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Survival analysis in a sample of oral cancer patients at a reference hospital in Rio de Janeiro, Brazil
34 ORAL ONCOLOGY
Oral Oncology 34 (1998) 347±352
Survival analysis in a sample of oral cancer patients at a reference hospital in Rio de Janeiro, Brazil I.C.G. Leite *, S. Koifman Department of Epidemiology, National School of Public Health, FIOCRUZ, Ministry of Health, Brazil Received 13 October 1997
Abstract This article gives the results of a 5-year survival analysis of 371 oral cancer patients who received medical care at a cancer reference hospital in Rio de Janeiro between 1986 and 1987. Patient pro®les based on selected risk factors for oral cancer and 5-year survival based on prognostically relevant variables are described. # 1998 Elsevier Science Ltd. All rights reserved. Keywords: Oral cancer; Survival analysis
1. Introduction Stell [1] comments that a number of overall advances in oncology in the past 25 years have not been seen speci®cally in head and neck cancer. According to that study, the most signi®cant progress in this area involved reconstruction and rehabilitation, which no doubt improved quantitative and qualitative survival. Most oral cancer deaths occur within 2 years, and 5-year survival can virtually be considered the equivalent of cure. Janot et al. [2] classify prognostic factors in head and neck squamous cell carcinoma as patient-related, tumour-related, and/or treatment-related. Jones [3] comments that few studies have been performed on prognostic indicators for survival in oral cancer. Few of these studies have been conclusive, while most have merely analysed treatment results and generally suer from biases in their de®nition of surgical treatment. As a whole, little attention has been paid to prognostic factors aecting oral cancer survival. Oral cancer is frequent in Asia (India, Singapore, and other countries of that region), representing some 50% of all diagnosed cancers. Incidence rates in Brazil for men are almost ten times higher than for women, as observed in population-based cancer registries. Based on studies of hospital registries with regard to anatomical cancer sites, oral cancer was the ®fth most common * Corresponding author. Federal University at Juiz de Fora-MG, Av, BaraÄo do Rio Branco, 1519/201 Juiz de Fora Gerais, Brazil. 1368-8375/98/$19.00 # 1998 Elsevier Science Ltd. All rights reserved. PII: S1368 -8 375(98)00019 -0
cancer for men and the seventh most common for women at the Cancer Hospital/National Cancer Institute (Rio de Janeiro, 1990), and the most common at a cancer reference hospital in Salvador (Bahia, 1991). This paper presents general characteristics of oral cancer 5-year survival in a sample of hospital patients in Rio de Janeiro. 2. Patients and methods The aim of this study was to describe 5-year survival of a group of patients with oral cancer (ICD-O 140± 145) identi®ed at the National Institute of Cancer (INCA), in Rio de Janeiro, Brazil, during the period between 1 January 1986 and 31 December 1987. We also attempted to de®ne the most signi®cant survival variables for this group in terms of anatomical location and treatment modality. Study variables were based on data obtained from a review of patient records and included the following: gender, age (<50, 50±70, and >70 years), race (white or non-white), stage (I±IV), anatomical site (lip, tongue, salivary gland, gums, ¯oor of mouth, and other unspeci®ed parts of the mouth), lymph node involvement (0, 1, and 2), presence or absence of distant metastasis, histopathological type, presence of histological dierentiation, and selected lifestyle habits (smoking and drinking). All 375 cases had histopathological and clinical con®rmation of oral cancer. Preliminary univariate analysis of this patient population was performed,
348
I.C.G. Leite, S. Koifman/Oral Oncology 34 (1998) 347±352
followed by survival analysis including tracing of Kaplan±Meier curves (univariate analyses) and Cox's regression (multivariate analysis). Cases submitted to prior treatment and histopathological types other than carcinomas were not included in the survival analysis, which was, therefore, performed on 371 patients. The start of follow-up was de®ned as the reported date of clinical suspicion recorded in the respective patient record. 3. Results The general characteristics of the 375 oral cancer patients are shown in Table 1. We observed an overall male/female ratio of 3.22 in this sample. A lower speci®c-site gender ratio was observed for other parts of the mouth (1:1.8) and salivary glands (1:2.0). The mean age among all cases was 58.6 years (47 years for salivary gland cancer and 60 years for lip cancer). A data review showed that 74.0% of cases were either illiterate or had not completed primary school (8th grade). Only 1.1% of the entire patient population (4 cases) had at least some university training. Occupational activity showed a preponderance of retired workers (22.6% of cases), followed by bricklayers (7.3%), small farmers (4.0%), shopkeepers (6.2%), and Table 1 Descriptive characteristics of oral cancer patients, Cancer Hospital/ INCA, Rio de Janeiro, 1986±1987 Variable Gender Female Male Age (years) <50 <50±70 >70 Stage I II III IV Anatomical site Lip Tongue Salivary gland Gums Floor of mouth Other unspeci®ed parts of the mouth Regional lymph node involvement 0 1 2 3 Distant metastasis 0 1
Percentage 23.7 76.3 28.0 52.3 19.7 8.6 10.5 31.0 49.9 10.2 35.6 4.0 6.7 11.9 31.5 45.8 27.1 11.8 15.3 95.6 4.4
