Gender differences in prognostic factors for oral cancer

Abstract

The aim of this study was to assess gender differences in prognostic factors among patients treated surgically for oral squamous cell carcinoma (OSCC). The medical records of 477 eligible patients (345 males, 132 females) obtained from the Brazilian Cancer Institute were reviewed. Survival was calculated by Kaplan–Meier method. Cox regression models were used to obtain adjusted hazard ratios (aHR) for males and females. Multivariate analysis showed that past tobacco use (aHR 0.2, 95% confidence interval (CI) 0.1–0.7) and regional metastasis (aHR 2.3, 95% CI 1.5–3.5) in males, and regional metastasis (aHR 2.2, 95% CI 1.2–4.3), distant metastasis (aHR 6.7, 95% CI 1.3–32.7), and hard palate tumours (aHR 11.8, 95% CI 3.3–47.7) in females, were associated with a higher risk of death. There were no differences in survival between males and females. Regional metastasis was found to be a negative prognostic factor in OSCC for both genders. Past tobacco use was an independent prognostic factor for worse survival among males, while distant metastasis and hard palate tumours were independent prognostic factors for worse survival among females. Further studies are necessary to corroborate the relationships found in this study.

Oral cancer accounts for 4% of all neoplastic diseases worldwide, and oral squamous cell carcinoma (OSCC) is the most frequent type, accounting for 90–95% of all cases. In Brazil, oral cancer is the fifth most common malignant neoplasm among males, but it is not among the 10 most frequent neoplasms in females.

Most patients diagnosed with OSCC are males of low socioeconomic status with a history of alcohol and tobacco use. However, special attention should be given to certain groups that do not fit into this well-known profile, as an increasing incidence of oral cancer is being seen among young females that is not related to smoking or alcohol consumption.

A sedentary lifestyle, environmental risks, and alcohol and tobacco use are general predisposing factors to disease. In recent years, some authors have pointed to lifestyle changes as a contributing factor to the change in OSCC profile in females. Alcohol and tobacco use is still lower among females than males, and the cancer incidence is six times lower in females than males.

Lymph node status appears to be the most important clinical prognostic indicator, but studies have shown that tumour differentiation, treatment, and the clinical stage of cancer are also good prognostic indicators. There are a multitude of factors involved in the prognosis of oral cancer and probably no single marker can accurately predict the outcome.

Some studies have investigated OSCC in women, although little is known about survival and prognostic factors, mainly because of the small sizes of the samples studied. Therefore, whether there are gender differences in prognostic factors remains an unanswered question. Identifying the profiles of these OSCC patient populations will allow clinicians to develop gender-specific treatment and care protocols and predict the prognosis. The aim of this study was to assess gender differences in prognostic factors among patients treated surgically for OSCC, based on socio-demographic and clinical prognostic indicators.

Materials and methods

Study population

This was a retrospective study based on data obtained from the Brazilian Cancer Institute Hospital Registry database, performed between 1 February and 28 December 2012. The study sample consisted of 345 males and 132 females diagnosed with primary OSCC. All patients had their histological OSCC diagnosis confirmed between 1 January 1999 and 31 December 2003. They were all living in the city of Rio de Janeiro, had no history of previous tumours, and underwent surgery as primary treatment (operable cases with or without adjuvant radiotherapy) at the Brazilian Cancer Institute. The study patients had tumours involving the following anatomical sites (International Classification of Diseases for Oncology codes): tongue (C02.0, C02.1, C02.3, C02.2, C02.8, C02.9), gingiva (C03.0, C03.1, C03.9), floor of the mouth (C04.0), hard palate (C05.0, C05.8, C05.9), and buccal mucosa (C06.0, C06.1, C06.2, C02.8, C02.9). All patients were followed for at least 1 month after treatment and for 5 years on a regular basis. Data were updated on a yearly basis. The preliminary data were obtained from an electronic database and complemented with a manual review of the medical records.

