Introduction

Oral cancer is among the ten most common forms of cancer in the world [1]. Oral cancer is much more predominant in Taiwanese males than in females and the prevalence in male peaks at age between 45 and 65 years old [2,3]. These patients have a high incidence of tobacco use, alcohol abuse, and betel nut chewing. A trend of rising incidence has been noted on a global scale irrespective of whether the examination is of Western countries or Asian countries such as Taiwan [3,4]. The increasing economic burden of oral cancer treatment has become obvious. Of all cancers in males in Taiwan, oral cancer had been ranked fourth in incidence and mortality since 1995. Up to $1195 million (in U.S. dollars) was spent on the treatment of oral cancer in 2004. As most countries, only a small percentage (0.4-3.6%) of these lesions occurred in patients younger than 45 years old. However, the number of young patients with oral cancer is increasing. Oral cancer is now a serious socioeconomic problem as well as an important public health issue in Taiwan.

Studies about whether age at diagnosis affects prognosis have produced conflicting data. Son and Kapp [5], Amsterdam and Strawitz [6] and Sakanria and Harari [7] concluded that young patients had a worse outcome than their older counterparts. Fridllander et al. [8], Pitman et al. [9], Vargas et al. [10], Glory et al. [11] and Pytynia et al. [12] noted that there were no significant differences in outcome between the different age groups. However, McGrefor et al. [13], Clark RM et al. [14], Hafkamp et al. [15], Carniol and Fried [16], and Lacy PD et al. [17] all showed that the prognosis for young patients was better. Because of the disparity in the results of these studies, the question of outcome between different age groups remains unanswered. The number of cases in these studies was small, and the power of each study was therefore in question.

We designed a population-based analysis between young patients and older patients with oral cancer in order to address the issue of outcome. The purpose of this study was to examine the relationship between different age groups and survival rates using a population-based database for patients following resection of oral cancer with reconstruction.

Materials and Methods

Results

The mean age of oral cancer patients was 53±11. The median follow-up time was 42 months (range, 2-60 months). Table 1 shows patient characteristics. Almost forty-six percent patients underwent surgery followed by adjuvant therapy. The youngest group (age<45) were more likely to be male, have tongue cancer, receive adjuvant therapy and possess a better SES. The oldest group (age>65) was associated with female gender and rural residential area (P<0.001).

The overall survival curves are shown in Figure 1. The 5-year survival rate for study population was 56% (95% confidence interval [CI], 54-59%): 60.1% (95% CI, 56-65%) for the youngest group, 56.7% (95% CI, 53-60%) for the middle-aged group, and 45.8% (95% CI, 40-52%) for the oldest group. The oldest group had the worst prognosis (P=0.001).

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Figure 1. Effect of age on survival rates of patients with oral cancer (n=2339).

https://doi.org/10.1371/journal.pone.0075855.g001

Table 2 shows the details of the adjusted hazard ratios based on the Cox proportional hazards regression model. After adjustment for the patients’ gender, primary tumor site, Charlson Comrobidity Index score, treatment modality, surgeon caseload, hospital teaching level, enrollee category, level of urbanization, and geographic region, the hazard ratio for death was 1.80-times (95% CI, 1.45-2.22; P<0.001) greater for the oldest group than for the youngest group. After adjusting for other factors, patients with an increased Charlson Comorbidity Index score, residing in the central and eastern geographic region, and receiving adjuvant therapy had a greater likelihood of death.

Table 3 and Table 4 reveal the survival rates for different age groups after propensity score stratification (<45 years vs. age 45-65, and <45 years vs. >65 years). In Table 3, there was no difference on 5-year survival rates between young age (<45 years) and middle-age group (45-65 years). In Table 4, patients with older age (>65 years) had lower 5-year survival rates in most situations, compared to those with young age (<45 years). The p-value for Cochran-Mantel-Haenszel statistics comparing survival rates for young age (<45 years) and older age (>65 years), controlling for propensity scores, was <0.001. The adjusted 5-year survival rates for oral cancer patients with young age (<45 years) were higher than those with older age (>65 years).

Without age group stratification, each additional year of age was associated with additional 2% death risk (HR, 1.02; 95% CI, 1.01-1.02). However, during stratified analysis, age was not associated with increased death risk (Table 5).

Cancer stage was not available in this database. In order to adjust the possible selection bias between different age groups, sensitivity test using simulation cancer stages was conducted (Appendix S1 and S2). Table 6 shows the results of the sensitivity test. Among oral cancer patients who underwent only surgery, we presumed that staging distribution in model A was the same in different age group (<45 years and >45 years) as that from the Bureau of Health Promotion of around 83% was early stage (AJCC stage I & II). It reveals that elder patients (>45 years) undergoing surgery alone had a 1.52-fold risk of mortality (95% CI, 1.15-2.01). In model B, we hypothesized that younger patients (<45 years) had 100% of early stage oral cancer. After adjusting other factors, elder patients (>45 years) still showed a 1.46-fold risk of mortality (95% CI, 1.10-1.95). Among oral cancer patients who underwent surgery with adjuvant therapy, the staging distribution in model A was assumed in the same way that near 77% patients were advanced stage (AJCC stage III & IV) in different age group. In model B, we hypothesized that elder patients (>45 years) had 100% of advanced stage oral cancer. The adjusted hazard ratios for death in both models disclose no statistically elevated among younger patients [HR, 1.16 (95% CI, 0.96-1.40); HR, 0.95 (95% CI, 0.67-1.36)].

In summary, oral cancer patients with young age (<45 years) didn’t confer a worse survival rates. The result was robust as the survival rates were determined using the Cox proportional regression model, stratification by propensity scores and sensitivity test.