drivers (3.8%). Housewives were the largest contingent among female patients. There was a strong correlation between cancer mortality and clinical stage at diagnosis (w2=81.87, P<0.001): 18.1% of stage I cases died, compared with 65.4% of cases diagnosed as stage IV. Ninety-®ve per cent of all cases were histologically proven squamous cell carcinomas and lymphoepithelial carcinomas. The remainder consisted of salivary gland tumours, whose predominant histological forms (59.3% of all cases) were adenoid cystic or mucoepidermoid carcinomas. Sixty-seven per cent of cases were classi®ed as well- or moderately-dierentiated tumours. There was a strong association between histological grade and lymph node involvement (P<0.01; w2=44.26, 9 d.f.). Lifestyle analysis showed that 76.5% of the cases were smokers and 8.1% were former smokers. The association between smoking and death as outcome was statistically signi®cant (P=0.01, w2=6.5). Among cigarette smokers, the mean daily consumption was 24.38 cigarettes, and the mean duration of the smoking habit was 39.4 years. Smokers displayed a higher oral cancer mortality risk than non-smokers (odds ratio (OR)=1.88; con®dence interval (CI)=0.5±3.7). Alcohol intake was reported by 59.3% of cases, and of these, 69.1% reported using distilled beverages. The same mortality pattern observed for smokers as compared with non-smokers was seen for drinkers versus nondrinkers (OR=1.85; CI=1.19±2.94). Higher alcohol intake was observed among males (75.7%), although among female cases who reported drinking, 75.2% did so on a daily basis. Daily alcohol intake was reported by only 21.6% of all cases. The association between alcohol intake and anatomical site was striking (over 60% of cancers of the tongue, lips, and ¯oor of the mouth occurred in regular drinkers); nevertheless, this pattern was not observed for salivary gland tumours. Death was more common among daily drinkers as compared with occasional ones (OR=2.55; CI=1.46±4.47). Men were at higher risk than women with regard to exposure to alcohol and tobacco (OR=5.88; CI=3.85±9.09 for smoking; OR=11.11; CI=7.14±20.0 for alcohol intake). The mean time between patients reporting initial symptoms and histological con®rmation of cancer was 15.8 months. The mean time between clinical suspicion and histological con®rmation was 43% shorter, 9.4 months. Prior treatment of these cancers was reported by 7.8% of cases, who experienced better survival than the others (OR=1.57; CI=0.67±3.42). The most prevalent treatment was radiotherapy (43.7%). Excisional surgery was more frequent in lip cancer (75.0%), and chemotherapy was employed in only 1.7% of all cases.
I.C.G. Leite, S. Koifman/Oral Oncology 34 (1998) 347±352
3.1. Survival analysis The mean overall survival time for this group of patients was 29.8 months (27.7±31.9). However, lip and salivary gland cancer showed a better prognosis (5-year survival > 60%). Mean survival as a function of patient characteristics and tumour/treatment variables is shown in Tables 2 and 3. Survival curves based on anatomical location were statistically dierent (log rank=24.27; P<0.001). The best prognosis was observed for salivary gland tumours (47.5 months) and lip cancer (44.6 months). The worst prognosis was seen in tumours of the tongue (25.4 months), one of the most prevalent oral cancer sites in Brazil. Mean survival curves for each anatomical site are shown in Fig. 1. 3.2. Multivariate survival analysis: Cox's regression Prognostic value for all variables (overall variable in¯uence) on survival in this entire group of patients was ascertained by Cox's regression model. Various selection methods can be used to identify the subset of independent variables related to the dependent variable. First, the in¯uence of variables on survival was analysed with regard to anatomical sites (®ve groups), followed by the inclusion of speci®c treatment modalities (three groups, i.e. surgery, radiotherapy, and others). Cox's regression was performed using the enter method (author's variable selection) and backward stepwise selection, based on compared probabilities of likelihood ratios following comparisons ascertained by Table 2 Survival analysis (Kaplan±Meier method) based on selected variables for oral cancer patients, Cancer Hospital, National Cancer Institute, Rio de Janeiro, 1986±1987 Variable (P value and log rank test) Gender (P=0.14) Females Males Age (years) (P=0.07) <50 50±70 >70 Race (P =0.10) White Non-white Smoking (P=0.01)* Non-smokers Former smokers Smokers Drinking (P<0.01)** Non-drinkers Former drinkers Drinkers * a=5%; ** a=1%.
Survival time, months (95% CI) 29.0 (23.6±34.3) 33.5 (30.4±35.5) 32.8 (27.8±37.8) 34.3 (30.6±37.9) 26.4 (20.7±32.2) 34.8 (31.4±38.2) 28.7 (24.5±33.0) 31.3 (28.3±34.3) 32.9 (23.5±42.3) 39.3 (32.4±46.2) 31.0 (27.5±34.5) 25.1 (16.0±34.1) 37.9 (33.3±42.5)
349
software algorithms. They produced quite similar models, and we present parameters here based on the latter. Variables with P values ranging from 0.05 to 0.10 were kept in the ®nal prognostic model. For both analyses, the initial follow-up time was based on the date of clinical suspicion. Variables selected for the ®nal model were related to patient characteristics and to tumour/treatment characteristics. Figure 2 represents a 5-year survival curve for all patients, with a survival rate just slightly above 20%. After Cox's analysis, relative risks for prognostic variables ascertained from the entire group of oral cancer patients were as follows:
Table 3 Survival time and tumour/treatment variables for oral cancer patients, Cancer Hospital, National Cancer Institute, Rio de Janeiro, 1986±1987 Variable (P value and log rank test) Anatomical site (P<0.01)** Lip Tongue Salivary gland Mouth (143±5) Treatment modality (P<0.01)** Surgery Radiotherapy Chemotherapy Surgery plus radiotherapy Others Stage (P<0.01)** I II III IV Tumour size (T) (P<0.01)** 1 2 3 4 Lymph node involvement (N) (P<0.01)** 0 1 2 3 Distant metastasis (M) (P<0.01)** Absent Present Histopathological type (P<0.01)** Lymphoepithelial or squamous cell carcinoma (1) Adenoid cystic or mucoepidermoid carcinoma (2) Histological dierentiation (P=0.96) Well-dierentiated (1) Moderately dierentiated (2) Poorly dierentiated (3) Undierentiated (4) * a = 5%; ** a = 1%.
