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Oral squamous cell carcinoma and cultural risk factors in patients at Benh Vien Ung Buou Oncology Hospital… Priebe, Sherry L. 2009

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ORAL SQUAMOUS CELL CARCINOMA AND CULTURAL RISK FACTORS IN PATIENTS AT BENH VIEN UNG BUOU ONCOLOGY HOSPITAL IN HO CHI MINH CITY, VIETNAM by Sherry Linn Priebe BDSc., University of British Columbia, 2003 Diploma in Dental Hygiene, University of Alberta, 1978  A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF  MASTER OF SCIENCE  in The Faculty of Graduate Studies  (Dental Science)  The University of British Columbia (Vancouver) April 2009 © Sherry Linn Priebe, 2009  ABSTRACT Introduction: In South-Central Asia, 80 per cent of head and neck cancers are found in the oral cavity and oropharynx. The reported etiological agents and risk factors for oral cancer include tobacco use, frequent alcohol consumption, the use of areca nut, compromised immune system, past history of cancer, dietary habits and infection with certain types of human papilloma viruses. Oral cancer is often not being detected in Vietnam until people experience unbearable normal oral function. The objectives of the study were to explore the structure of oral health care in Vietnam (oral health awareness, patient referral pathways and follow up), to examine the patterns of oral squamous cell carcinoma and its risk indicators and estimate the time trend in prevalence of risk habits in southern Vietnamese patients in the Benh Vien Buou Oncology Hospital in Ho Chi Minh City, Vietnam.  Material and Methods: A retrospective clinical study was performed with a data collection from July 1, 2005 to April 1, 2006 at the Ho Chi Minh City (HCMC) Oncology hospital in Vietnam. Of the 161 cases of diagnosed head and neck cancer, 147 subjects were diagnosed with oral squamous cell carcinoma (OSCC), including 100 male and 47 female adults aged 24 to 85 years. Data was collected by a structured interview and clinical examination. The structured interview inquired about the patients’ medical history ad the history of the lesion. Further self reported data included demographic data and cultural risk habits such as tobacco, alcohol and betel quid use and their amount, type and frequency, tooth brushing frequency and reason for the last dental visit. The clinical examination included: examination, imaging including computerized tomography (CT) scan and/or  panoramic  x-ray,  pathology  reports,  biopsy  and  surgical  reports.  The  ii  clinicopathological assessment of the oral cancerous lesion evaluated the type, size, location and severity of the lesion.  Results: Over 40 per cent of the women with OSCC reported chewing betel quid and the most prevalent risk habit in males was smoking (91.0%). Daily alcohol use was reported by 79.0 per cent of males and 2.1 per cent of females. Two thirds of the cases of OSCC were diagnosed at the TNM 2nd and 3rd stages of cancer (tumour size and spread throughout the body). The more advanced stages of cancer were observed in males. The prevalence of tobacco and alcohol use in males with OSCC was higher in the present study than in previous studies. Oral hygiene status (evaluated by OHI-S index) was mostly ‘poor’ (50.8%) and ‘moderate’ (36.9%) in the majority of patients.  Discussion: High prevalence of cultural risk habits of cancer in both genders was reported in OSCC Vietnamese patients at the Oncology hospital. An increased tobacco and alcohol use was observed in male OSCC patients when compared to past studies. Cancer was diagnosis at earlier stages in the present study than in past studies.  iii  TABLE OF CONTENTS Abstract................................................................................................................................ii Table of Contents...............................................................................................................iv List of Tables.......................................................................................................................v List of Figures ....................................................................................................................vi Acknowledgements...........................................................................................................vii Chapter 1 The Epidemiology of Oral Cancer ....................................................................1 1.1 Introduction...........................................................................................................................1 1.2 Review of the Literature ......................................................................................................2 1.3 Behavioural and Cultural Habits Related to the Risk of Oral Cancer.........................8 1.3.1 Tobacco Use ......................................................................................................8 1.3.2 Alcohol Use .......................................................................................................9 1.3.3 Areca Nut and Betel Quid Use ................................................................... 11 1.4 Rationale for the Study of Oral Squamous Cell Carcinoma and its Risk Factors in a Resource-Poor Country ................................................................................................. 13 1.5 Aims of the Study .............................................................................................................. 14 Chapter 2 Material and Methods......................................................................................15 2.1 Study Design ........................................................................................................................ 15 2.2 Subjects ................................................................................................................................. 18 2.3 Clinical Assessments........................................................................................................... 18 2.4 Data Analyses....................................................................................................................... 22 Chapter 3 Results ..............................................................................................................23 3.1 Oral Health Awareness, Structure of Oral Health Care and Referral Pathways in Vietnam ........................................................................................................................................ 23 3.2 Clinical Study of the Patterns of Oral Squamous Cell Carcinoma and its Risk Habits in Patients in the Oncology Hospital in Ho Chi Minh City.................................. 29 ..... 