccr Inst. 33:

1309-1316. 1964.

Kaplan, M.J.. Sabio. I I.. Wnncho. H.J. and Cantrcll. K.W.

Squamous cell carcinoma in the immunosupprcssed patient:

Fanconi’s anemia. Laryngoscope. 95: 771-775, 1985.

Keane. W.M.. Atkin. J.P.. Wetmore. R. and Vidas. M. Epi-

demiology of head and neck cancer. Laryngoscopc 91:

2037-2045. 1981.

Panis, X.. Nguyen, T.D.. Pauchet. P.. Legros, M. and Des-

phieux. J.L. Carcinome ipidermoide des voies a&o-diges-

tives chez la femme (oesophage exclu). J. Fr. Oto. Rhino-

Laryngol. 33: 321-325. 1984.

Reed. I(., Ravikumar. T.S.. Gilford. R.R.M. and Grage.

T.G. The association of Fanconi’s anemia and squamous

cell carcinoma. Cancer 52: 926928, 1983.

Rothman. K.J. Epidemiology of head and neck Cancer. Lar-

yngoscopc 8X: 435437, 197X.

Scully. C. and Ward Booth, P. Oral carcinoma: evidcncc

for viral oncogcncsis. Br. J. Oral. Surg. 22: 367-371, 1984.

Shillitoe, E.J., Greenspan, D., Greenspan. J.S. et al. Anti- body to early and late antigens of herpes simplex virus type

1 in patient with oral cancer. Cancer 54: 266-273, 1984.

Usenius, T., Karja, J. and Collan. Y. Squamous cell carci-

noma of the tongue in children. Cancer 60: 236-239. 198’7.

Winn. D.M.. Blot, W.J.. Shy. C.M., Pickle. L.W.. Toledo. A. and Fraumeni. J.F. SnulTdipping and oral CilllCCr illllOlVJ

women in the SouthCrll United States. N. Engl. J. Med. 304:

745-749. 198 I. Zur Hau.qen. H. Papil!omaviruses in human Ci-lIlCcTS. CallCCr

59: l692- E696. 1987.