IMPACT OF PROGNOSTIC VARIABLES ON THE SURVIVAL OUTCOME OF ORAL SQUAMOUS CELL CARCINOMA AND NASOPHARYNGEAL CARCINOMA PATIENTS

the subjects: Gender (p=0.022), age (p=0.001), T4 sized tumor (p=0.007), N status (p=0.037), M status (p=0.001), histological grading (p=0.043), hemoglobin (p=0.011) and cancer being the cause of death (p=0.001) in of carcinoma and nasopharyngeal carcinoma metastasise, while, some large cancers never metastasise 19 . Studies have shown nodal involvement as an important predictor of the overall survival of the patients 23,24, so much so that patients with occult metastasis had 5-fold increased risk of dying from cancer as compared to patients with no occult metastases 13 . The negative effect of occult nodal metastases on the survival outcome of patients is evident by the fact that when patients with occult metastases receive radiotherapy, their disease specific survival is still poorer as compared to patients with pathologically negative necks (DSS rate, 60% vs. 87%) 13 . Our findings support the findings of previous studies, as a statistically significant relationship (p=0.037) was seen between N status and overall survival of the subjects.


Introduction
The reported morbidity of Oral Squamous Cell Carcinoma (OSCC) and Nasopharyngeal Carcinoma (NPC) throughout the world is high. The dilemma is that numerous patients develop OSCC and NPC who do not have a history of usage or exposure to the established risk factors.

Objectives
To extract socio-demographic, clinic pathological, histopathological and therapeutic data of OSCC / NPC patients from the online database software of King Fahd Medical City and Saudi Cancer Registry databases and to compare all of these variables with the "Overall Survival" of OSCC and NPC patients Methods The study was retrospective in nature. It comprised of a cohort of patients treated for Oral Squamous Cell Carcinoma (OSCC) / ISSN: 2320-5407 Int. J. Adv. Res. 7 (5), 869-880 870 factors of OSCC. In contrast, nasopharyngeal carcinoma (NPC) is comparatively rare in most parts of the world. Causative agents such as Epstein-Barr virus infection, vitamin C deficiency and dietary products containing Nnitrosamines have been considered as potential causative factors of NPC. But the dilemma is that numerous patients develop OSCC and NPC who do not have a history of usage or exposure to the above mentioned risk factors. Surprisingly the outcome of some such tumors is unpredictable. These observations indicate that apart from the formerly identified risk factors other factors yet undetermined may also influence prognosis of OSCC and NPC, which can affect the survival outcome of such patients.
Anemia is commonly associated with cancer, about 50-60% of patients suffering from cancer develop anemia at variable stages of the disease 3 . It is likely that anemia also plays a deleterious role in progression of cancer. Anemia influences progression of cancer due to the effect of hypoxia on tumor cells which leads to decreased tumor oxygenation. Decreased tumor oxygenation in turn renders the hypoxic tumor cells resistant to oncological therapies specially radiotherapy 4 . Various studies have highlighted an association of anemia with progression of cancer. For instance a study on cervical carcinoma showed anemia as a strong prognostic factor for progression of cancer & demonstrated its correlation with patient survival 5 . Furthermore a study showed increased lymph node metastasis to be associated with increase in severity of anemia in OSCC patients 6 . Anemia itself is assessed on the level of Hemoglobin (Hb) in patient's blood. Previous studies have shown that pre-treatment hemoglobin has been shown to be of clinical significance in evaluating progression of a disease 7 .
The purpose of this research project is to assess the role of various socio-demographic, clinic pathological, histopathological and therapeutic variables in the progression of OSCC and NPC by comparing the level of these independent variables with Overall Survival of OSCC and NPC patients.

Aim Of Research Project
 The aim of this research project is to assess the role of socio-demographic, clinicopathological, histopathological and therapeutic variables in determining the prognosis of oral squamous cell carcinoma and nasopharyngeal carcinoma

Objectives Of Research Project
 To extract preliminary data (socio-demographic, clinicopathological, histopathological and therapeutic data of OSCC / NPC patients) from the online database software of King Fahd Medical City and Saudi Cancer Registry databases  To compare all of these variables "socio-demographic", "clinicopathological", "histopathological" with "Overall Survival" of OSCC and NPC patients to determine the impact of these independent variables on the prognosis of OSCC and NPC

Materials & Methods
The research is retrospective and comprises a cohort of patients treated for Oral Squamous Cell Carcinoma (OSCC) / Nasopharyngeal Carcinoma (NPC) at King Fahd Medical City (KFMC) (a tertiary care hospital) located in Riyadh, Saudi Arabia. Furthermore, data will be extracted from the Dental medical records system. The study subjects are patients who were treated for OSCC / NPC.