Data collection

The following socio-demographic and clinical and pathological variables were obtained from the medical records for analysis: age (<40, 40–59, and ≥60 years) ; tobacco use (none, current, and past) and alcohol use (none, current, and past); body mass index (BMI; <18.5, 18.5–24.9, and ≥25 kg/m 2 ) ; treatment (surgery, or surgery with adjuvant radiation therapy). For alcohol and tobacco use, ‘none’ meant that the patient did not use these substances or had stopped using them for at least 5 years; ‘past use’ meant that the patient reported quitting smoking or alcohol use for less than 5 years. Schooling was used as an indicator of socio-economic status (<4, 4–7, and ≥8 years). Anatomical sites were categorized according to the Union for International Cancer Control (UICC) guidelines for oral cancer: tongue, floor of the mouth, gingiva, hard palate, and buccal mucosa. The UICC staging system was used to classify the clinical stage as either early (I/II) or advanced (III/IV). Histopathological grading of the surgery specimens was performed according to the World Health Organization (WHO) grading system and categorized into well-differentiated, moderately differentiated, and poorly differentiated. Metastasis was classified as no metastasis, regional metastasis, and metastasis to distant organs.

All data were collected at the time of first record analysis and additional information obtained in the follow-ups was added, up to 28 December 2012. For patients who were lost to follow-up before 5 years, the date of censorship was considered as the last date the patient was contacted by the hospital.

Statistical analysis

The null hypothesis tested was no difference in overall survival between males and females. All analyses were performed separately for males and females. The χ 2 test was used to assess differences between the variables analyzed and by gender. Overall survival was estimated using the Kaplan–Meier method from the date of first histopathological diagnosis to the date of death, or censoring (after 5 years of follow-up). Patients lost to follow-up were censored at the date of the last registered visit to the hospital. Differences in survival rates were assessed using the log-rank test. To assess prognostic factors associated with gender, hazard ratios (HR) were calculated, together with 95% confidence intervals (95% CI). The multivariate analysis of overall survival was performed using Cox proportional hazard regression models. For males and females, model 1 was the univariate analysis (hazard ratio), and variables with a P -value of <0.20 were included in the multivariate model to predict independent prognostic factors. The significance level was set at P ≤ 0.05 for all analyses. Cox regression models were performed separately for males and females, and all selected variables were adjusted for in model 2. The variable ‘metastasis’ was used as a proxy of staging to adjust for the Cox model, mainly due to a small number of missing values in the medical records. All statistical analyses were run in IBM SPSS Statistics for Windows, version 20.0 (IBM Corp., Armonk, NY, USA). This study was approved by the Institutional Review Board of the Brazilian Cancer Institute.

Results

Only three patients were followed for less than 1 month after surgery; these patients were excluded from the study. A total 477 individuals were included in the analysis. Based on follow-up information gathered up to the end of this study, 164 patients died, of whom 124 (75.6%) were male and 40 (24.4%) female.

Patient characteristics

Male patients who survived and died had similar profiles: most were 40–59 years of age, had had less than 4 years of schooling, were current users of alcohol and tobacco, and had a BMI of 18.5–24.9 kg/m 2 . The tongue was the most common site affected by oral cancer. Those who died had tumours at more advanced clinical and pathological stages compared to those who survived. Most males were treated with surgery and adjuvant radiotherapy, had regional metastasis, and moderately differentiated tumours. Female patients, regardless of their status, showed a different pattern of alcohol and tobacco use than males and a greater proportion were non-users. With regard to BMI, females had higher BMIs than males. The χ 2 test revealed gender differences for most variables analyzed ( Table 1 ).