Survival time (months) 44.6 25.4 47.5 34.5
(36.7±52.5) (21.7±29.2) (36.1±58.8) (30.5±38.4)
46.2 23.3 24.2 41.2 12.9
(40.9±51.5) (19.9±26.8) (9.1 ±39.2) (36.5±45.9) (5.4 ±20.4)
57.1 45.2 32.6 24.5
(52.0±62.2) (37.3±53.2) (27.7±37.5) (21.0±27.9)
52.6 37.7 30.3 24.4
(45.8±59.4) (31.5±43.8) (25.9±34.8) (20.0±28.7)
42.0 28.3 22.9 16.9
(38.1±46.0) (23.3±33.3) (16.3±29.4) (12.3±21.5)
32.1 (29.3±34.9) 25.2 (15.2±35.3) 31.3 (28.6±33.9) 52.6 (44.0±61.2) 33.4 32.7 33.6 37.6
(27.5±39.2) (29.2±36.2) (21.3±45.9) (37.6±37.6)
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I.C.G. Leite, S. Koifman/Oral Oncology 34 (1998) 347±352
. histopathological type (squamous cell and lymphoepithelial carcinomas versus adenoid cystic and mucoepidermoid carcinomas): b=0.42 (0.19±0.97); . metastasis (present versus absent): b=0.65 (0.58±0.74); . lymph node involvement (present versus absent): b=1.27 (1.14±1.42); . treatment modality (surgery and radiotherapy versus others): b=1.02 (1.01±1.03); . tobacco/alcohol interaction (both present versus both absent): b=1.02 (1.01±1.03); . gender (male versus female): b=0.59 (0.42±0.82); . stage (I versus others): b=1.21 (1.09±1.36). The value of b is the estimate of the change in the dependent variable that can be attributed to a change of
one unit in the independent variable. If the exponential (b) is greater than 1, the odds are increased, while if the value is less than 1, the odds are decreased. It was not possible to de®ne the prognostic variables for salivary gland cancer and for chemotherapy treatment and combined types of treatment (it was not possible to ®t the model to these cases). The most common prognostic variables were lymph node involvement (N) and distant metastasis (M) for all anatomical locations. As lymph node involvement or distant metastasis stage increased, a proportional decrease in survival was observed, except for lip cancer. The gender variable was present in all models. The age at diagnosis was an important predictive factor for surgical treatment (b=2.25; CI=1.37±7.78). Smoking was the variable with the most impressive single
Fig. 1. Function of survival per anatomic site of 371 cases of oral cancer. National Cancer Insitute 1986±1987.
Fig. 2. Function of survival based on prognostic covariates of 371 cases of oral cancer (ICD-O 140±145). National Cancer Institute 1986±1987.
I.C.G. Leite, S. Koifman/Oral Oncology 34 (1998) 347±352
in¯uence on survival in lip cancer (b=12.47). The clinical stage at diagnosis was also an important predictor for survival in both lip tumours and those of other parts of the mouth. Particularly for lip cancer, survival time fell dramatically with higher stages, an eect observed using the Kaplan±Meier analysis. Treatment modality was present in the ®nal regression model for all sites. Surgery and radiotherapy entailed better prognosis as compared with combinations of chemotherapy and radiotherapy and/or other treatment modalities, as well as with any other single treatment. Personal habits (especially drinking) were statistically signi®cant in relation to treatment survival rates. This statistical method can be used to construct a predictive model for oral cancer based on the abovementioned prognostic variables. The model generates a prognosis for a given patient with a speci®c subset of variables. The predictive model for oral cancer was based on stage (N and M variables), the type of treatment (with a better prognosis related to surgery), histopathological type, and individually related variables (such as tobacco/alcohol interaction and gender). The prognostic factors were independent and could be used as such in a predictive model. 4. Discussion The main descriptive characteristics of our oral cancer cases corroborate previous reports from the literature. In this study, the mean age for oral cancer patients was 58.6 years; this ®gure was heavily in¯uenced by salivary gland patients, who were diagnosed at younger ages. The overall mean was similar to the ®ndings of Janot et al. [2], Kabat et al. [4], and Franco et al. [5]. Had salivary gland tumours been excluded, the mean age would have been 60.1 years. Even so, the mean age was lower than the 66 years reported by Antoniades et al. [6], Jones [3], and Overholt et al. [7]. However, the pattern of late involvement of women [6±9] (60.2 years old) as compared with men's age at diagnosis (56.2 years old) was maintained. Traditionally, the literature presents oral cancer as a condition particularly aecting males [8, 10]. The predominant locations have been the lip, mouth, and tongue [1, 10±13] and our study is in agreement with these ®ndings. There is also agreement with regard to the predominant histopathological type, i.e. squamous cell carcinoma [14±16]. Radiotherapy alone was the most common treatment modality, including more than 50% of cases, as observed by Moore et al. [17]. In our analysis, the risk factors most heavily associated with oral tumours were smoking and alcohol. It is important to note that the association was weak