Discussion

Oral cancer is a disease of middle-aged and old men who use tobacco, alcohol, and betel nut. An increasing incidence rate of oral cancer has been noted in younger patients. The primary objective of this study was to compare the survival rates of oral cancer patients younger than 45 with those of patients older than 45. After adjustment for the patients’ gender, primary tumor site, Charlson Comrobidity Index score, treatment modality, surgeon caseload, hospital teaching level, enrollee category, level of urbanization, and geographic region, the hazard ratio for death was 1.8-times (P<0.001) greater for the oldest group (>65 years) than for the youngest group (<45 years). This negative association remained statistically significant by using propensity score for analysis. Sensitivity test using simulation stage also revealed no elevated risk of mortality among younger patients (<45 years).

The literature concerning prognosis for young patients with oral cancer is conflicting. Some studies concluded that the disease was more aggressive in younger patients [3-5]. Some studies revealed that younger patients had a better survival rate [11-15]; however, other studies did not show a significant difference between the different age groups [6-10]. A common problem in these studies was a small sample size. Using a population-based database, our study provided strong evidence to support the proposition that young oral cancer patients did not have a worse prognosis. It has been suggested that oral cancer in young patients is a different entity. Ligen et al. found that increased p53 expression without mutation in exon 5-9 was noted in squamous cell carcinoma of the oral cavity in young, non-smoking patients [32]. Schantz et al. reported greater chromosome fragility in lymphocytes from young patients with head and neck cancer following belomycin treatment [33]. Other authors have reported that cyclin D1 gene polymorphism (CCND1) was associated with the early onset of head and neck cancer, and contributed to susceptibility to head and neck cancer, particularly in young non-smokers and non-drinkers in a case-control study [34]. Oral mucosa is similar to genital mucosa. The susceptibility of both mucosae to herpes simplex virus (HSV) and human papilloma virus (HPV) has suggested that HSV and HPV play a role in the cause of oral cancer. Parkin et al. and zur Hausen reported that up to 25% of oral cancer is associated with HPV infection [1,35] Hafkamp et al. [36] suggested that HPV is more commonly detected in young patients with head and neck cancer and it has been related to down-regulation of pRb, overexpression of p16^INK4A and wild-type p53. Kassim and Daley reported that HSV-1 has a direct relationship with oral squamous cell carcinoma, but its role in cellular transformation is not clear [37].

The quality of the risk-adjustment technique used in analyzing administrative information is an important issue. In the first part of our study, the Cox proportional regression model was used to validate the effect of young age versus middle and old age. We found a significantly increased adjusted hazard ratio for oral cancer patients in the old age group. Old age (>65 years) patients were found to have a 83% higher risk of death (P<0.001) after adjusting for comorbid conditions and other confounding factors. However, there were differences with regard to age, gender, tumor site and clinical condition between different age groups and the results of the Cox proportional regression model could be challenged by others. In the second part of our series, propensity scores were used to stratify the patients into five groups with similar propensity scores in order to reduce the effects of selection bias between the different age groups [28,29,38]. Oral cancer patients with young age (<45 years) did not have a higher risk of mortality, compared to middle age (45-65 years) or old age (>65 years) patients. Difference of carcinogenesis in oral cancer between young age and old age patients may explain some of results we observed.

Cancer stage is an important factor for long-term survival in oral cancer, but it is not available in our database. However, oral cancer stage is largely related to primary tumor size, metastatic lymph node site and number, and it causes whether surgery alone or surgery with adjuvant chemo-radiotherapy will be performed. We applied another national database to gain the distribution of oral cancer stage under different treatment modalities (surgery or surgery with adjuvant therapy) in Taiwan. We further performed a sensitivity test with simulation cancer stage. Among oral cancer patients who underwent only surgery, we set the number of early stage (AJCC stage I & II) patients in the younger group (<45 years) in two different models which were 83% (around nationwide percentage) and 100%. Similarly, among oral cancer patients undergoing surgery with adjuvant therapy, advanced stage (AJCC III & IV) patients in the elder group (>45 years) in two different models were set as 77% (around nationwide percentage) and 100%. Even in the most impossible scenario (all younger patients undergoing surgery alone were belonged to early stage oral cancer or all elder patients undergoing surgery with adjuvant therapy were belonged to advanced stage oral cancer), younger group (<45 years) remained no elevated risk of mortality.

Our study has several limitations. First, it is lack of access to detailed information from the insurance claims database with regard to oral cancer stage, which is the important variable of the survival. However, we performed sensitivity test by using simulation cancer stage and the results were consistent. Further study is indicated using cancer registry data with more details on staging. Second, the database lacks information of lifestyle factors such as dietary habits, alcohol, betel nut or tobacco use, which may be risk factors and prognostic factors for oral cancer [39]. Third, oral cancer patients who received only resection were not included, so that the interpretation of these results is limited to oral cancer patients who received resection and reconstruction. However, given the robust magnitude of the effects and statistical significance of the effects in this study, these limitations are unlikely to compromise our results.

In summary, our findings showed the effect of age on the rate of survival for oral cancer patients in a population-based study. For those oral cancer patients who underwent wide excision and reconstruction with or without adjuvant therapy, young age did not confer a worse prognosis using the Cox proportional regression model, propensity score and sensitivity test. Further research is necessary to investigate the etiology and molecular markers for oral cancer in young patients. Young patients with oral cancer may be treated using general guidelines and there may be no need for more aggressive treatment.

Supporting Information

Acknowledgments

Disclaimer: The interpretations and conclusions contained herein do not represent those of the Bureau of National Health Insurance, the Department of Health, or the National Health Research Institute.

This study is based on data from the National Health Insurance Research Database provided by the Bureau of National Health Insurance, Department of Health, Taiwan, and managed by the National Health Research Institute.