Table 1
Socio-demographic and clinical characteristics, use of alcohol and tobacco, and body mass index of the participants, according to gender.
Variables a Male Female P -value
Survived ( n = 221) Died ( n = 124) Survived ( n = 92) Died ( n = 40)
n (%) n (%) n (%) n (%)
Age, years
<40 7 3.2 9 7.3 11 12.0 2 5.0
40–59 136 61.5 70 56.5 25 27.2 11 27.5
≥60 78 35.3 45 36.3 56 60.9 27 67.5
Total 221 100.0 124 100.0 92 100.0 40 100.0 <0.001
Schooling, years
<4 138 62.4 91 73.4 70 76.1 28 70.0
4–7 44 19.9 21 16.9 8 8.7 5 12.5
>8 39 17.6 12 9.7 14 15.2 7 17.5
Total 221 100.0 124 100.0 92 100.0 40 100.0 0.05
Tobacco use
No 12 5.5 7 5.8 35 38.9 16 41.0
Past 48 21.8 16 13.2 12 13.3 3 7.7
Current 160 72.7 98 81.0 43 47.8 20 51.3
Total 220 100.0 121 100.0 90 100.0 39 100.0 <0.001
Alcohol use
No 19 8.6 11 9.2 54 60.0 25 69.4
Past 55 25.0 27 22.5 12 13.3 5 13.9
Current 146 66.4 82 68.3 24 26.7 6 16.7
Total 220 100.0 120 100.0 90 100.0 36 100.0 <0.001
Body mass index, kg/m 2
<18.5 10 5.4 17 16.3 3 3.9 3 9.1
18.5–24.9 106 57.6 62 59.6 33 43.4 11 33.3
≥25 68 37.0 25 24.1 40 52.6 19 57.6
Total 184 100.0 104 100.0 76 100.0 33 100.0 <0.001
Anatomical site
Tongue (C02) 90 40.7 48 38.7 41 44.6 19 47.5
Floor of the mouth (C03) 8 3.6 5 4.0 8 8.7 4 10.0
Gingiva (C04) 57 25.8 24 19.4 7 7.6 2 5.0
Hard palate (C05) 4 1.8 4 3.2 0 0.0 3 7.5
Buccal mucosa (C06) 62 28.1 43 34.7 36 39.1 12 30.0
Total 221 100.0 124 100.0 92 100.0 40 100.0 <0.001
Clinical stage
Early (I/II) 116 53.7 54 43.5 58 65.9 23 59.0
Advanced (III/IV) 100 46.3 70 56.5 30 34.1 16 41.0
Total 216 100.0 124 100.0 88 100.0 39 100.0 0.05
Treatment
Surgery 84 38.0 33 26.6 55 59.8 6 15.0
Surgery + RXT b 137 62.0 91 73.4 37 40.2 34 85.0
Total 221 100.0 124 100.0 92 100.0 40 100.0 0.01
WHO grading system
Well-differentiated 31 14.6 10 8.5 20 23.8 4 10.3
Moderately differentiated 179 84.0 100 85.5 60 71.4 32 82.0
Poorly differentiated 3 1.4 7 6.0 4 4.8 3 7.7
Total 213 100.0 117 100.0 84 100.0 39 100.0 0.05
Metastasis
No 146 66.1 56 45.2 67 72.8 21 52.5
Regional 72 32.6 65 52.4 25 27.2 17 42.5
Distant 3 1.4 3 2.4 0 0.0 2 5.0
Total 221 100.0 124 100.0 92 100.0 40 100.0 0.26
RXT, radiotherapy; WHO, World Health Organization.

a Total may vary due to missing values.

b Surgery with adjuvant radiotherapy.

Effect of prognostic factors on overall survival

There were 164 (34.4%) deaths during the study period. No statistically significant gender difference was observed in the survival curves ( P = 0.25) ( Fig. 1 ). Males aged 40–59 years ( P = 0.05), with a BMI ≥ 25.0 kg/m 2 ( P < 0.01), who underwent only surgical treatment ( P = 0.01), and who had well-differentiated tumours ( P = 0.02) and no metastasis ( P < 0.01) showed higher survival rates. Among females, patients with gingival tumours ( P < 0.01), who underwent surgical treatment ( P < 0.01), and who had no metastasis ( P = 0.02) showed better survival ( Table 2 ).

Fig. 1
Kaplan–Meier estimates of survival for patients with oral squamous cell carcinoma, stratified by gender.