351
between these lifestyle habits and salivary gland neoplasms [17]. Men usually display a better mean survival time than women [18, 19]. Franco et al. [20] commented that women are at greater risk of seeking medical care too late or failing to submit to treatment. Gender was strongly related to survival in our study. While women had a longer mean survival time than men overall, when the data were controlled for tumour site, survival by gender was similar to other reports. We also observed ethnic dierences in survival, as reported elsewhere in the literature, in which non-whites usually have lower mean survival times than whites [21]. In our study, the patient records showed a worse prognosis among non-white patients, an observation that was statistically signi®cant for lip tumours (P=0.03). In terms of lifestyle, the mean survival time among non-drinkers and non-smokers was longer. According to Silverman and Gorsky [15], smoking and drinking entail a much higher risk for developing a new oral cancer. In terms of anatomical location, the worst mean survival time was associated with tumours of the tongue, ¯oor of the mouth, and palate. In the study by Silverman and Gorsky [15], the worst prognosis was for advanced lesions of the tongue (19% 5-year survival). According to other reports, lip cancer has the best prognosis [8, 10]. Beltrami et al. [8] concluded that oral tumours show poor survival (35% 5-year survival) as compared with lip tumours. Boetta et al. [18] described oropharyngeal tumours as having a worse mean survival time than oral tumours. Univariate analysis performed in this study showed that the best survival times occurred for salivary gland and lip tumours (47.5 months and 44.6 months, respectively). Tongue cancer had the shortest mean survival time (25.4 months). Lymph node involvement (N stage) was strongly related to prognosis, corroborating other studies [3, 9, 11], while other authors did not ®nd that this variable was relevant As for tumour size, neoplasms classi®ed as T, had the best likelihood of cure, and this was considered an important prognostic variable in other studies [4, 8, 22]. A trend towards better survival has been observed among patients with no evidence of distant metastasis at the time of diagnosis. A reduction of survival time in association with metastasis is reported by Frierson and Cooper [19], who observed a 50% reduction in survival when metastasis was detected at the time of diagnosis. Our study shows a statistically signi®cant proportional decrease in patient survival time associated with higher tumour stage, except for salivary gland tumours. This variable is commonly described as the most relevant one for prognosis.
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5. Conclusions Our report on survival data from a sample of oral cancer patients in Rio de Janeiro showed the following: (a) Oral tumours entailed moderate mortality, with 29.8 months as the mean survival time. This situation was aggravated by the fact that the most common tumour site (the tongue) was the one with the shortest mean survival time. (b) There was strong evidence of an association between these neoplasms and both smoking and alcohol abuse, while salivary gland tumours had the weakest evidence of association with these two risk factors. (c) The subpopulations at highest risk amongst this group of cancer patients were males aged 40 years and older, drinkers, and heavy smokers, as well as small farmers and construction workers and those with less schooling. We emphasise both the age groups involved, with a trend towards the involvement of younger age groups, probably due to the spread of exposure to risk factors, and the presence of women among the case group for such neoplasms. (d) The main prognostic variables aecting survival were clinical stage (based on tumour size, node involvement, and distant metastasis), gender, advanced age at diagnosis, and treatment modality. Again, we stress the importance of timing in survival-related events (the less time elapsed between initial symptoms, diagnostic suspicion, and de®nition of treatment, the better the mean survival time). Acknowledgements I. Leite is indebted to Dr Antonio Carlos AndreÂs for revising the English manuscript, to Dr Koifman for orientation in this work and Dr Christina C. Rodrigues for her important help during the work. References [1] Stell PM. Cancer of the head and neck: are we doing any better? (letter). The Lancet 1985;nov. 16.