Sample Size Calculation with Statistical Justification:
The sample size is 420; a two-sided 95% confidence interval for a single proportion using the large sample normal approximation will extend (margin of error) 0.05 from the observed proportion for an expected proportion (OS) of 58.6%.  Hemoglobin (sub-categorized into separate categories titled "NORMAL Hb", "MILD ANEMIA" and "SEVERE ANEMIA" utilizing the hemoglobin (Hb) values defined by the World Health Organization (WHO), the patients were divided into a three groups: normal (female Hb≥12.0 g/dl; male Hb≥13.0 g/dl), mild anemia (female Hb = 11.0-11.9 g/dl; male Hb = 11.0-12.9 g/dl), and severe anemia (female & male Hb<11.0 g/dl)  Initial Biopsy To Postop Survival Data collection did not include collection of subject's name and every measure was taken to maintain subject's confidentiality and privacy.

Statistical Analysis
SPSS was utilized for statistical analysis. Descriptive statistics was performed to demonstrate the frequency distribution of all the measured variables. A univariate analysis (chi-square test) was performed to look for association(s) between all of the measured variables and the overall survival of the subjects. P value < 0.05 was considered to be statistically significant. Kaplan-Meier Survival Analysis was performed in order to look for an association between the "hemoglobin" variable and "Dependent Variable" namely Overall Survival to evaluate the Survival Function S(t) and Hazard Function ( ) of variable.     Table 1.