Table 2
Survival rates of participants according to gender and socio-demographic, use of alcohol and tobacco, body mass index, and clinical parameters.
Variable Males Females
Overall 5-year survival (%) P -value Overall 5-year survival (%) P -value
Age, years
<40 43.8 84.6
40–59 66.0 69.4
≥60 63.4 0.05 67.5 0.66
Schooling, years
<4 60.3 71.4
4–7 67.7 61.5
>8 76.5 0.14 69.7 0.78
Tobacco use
No 63.2 68.7
Past 75.0 80.0
Current 62.0 0.18 68.3 0.50
Alcohol use
No 63.3 68.4
Past 67.1 70.6
Current 64.0 0.73 80.0 0.45
Body mass index, kg/m 2
<18.5 37.0 50.0
18.5–24.9 73.1 75.0
≥25 63.1 <0.01 67.0 0.23
Anatomical site
Tongue (C02) 65.2 68.0
Floor of the mouth (C03) 61.5 66.7
Gingiva (C04) 70.4 77.8
Hard palate (C05) 50.0 0
Buccal mucosa (C06) 59.0 0.18 75.0 <0.01
Clinical stage
Early (I/II) 68.2 71.6
Advanced (III/IV) 58.8 0.21 65.2 0.22
Treatment
Surgery 71.8 90.2
Surgery + RXT a 60.1 0.01 52.1 <0.01
WHO grading system
Well-differentiated 75.6 83.3
Moderately differentiated 64.2 65.2
Poorly differentiated 30.0 0.02 57.1 0.21
Metastasis
No 72.3 76.1
Regional 52.6 59.5
Distant 50.0 <0.01 0 0.02
RXT, radiotherapy; WHO, World Health Organization.

a Surgery with adjuvant radiotherapy.

Tables 3 and 4 show Cox regression models with HRs and 95% CIs, and adjusted HR (aHR) for selected variables. For males, the adjusted model showed past tobacco use (aHR 0.2, 95% CI 0.1–0.7) and regional metastasis (aHR 2.3, 95% CI 1.5–3.5) to be associated with a higher risk of death. For females, the adjusted model included two variables; hard palate tumours (aHR 11.8, 95% CI 3.3–47.7) and regional (aHR 2.2, 95% CI 1.2–4.3) and distant metastasis (aHR 6.7, 95% CI 1.3–32.7) were associated with a greater risk of death.

Table 3
Hazard ratios (HR) of independent predictors for overall survival for males.
Variables Univariate analysis Multivariate analysis a
HR (95% CI) P -value HR (95% CI) P -value
Age, years
<40 1.0 1.0
40–59 0.4 (0.2–0.8) 0.3 (0.1–0.9)
≥60 0.5 (0.2–1.1) 0.05 0.45 (0.1–1.0) 0.1
Schooling, years
<4 1.0 1.0
4–7 0.6 (0.4–1.1) 1.0 (0.5–1.8)
>8 0.6 (0.3–1.1) 0.15 0.6 (0.3–1.3) 0.5
Tobacco use
No 1.0 1.0
Past 0.5 (0.2–1.3) 0.2 (0.1–0.7)
Current 0.9 (0.4–1.9) 0.19 0.4 (0.1–1.1) 0.04
Alcohol use
No 1.0
Past 0.7 (0.3–1.5)
Current 0.8 (0.4–1.5) 0.7 b b
Body mass index, kg/m 2
<18.5 1.0 1.0
18.5–24.9 0.4 (0.2–0.7) 0.5 (0.3–1.1)
≥25 0.3 (0.1–0.5) <0.01 0.4 (0.2–0.9) 0.1
Anatomical site
Tongue (C02) 1.0 1.0
Floor of the mouth (C03) 1.2 (0.4–3.7) 1.6 (0.5–4.7)
Gingiva (C04) 0.7 (0.4–1.1) 0.8 (0.4–1.5)
Hard palate (C05) 1.9 (0.7–5.5) 4.9 (1.4–17.0)
Buccal mucosa (C06) 1.1 (0.7–1.7) 0.2 1.0 (0.6–1.7) 0.1
WHO grading system
Well-differentiated 1.0 1.0
Moderately differentiated 1.8 (0.9–3.6) 2.0 (0.9–4.5)
Poorly differentiated 3.7 (1.4–9.9) <0.01 3.2 (1.0–10.1) 0.1
Metastasis
No 1.0 1.0
Regional 2.5 (1.7–3.5) 2.3 (1.5–3.5)
Distant 2.1 (0.6–6.8) <0.01 1.9 (0.4–8.4) <0.01
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Jan 17, 2018 | Posted by in Oral and Maxillofacial Surgery | Comments Off on Gender differences in prognostic factors for oral cancer
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