[2] Janot F, et al. Prognostic value of clinicopathological parameters in head and neck squamous cell carcinoma: a prospective analysis. British Journal of Cancer 1996;73:531±538. [3] Jones AS. Prognosis in mouth cancer:tumour factors. Oral Oncology, European Journal of Cancer 1994;30B(1):8±15. [4] Kabat G, et al. The role of tobacco, alcohol use, and body mass index in oral and pharyngeal cancer. International Journal of Epidemiology 1994;23(6):1137±1144. [5] Franco E, et al. Risk factors for oral cancer in Brazil: a casecontrol study. International Journal of Cancer 1989;43:992± 1000. [6] Antoniades DZ, et al. Squamous cell carcinoma of the lips in a Northern Greek population. Evaluation of prognostic factors on 5-years survival rate. Oral Oncology, European Journal of Cancer 1995;31B(5):333±339. [7] Overholt SM, et al. Prognostic factors aecting outcome in lower gingival carcinoma. Laryngoscope 1996;106:1335±1340. [8] Beltrami CA, et al. Progonostic factors in squamous cell carcinoma of the oral cavity. Path Res Pract 1992;188:510±516. [9] Percy C, Dolman A. Comparison of the coding of death certi®cates related to cancer in seven countries. Pub Health Rep 1977;93(4):335±350. [10] IARC Monographs on the Carcinogenic Risk of Chemicals to Humans, Tobacco Smoking, no. 38, 1985. [11] Nair KM, et al. Independent predictors of response and diseasefree survival in oral cancer treated with radical radiation therapy. Cancer 1992;69(9):2221±2226. [12] National Institute of Dental Research. Prevention and early detection: keys to oral cancer. JADA 1993;124:81±82. [13] Stefani E, et al. Hand-rolled cigarette smoking and risk of cancer of the mouth, pharynx and larynx. Cancer 1992;70(3):679± 682. [14] Chen J, et al. Lip cancer. Cancer 1992;70(8):2025±2030. [15] Silverman S, Gorsky M. Epidemiologic and demographic update in oral cancer: California and national dataÐ1973 to 1985. JADA 1990;120:495±499. [16] Smith E. An analysis of cohort mortality from tongue in Japan, England and Wales and the United States. International Journal of Epidemiology 1982;11(4):329±335. [17] Moore C, et al. Evaluation of size in prognosis of oral cancer. Cancer 1986;58:158±162. [18] Boetta P, et al. A population-based study of prognostic factors in oral and oropharyngeal cancer. Oral Oncology, European Journal of Cancer 1994;30B(6):369±373. [19] Frierson HF, Cooper PH. Prognostic factors in squamous cell carcinoma of the lower lip. Human Pathology 1986;17(4):346± 353. [20] Franco E, et al. Race and gender in¯uences on the survival of patients with mouth cancer. J Clin Epidemiol 1993;46(l): 37±46. [21] Sankaranarayanan R, Kerala MD. Oral cancer in India: an epidemiologic and clinical review. Oral Surgery Oral Medicine Oral Pathology 1990;69(3):325±330. [22] Bryne M, et al. Prognostic value of rhesus blood groups in oral squamous cell carcinomas. Cancer 1991;68:2213±2216.
Oral Oncology 34 (1998) 347±352
Survival analysis in a sample of oral cancer patients at a reference hospital in Rio de Janeiro, Brazil I.C.G. Leite *, S. Koifman Department of Epidemiology, National School of Public Health, FIOCRUZ, Ministry of Health, Brazil Received 13 October 1997
Abstract This article gives the results of a 5-year survival analysis of 371 oral cancer patients who received medical care at a cancer reference hospital in Rio de Janeiro between 1986 and 1987. Patient pro®les based on selected risk factors for oral cancer and 5-year survival based on prognostically relevant variables are described. # 1998 Elsevier Science Ltd. All rights reserved. Keywords: Oral cancer; Survival analysis
1. Introduction Stell [1] comments that a number of overall advances in oncology in the past 25 years have not been seen speci®cally in head and neck cancer. According to that study, the most signi®cant progress in this area involved reconstruction and rehabilitation, which no doubt improved quantitative and qualitative survival. Most oral cancer deaths occur within 2 years, and 5-year survival can virtually be considered the equivalent of cure. Janot et al. [2] classify prognostic factors in head and neck squamous cell carcinoma as patient-related, tumour-related, and/or treatment-related. Jones [3] comments that few studies have been performed on prognostic indicators for survival in oral cancer. Few of these studies have been conclusive, while most have merely analysed treatment results and generally suer from biases in their de®nition of surgical treatment. As a whole, little attention has been paid to prognostic factors aecting oral cancer survival. Oral cancer is frequent in Asia (India, Singapore, and other countries of that region), representing some 50% of all diagnosed cancers. Incidence rates in Brazil for men are almost ten times higher than for women, as observed in population-based cancer registries. Based on studies of hospital registries with regard to anatomical cancer sites, oral cancer was the ®fth most common * Corresponding author. Federal University at Juiz de Fora-MG, Av, BaraÄo do Rio Branco, 1519/201 Juiz de Fora Gerais, Brazil. 1368-8375/98/$19.00 # 1998 Elsevier Science Ltd. All rights reserved. PII: S1368 -8 375(98)00019 -0
cancer for men and the seventh most common for women at the Cancer Hospital/National Cancer Institute (Rio de Janeiro, 1990), and the most common at a cancer reference hospital in Salvador (Bahia, 1991). This paper presents general characteristics of oral cancer 5-year survival in a sample of hospital patients in Rio de Janeiro. 2. Patients and methods The aim of this study was to describe 5-year survival of a group of patients with oral cancer (ICD-O 140± 145) identi®ed at the National Institute of Cancer (INCA), in Rio de Janeiro, Brazil, during the period between 1 January 1986 and 31 December 1987. We also attempted to de®ne the most signi®cant survival variables for this group in terms of anatomical location and treatment modality. Study variables were based on data obtained from a review of patient records and included the following: gender, age (<50, 50±70, and >70 years), race (white or non-white), stage (I±IV), anatomical site (lip, tongue, salivary gland, gums, ¯oor of mouth, and other unspeci®ed parts of the mouth), lymph node involvement (0, 1, and 2), presence or absence of distant metastasis, histopathological type, presence of histological dierentiation, and selected lifestyle habits (smoking and drinking). All 375 cases had histopathological and clinical con®rmation of oral cancer. Preliminary univariate analysis of this patient population was performed,