Results:-
Surgery and radiotherapy was the most common treatment modality (n=73, 17.4%) which was utilized for the treatment of cancer in our subjects, followed by neoadjuvant chemotherapy and radiotherapy (n=64, 15.3%), neoadjuvant chemotherapy and concomittant chemo radiotherapy (n=42,10.0%), radiotherapy (n=38, 9.1%) and surgery (n=30, 7.2%). Rest of the treatment modalities are listed in the Table 1. Only sixty (14.3%) subjects encountered complications because of the treatment, which was provided to them. Amongst those who encountered complications, 47 suffered from minor morbidity, 12 suffered from major morbidity and 1 died because of the complications. Of all the subjects in our study only 30 (7.1%) had a recurrence.
Subjects were contacted via telephonic interview. Approximately 77% (n=323) of our subjects were alive when they were contacted, while, 23% (n=97) had deceased. Cancer was the cause of death of 44 (10.5%) subjects ( Table 1). One of the objectives of our study was to look for any association(s) of the studied parameters with the overall survival of our subjects. Following parameters had a statistically significant association with the overall survival of the subjects: Gender (p=0.022), age (p=0.001), T4 sized tumor (p=0.007), N status (p=0.037), M status (p=0.001), histological grading (p=0.043), hemoglobin (p=0.011) and cancer being the cause of death (p=0.001) ( Table 2). In addition to that, Kaplan-Meier survival analysis showed that low haemoglobin levels were associated with poor overall survival outcome of the subjects (Figure 1).
In our study, males comprised of majority of the subjects (63%), while, more than half of the subjects (54%) were greater than 50 years of age. This in agreement with the literature as in a cohort study of OSCC patients the male-tofemale ratio was 5.3:1 and the average age at the time of the diagnosis of the patients was 56 years 8 . OSCC is considered as a type of cancer which usually affects men more commonly than women and affects individuals between the fifth and sixth decade of life 9 , although, the male-to-female ratio and the age might vary from region to region and might be dependent on other factors.
Tobacco is considered as one of the leading causative factors of OSCC 9 . For instance, a study reported that 72.6% of the OSCC patients were tobacco users 8 . However, tobacco is used in different forms and the affect of these forms of tobacco might vary on upper aero-digestive tract cancers. In some studies, oral cavity seems to be the least affected site of the entire upper aero-digestive tract by the carcinogenic effect of smoked tobacco, whereas, larynx seems to be the most affected site 10,11 . In contrast, pipe smoking and cigar are considered as a leading cause of development of cancer in the oral cavity 11 . While, chewable tobacco causes a six fold increase in the risk of oral cancer (OR 5.8), as compared to oropharyngeal cancer which has been shown to have a minute risk (OR 1.2) 12 . Surprisingly, in our study only 14.5% of the subjects had a history of tobacco usage. The presence of different types of cancers in our sample including NPC might be a reason behind the less number of tobacco users in our sample, as other cancers including NPC might have different etiological factors as compared to OSCC. However, numerous patients develop OSCC and NPC who do not have a history of usage or exposure to the established causative factors, which raises an interesting prospect regarding the role of other clinicopathological factors in the development of these cancers. Around 95% (n=397) of the subjects in our study had a positive nodal involvement at the time of initial diagnosis. In some of the previous studies the incidence of occult metastases was 28% 13 , 23% 14 and 21% 15 .
The treatment modalities of OSCC are still the same; surgery being the main treatment modality, it might be the only treatment performed or it might be followed by radiotherapy, radiotherapy might be performed only or in combination with chemotherapy (chemo radiotherapy) which is used as an adjuvant treatment to surgery or as a palliative treatment 16 . Technological advances in surgery, postoperative radiotherapy and concurrent chemo radiotherapy has remarkably improved the survival outcome of OSCC patients during the last decade 17,18 . Surgery and postoperative radiotherapy was the most common treatment modality (n=73, 17.4%) in our study, followed by neoadjuvant chemotherapy and radiotherapy (n=64, 15.3%), neoadjuvant chemotherapy and concomittant chemo radiotherapy (n=42,10.0%), radiotherapy only (n=38, 9.1%) and surgery only (n=30, 7.2%).
Of all the subjects in our study only 30 (7.1%) had a recurrence. Recurrence significantly reduces survival in oral cancer patients 19 . Previous studies have shown that numerous OSCC patients die for reasons not related to the cancer itself 20 . For instance, the main causes of death in a study based on OSCC patients were other malignancies, cardiac, vascular and pulmonary diseases 19 . Our findings are in line with these studies, as cancer was the cause of death of only 10.5% of the subjects in our study. Although it might be plausible that post treatment complications (as shown in Table 1) might have contributed to the decline in the quality of life of subjects as at least one subject died because of the complications caused by the treatment.
Despite several improvements in the diagnostics and treatment modalities of head and neck cancer, the 5-year survival rate seems to be unaltered over the last two decades 6 . Various clinicopathological parameters might affect the overall survival of such patients. For instance, in our study a statistically significant association was observed between age and overall survival of the subjects (p=0.001). Numerous studies support our findings that age is significantly associated with disease-specific survival 8 . Some studies showed higher mortality in elderly patients when compared to younger patients 21 , while, others reported higher death rate in younger patients. E.g.; under 40 years of age 22 .
Previous studies suggested primary tumour size as reliable indicator of patient's survival outcome 23,24 . Our study showed a statistically significant relationship (p=0.007) between large sized tumors. E.g.; T4 stage tumor and overall survival of the subjects.
Although the size of the primary tumour plays a cardinal role in determining the potential of a tumour to metastasize, it is plausible that cancers of minuscule size can metastasise, while, some large cancers never metastasise 19 . Studies have shown nodal involvement as an important predictor of the overall survival of the patients 23,24, so much so that patients with occult metastasis had 5-fold increased risk of dying from cancer as compared to patients with no occult metastases 13 . The negative effect of occult nodal metastases on the survival outcome of patients is evident by the fact that when patients with occult metastases receive radiotherapy, their disease specific survival is still poorer as compared to patients with pathologically negative necks (DSS rate, 60% vs. 87%) 13 . Our findings support the findings of previous studies, as a statistically significant relationship (p=0.037) was seen between N status and overall survival of the subjects.
In addition to the size of the primary tumor and nodal involvement, other indicators of patient's survival outcome are the histological grade and distant metastases 25 . A statistically significant association was observed between M status (p=0.001), histological grading (p=0.043), and overall survival of our subjects.
In the current study, low haemoglobin levels were found to be associated with poor survival outcome of the subjects (p=0.011) (figure 1). Studies have shown anemia to be a prognostic factor for the development of local recurrence (p= 0.001) and ultimately poor prognosis of the patients 6 . Anemia causes resistance to radiation because most likely the haemoglobin level affects tumor response to radiation through the delivery of oxygen to the tumor 26 .
The findings of this study will aid the clinician in diagnosing and treating future cancer patients. This study has identified clinicopathological parameters, which play an important role in determining the survival outcome of oral squamous cell carcinoma and nasopharyngeal carcinoma patients.
Limitations of this study Following are some of the limitations of this study: 1) Retrospective nature of the study 2) Availability of some of the online data in the form of notes. Extraction of this type of data was time consuming 3) Data for some subjects was missing 4) Some of the patients were referred from other hospitals. Data of those hospitals was not obtainable One of the major problems which we faced was cleaning and organization of data. Rigorous efforts were made to organize the data for the purpose of statistical analysis Our work is still in process. We plan to use Kaplan Meier survival analysis to determine the impact of tumor size and nodal involvement on the survival outcome of patients. But a Future research project can focus on some of the parameters which were missing in this study, such as role of molecular markers e.g; HPV 16, HPV 18, EBV, htert gene, VEGF etc. in the prognosis of cancers. In addition to that, some of the important parameters which were lacking in this study such as depth of invasion of the tumor and involvement of margins, neuro-invasion (the online data was missing) can be investigated to see their impact on the prognosis of patients.

Conclusion:-
This study has identified clinicopathological parameters, which play an important role in determining the survival outcome of oral squamous cell carcinoma and nasopharyngeal carcinoma patients. This study showed a statistically relationship between age, gender, tumor size, nodal involvement, distant metastasis, histological grading, level of hemoglobin and survival outcome of the oral squamous cell carcinoma and nasopharyngeal carcinoma patients. In addition to that, this study also showed the significance of different level of hemoglobin in determining the overall survival outcome of the patients.
Further more studies can focus on some of the parameters which were missing in this study, such as role of molecular markers e.g; HPV 16, HPV 18, EBV, htert gene, VEGF etc. in the prognosis of cancers. In addition to that, some of the important parameters which were lacking in this study such as depth of invasion of the tumor and involvement of margins, neuro-invasion (the online data was missing) can be investigated to see their impact on the prognosis of patients