348
I.C.G. Leite, S. Koifman/Oral Oncology 34 (1998) 347±352
followed by survival analysis including tracing of Kaplan±Meier curves (univariate analyses) and Cox's regression (multivariate analysis). Cases submitted to prior treatment and histopathological types other than carcinomas were not included in the survival analysis, which was, therefore, performed on 371 patients. The start of follow-up was de®ned as the reported date of clinical suspicion recorded in the respective patient record. 3. Results The general characteristics of the 375 oral cancer patients are shown in Table 1. We observed an overall male/female ratio of 3.22 in this sample. A lower speci®c-site gender ratio was observed for other parts of the mouth (1:1.8) and salivary glands (1:2.0). The mean age among all cases was 58.6 years (47 years for salivary gland cancer and 60 years for lip cancer). A data review showed that 74.0% of cases were either illiterate or had not completed primary school (8th grade). Only 1.1% of the entire patient population (4 cases) had at least some university training. Occupational activity showed a preponderance of retired workers (22.6% of cases), followed by bricklayers (7.3%), small farmers (4.0%), shopkeepers (6.2%), and Table 1 Descriptive characteristics of oral cancer patients, Cancer Hospital/ INCA, Rio de Janeiro, 1986±1987 Variable Gender Female Male Age (years) <50 <50±70 >70 Stage I II III IV Anatomical site Lip Tongue Salivary gland Gums Floor of mouth Other unspeci®ed parts of the mouth Regional lymph node involvement 0 1 2 3 Distant metastasis 0 1
Percentage 23.7 76.3 28.0 52.3 19.7 8.6 10.5 31.0 49.9 10.2 35.6 4.0 6.7 11.9 31.5 45.8 27.1 11.8 15.3 95.6 4.4
drivers (3.8%). Housewives were the largest contingent among female patients. There was a strong correlation between cancer mortality and clinical stage at diagnosis (w2=81.87, P<0.001): 18.1% of stage I cases died, compared with 65.4% of cases diagnosed as stage IV. Ninety-®ve per cent of all cases were histologically proven squamous cell carcinomas and lymphoepithelial carcinomas. The remainder consisted of salivary gland tumours, whose predominant histological forms (59.3% of all cases) were adenoid cystic or mucoepidermoid carcinomas. Sixty-seven per cent of cases were classi®ed as well- or moderately-dierentiated tumours. There was a strong association between histological grade and lymph node involvement (P<0.01; w2=44.26, 9 d.f.). Lifestyle analysis showed that 76.5% of the cases were smokers and 8.1% were former smokers. The association between smoking and death as outcome was statistically signi®cant (P=0.01, w2=6.5). Among cigarette smokers, the mean daily consumption was 24.38 cigarettes, and the mean duration of the smoking habit was 39.4 years. Smokers displayed a higher oral cancer mortality risk than non-smokers (odds ratio (OR)=1.88; con®dence interval (CI)=0.5±3.7). Alcohol intake was reported by 59.3% of cases, and of these, 69.1% reported using distilled beverages. The same mortality pattern observed for smokers as compared with non-smokers was seen for drinkers versus nondrinkers (OR=1.85; CI=1.19±2.94). Higher alcohol intake was observed among males (75.7%), although among female cases who reported drinking, 75.2% did so on a daily basis. Daily alcohol intake was reported by only 21.6% of all cases. The association between alcohol intake and anatomical site was striking (over 60% of cancers of the tongue, lips, and ¯oor of the mouth occurred in regular drinkers); nevertheless, this pattern was not observed for salivary gland tumours. Death was more common among daily drinkers as compared with occasional ones (OR=2.55; CI=1.46±4.47). Men were at higher risk than women with regard to exposure to alcohol and tobacco (OR=5.88; CI=3.85±9.09 for smoking; OR=11.11; CI=7.14±20.0 for alcohol intake). The mean time between patients reporting initial symptoms and histological con®rmation of cancer was 15.8 months. The mean time between clinical suspicion and histological con®rmation was 43% shorter, 9.4 months. Prior treatment of these cancers was reported by 7.8% of cases, who experienced better survival than the others (OR=1.57; CI=0.67±3.42). The most prevalent treatment was radiotherapy (43.7%). Excisional surgery was more frequent in lip cancer (75.0%), and chemotherapy was employed in only 1.7% of all cases.
I.C.G. Leite, S. Koifman/Oral Oncology 34 (1998) 347±352
3.1. Survival analysis The mean overall survival time for this group of patients was 29.8 months (27.7±31.9). However, lip and salivary gland cancer showed a better prognosis (5-year survival > 60%). Mean survival as a function of patient characteristics and tumour/treatment variables is shown in Tables 2 and 3. Survival curves based on anatomical location were statistically dierent (log rank=24.27; P<0.001). The best prognosis was observed for salivary gland tumours (47.5 months) and lip cancer (44.6 months). The worst prognosis was seen in tumours of the tongue (25.4 months), one of the most prevalent oral cancer sites in Brazil. Mean survival curves for each anatomical site are shown in Fig. 1. 3.2. Multivariate survival analysis: Cox's regression Prognostic value for all variables (overall variable in¯uence) on survival in this entire group of patients was ascertained by Cox's regression model. Various selection methods can be used to identify the subset of independent variables related to the dependent variable. First, the in¯uence of variables on survival was analysed with regard to anatomical sites (®ve groups), followed by the inclusion of speci®c treatment modalities (three groups, i.e. surgery, radiotherapy, and others). Cox's regression was performed using the enter method (author's variable selection) and backward stepwise selection, based on compared probabilities of likelihood ratios following comparisons ascertained by Table 2 Survival analysis (Kaplan±Meier method) based on selected variables for oral cancer patients, Cancer Hospital, National Cancer Institute, Rio de Janeiro, 1986±1987 Variable (P value and log rank test) Gender (P=0.14) Females Males Age (years) (P=0.07) <50 50±70 >70 Race (P =0.10) White Non-white Smoking (P=0.01)* Non-smokers Former smokers Smokers Drinking (P<0.01)** Non-drinkers Former drinkers Drinkers * a=5%; ** a=1%.
Survival time, months (95% CI) 29.0 (23.6±34.3) 33.5 (30.4±35.5) 32.8 (27.8±37.8) 34.3 (30.6±37.9) 26.4 (20.7±32.2) 34.8 (31.4±38.2) 28.7 (24.5±33.0) 31.3 (28.3±34.3) 32.9 (23.5±42.3) 39.3 (32.4±46.2) 31.0 (27.5±34.5) 25.1 (16.0±34.1) 37.9 (33.3±42.5)
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software algorithms. They produced quite similar models, and we present parameters here based on the latter. Variables with P values ranging from 0.05 to 0.10 were kept in the ®nal prognostic model. For both analyses, the initial follow-up time was based on the date of clinical suspicion. Variables selected for the ®nal model were related to patient characteristics and to tumour/treatment characteristics. Figure 2 represents a 5-year survival curve for all patients, with a survival rate just slightly above 20%. After Cox's analysis, relative risks for prognostic variables ascertained from the entire group of oral cancer patients were as follows:
Table 3 Survival time and tumour/treatment variables for oral cancer patients, Cancer Hospital, National Cancer Institute, Rio de Janeiro, 1986±1987 Variable (P value and log rank test) Anatomical site (P<0.01)** Lip Tongue Salivary gland Mouth (143±5) Treatment modality (P<0.01)** Surgery Radiotherapy Chemotherapy Surgery plus radiotherapy Others Stage (P<0.01)** I II III IV Tumour size (T) (P<0.01)** 1 2 3 4 Lymph node involvement (N) (P<0.01)** 0 1 2 3 Distant metastasis (M) (P<0.01)** Absent Present Histopathological type (P<0.01)** Lymphoepithelial or squamous cell carcinoma (1) Adenoid cystic or mucoepidermoid carcinoma (2) Histological dierentiation (P=0.96) Well-dierentiated (1) Moderately dierentiated (2) Poorly dierentiated (3) Undierentiated (4) * a = 5%; ** a = 1%.
Survival time (months) 44.6 25.4 47.5 34.5
(36.7±52.5) (21.7±29.2) (36.1±58.8) (30.5±38.4)
46.2 23.3 24.2 41.2 12.9
(40.9±51.5) (19.9±26.8) (9.1 ±39.2) (36.5±45.9) (5.4 ±20.4)
57.1 45.2 32.6 24.5
(52.0±62.2) (37.3±53.2) (27.7±37.5) (21.0±27.9)
52.6 37.7 30.3 24.4
(45.8±59.4) (31.5±43.8) (25.9±34.8) (20.0±28.7)
42.0 28.3 22.9 16.9
(38.1±46.0) (23.3±33.3) (16.3±29.4) (12.3±21.5)
32.1 (29.3±34.9) 25.2 (15.2±35.3) 31.3 (28.6±33.9) 52.6 (44.0±61.2) 33.4 32.7 33.6 37.6
(27.5±39.2) (29.2±36.2) (21.3±45.9) (37.6±37.6)
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. histopathological type (squamous cell and lymphoepithelial carcinomas versus adenoid cystic and mucoepidermoid carcinomas): b=0.42 (0.19±0.97); . metastasis (present versus absent): b=0.65 (0.58±0.74); . lymph node involvement (present versus absent): b=1.27 (1.14±1.42); . treatment modality (surgery and radiotherapy versus others): b=1.02 (1.01±1.03); . tobacco/alcohol interaction (both present versus both absent): b=1.02 (1.01±1.03); . gender (male versus female): b=0.59 (0.42±0.82); . stage (I versus others): b=1.21 (1.09±1.36). The value of b is the estimate of the change in the dependent variable that can be attributed to a change of
one unit in the independent variable. If the exponential (b) is greater than 1, the odds are increased, while if the value is less than 1, the odds are decreased. It was not possible to de®ne the prognostic variables for salivary gland cancer and for chemotherapy treatment and combined types of treatment (it was not possible to ®t the model to these cases). The most common prognostic variables were lymph node involvement (N) and distant metastasis (M) for all anatomical locations. As lymph node involvement or distant metastasis stage increased, a proportional decrease in survival was observed, except for lip cancer. The gender variable was present in all models. The age at diagnosis was an important predictive factor for surgical treatment (b=2.25; CI=1.37±7.78). Smoking was the variable with the most impressive single
Fig. 1. Function of survival per anatomic site of 371 cases of oral cancer. National Cancer Insitute 1986±1987.
Fig. 2. Function of survival based on prognostic covariates of 371 cases of oral cancer (ICD-O 140±145). National Cancer Institute 1986±1987.
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in¯uence on survival in lip cancer (b=12.47). The clinical stage at diagnosis was also an important predictor for survival in both lip tumours and those of other parts of the mouth. Particularly for lip cancer, survival time fell dramatically with higher stages, an eect observed using the Kaplan±Meier analysis. Treatment modality was present in the ®nal regression model for all sites. Surgery and radiotherapy entailed better prognosis as compared with combinations of chemotherapy and radiotherapy and/or other treatment modalities, as well as with any other single treatment. Personal habits (especially drinking) were statistically signi®cant in relation to treatment survival rates. This statistical method can be used to construct a predictive model for oral cancer based on the abovementioned prognostic variables. The model generates a prognosis for a given patient with a speci®c subset of variables. The predictive model for oral cancer was based on stage (N and M variables), the type of treatment (with a better prognosis related to surgery), histopathological type, and individually related variables (such as tobacco/alcohol interaction and gender). The prognostic factors were independent and could be used as such in a predictive model. 4. Discussion The main descriptive characteristics of our oral cancer cases corroborate previous reports from the literature. In this study, the mean age for oral cancer patients was 58.6 years; this ®gure was heavily in¯uenced by salivary gland patients, who were diagnosed at younger ages. The overall mean was similar to the ®ndings of Janot et al. [2], Kabat et al. [4], and Franco et al. [5]. Had salivary gland tumours been excluded, the mean age would have been 60.1 years. Even so, the mean age was lower than the 66 years reported by Antoniades et al. [6], Jones [3], and Overholt et al. [7]. However, the pattern of late involvement of women [6±9] (60.2 years old) as compared with men's age at diagnosis (56.2 years old) was maintained. Traditionally, the literature presents oral cancer as a condition particularly aecting males [8, 10]. The predominant locations have been the lip, mouth, and tongue [1, 10±13] and our study is in agreement with these ®ndings. There is also agreement with regard to the predominant histopathological type, i.e. squamous cell carcinoma [14±16]. Radiotherapy alone was the most common treatment modality, including more than 50% of cases, as observed by Moore et al. [17]. In our analysis, the risk factors most heavily associated with oral tumours were smoking and alcohol. It is important to note that the association was weak
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between these lifestyle habits and salivary gland neoplasms [17]. Men usually display a better mean survival time than women [18, 19]. Franco et al. [20] commented that women are at greater risk of seeking medical care too late or failing to submit to treatment. Gender was strongly related to survival in our study. While women had a longer mean survival time than men overall, when the data were controlled for tumour site, survival by gender was similar to other reports. We also observed ethnic dierences in survival, as reported elsewhere in the literature, in which non-whites usually have lower mean survival times than whites [21]. In our study, the patient records showed a worse prognosis among non-white patients, an observation that was statistically signi®cant for lip tumours (P=0.03). In terms of lifestyle, the mean survival time among non-drinkers and non-smokers was longer. According to Silverman and Gorsky [15], smoking and drinking entail a much higher risk for developing a new oral cancer. In terms of anatomical location, the worst mean survival time was associated with tumours of the tongue, ¯oor of the mouth, and palate. In the study by Silverman and Gorsky [15], the worst prognosis was for advanced lesions of the tongue (19% 5-year survival). According to other reports, lip cancer has the best prognosis [8, 10]. Beltrami et al. [8] concluded that oral tumours show poor survival (35% 5-year survival) as compared with lip tumours. Boetta et al. [18] described oropharyngeal tumours as having a worse mean survival time than oral tumours. Univariate analysis performed in this study showed that the best survival times occurred for salivary gland and lip tumours (47.5 months and 44.6 months, respectively). Tongue cancer had the shortest mean survival time (25.4 months). Lymph node involvement (N stage) was strongly related to prognosis, corroborating other studies [3, 9, 11], while other authors did not ®nd that this variable was relevant As for tumour size, neoplasms classi®ed as T, had the best likelihood of cure, and this was considered an important prognostic variable in other studies [4, 8, 22]. A trend towards better survival has been observed among patients with no evidence of distant metastasis at the time of diagnosis. A reduction of survival time in association with metastasis is reported by Frierson and Cooper [19], who observed a 50% reduction in survival when metastasis was detected at the time of diagnosis. Our study shows a statistically signi®cant proportional decrease in patient survival time associated with higher tumour stage, except for salivary gland tumours. This variable is commonly described as the most relevant one for prognosis.
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5. Conclusions Our report on survival data from a sample of oral cancer patients in Rio de Janeiro showed the following: (a) Oral tumours entailed moderate mortality, with 29.8 months as the mean survival time. This situation was aggravated by the fact that the most common tumour site (the tongue) was the one with the shortest mean survival time. (b) There was strong evidence of an association between these neoplasms and both smoking and alcohol abuse, while salivary gland tumours had the weakest evidence of association with these two risk factors. (c) The subpopulations at highest risk amongst this group of cancer patients were males aged 40 years and older, drinkers, and heavy smokers, as well as small farmers and construction workers and those with less schooling. We emphasise both the age groups involved, with a trend towards the involvement of younger age groups, probably due to the spread of exposure to risk factors, and the presence of women among the case group for such neoplasms. (d) The main prognostic variables aecting survival were clinical stage (based on tumour size, node involvement, and distant metastasis), gender, advanced age at diagnosis, and treatment modality. Again, we stress the importance of timing in survival-related events (the less time elapsed between initial symptoms, diagnostic suspicion, and de®nition of treatment, the better the mean survival time). Acknowledgements I. Leite is indebted to Dr Antonio Carlos AndreÂs for revising the English manuscript, to Dr Koifman for orientation in this work and Dr Christina C. Rodrigues for her important help during the work. References [1] Stell PM. Cancer of the head and neck: are we doing any better? (letter). The Lancet 1985;nov. 16.
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