3.2.1 Self-Reported Data of Risk Indicators and Univariate and Bivariate Statistics36 Chapter 4 Discussion ........................................................................................................45 4.1 Oral Health Awareness, Structure of Oral Health Care and Patient Referral Pathways in Vietnam ................................................................................................................. 23 4.2 Patterns of Oral Squamous Cell Carcinoma and its Risk Factors in Patients in the Oncology Hospital in Ho Chi Minh City .............................................................................. 49 4.3 Time Trends in Prevalence of Risk Habits in Vietnamese Oral Squamous Cell Carcinoma patients..................................................................................................................... 56 4.4 Limitations and Bias 62 4.5 Challenges, Obstacles and Adversities of a Foreigner Performing a Study in a Resource-Poor Country ............................................................................................................ 70 Reference List ...................................................................................................................73 Appendix A. Interview Survey of Oral Squamous Cell Carcinoma Patients ..................82 Appendix B. UBC Research Ethics Board Certificate of Expediated Approval............86  iv  LIST OF TABLES Table 1. Simplified Oral Hygiene Index (OHI – S) ........................................................................... 16 Table 2. International Cancer Classification (TNM).......................................................................... 19 Table 3. The Karnofsky Performance Scale ........................................................................................ 21 Table 4. Background and baseline clinical data of patients diagnosed with OSCC in Oncology Hospital HCMC, Vietnam in 2005-2006.............................................................................................. 29 Table 5. Time Trends- A comparison of risk behaviours................................................................. 32 Table 6. Gender differences in risk habit distribution in OSCC Vietnamese patients................ 36 Table 7. Oral Hygiene Status of OSCC patients................................................................................. 39 Table 8. Gender patterns in clinical characteristics of lesions in OSCC patients......................... 41  v  LIST OF FIGURES Figure 1. Diagram for the drawing of the clinical description of the lesion ......................... 18 Figure 2. Self reported reasons for seeking professional help at the Oncology hospital ............ 40 Figure 3. Gender differentiation of lesion location............................................................................ 41  vi  ACKNOWLEGEMENTS The author wishes to thank her supervisor Dr. Jolanta Aleksejūnienė, and committee members Dr. Shafik Dharamsi, Dr. Richard Mathias, and Dr. Christopher Zed for supporting her passion of study and research in a foreign country. Additional thanks to the professors and faculties of Oral Pathology and Odonto-Stomatology at the University of Medicine and Pharmacy in Ho Chi Minh City, Vietnam being Dr. Nguyen Thi Hong, Dr. Tran Kin Cuc, Dr. Ngo Dong Khanh, Dr. Anh Lan and Dr. Hoang Tu Hung. This research would not have been possible without the approval and permission of Dr. Nguyen Chan Hung, director of the Oncology Hospital, and Dr. Huynh Cong Dam, director of the National Hospital. The Oncology surgeons Dr. Dang Huy Quoc Thinh, Dr. Tzan Thi Anh Tuong and the staff in the Head and Neck department of the Oncology hospital willingly gave of their time to provide a tour of the hospital with discussions of oral cancer and the subjects’ diagnosis. Finally, the author wishes to thank the clinicians and surgeons of the study including Dr. Nguyen Thi Hong, Dr. Tran Kin Cuc and Dr. Nguyen Thi Phuong Thao.  vii  CHAPTER 1 THE EPIDEMIOLOGY OF ORAL CANCER 1.1 Introduction Cancer is a serious public health problem. Oral cancer is more common in resourcepoor countries than in resource-rich countries (1).Worldwide, the prevalence of oral cancer is particularly high among men with annual incidence rates for oral cancer varying from 1 to 10 cases per 100,000 individuals (2). In south-central Asia, cancer of the oral cavity ranks among the three most common types of cancer (2). A substantial increase in the incidence of oral cancers has been reported in Denmark, Germany, Scotland and Central and Eastern Europe and to a lesser extent in Australia, Japan, New Zealand and the USA (3). However, it is still unclear if this is an actual increase or difference between reports of varying quality as adjusted incidence ratios were not presented. It has been suggested that the cancer epidemic in resource-rich countries, and increasingly in resource-poor countries, is due to the combined effect of the ageing of populations, and the increasing levels of cancer related risk factors such as tobacco, unhealthy diet, physical inactivity and infections (3). The two risk factors of tobacco use and alcohol abuse have been estimated to account for about 90 per cent of cancers in the oral cavity (4). Furthermore, oral cancer risk increases when tobacco is used in combination with alcohol and/or betel quid with areca nut (4). The social and cultural habits that may predispose people to oral cancer are common in resource-poor countries in Southeast Asia and remain prevalent among its users following migration to other and better resourced countries (5). As a result, countries that once rarely experienced high levels of oral cancer will likely see an increase of this  1  disease. It has been suggested that following migration from these countries to North America, the risk habits of these immigrants have remained unchanged (5;6). Increasing the level of awareness among oral health professionals about oral cancer and the range of possible contributing risk factors, as well as developing better early diagnosis are of key importance in reducing morbidity rates (7).  1.2 Review of the Literature Oral cancer is the fifth most common cancer in the world (1). Cancer rates are increasing at an alarming rate worldwide estimated from 10 million in 2000 to 15 million in 2020 (1). With over 400,000 cases diagnosed yearly, oral cancer is responsible for more deaths globally than melanoma, Hodgkin’s disease, or cervical cancer (1;8). Cancer of the mouth and pharynx ranks third in resource-poor countries (9). In most regions of the world, about 40 per cent of head and neck cancers are known to be squamous cell carcinomas starting in the oral cavity, and in South-Central Asia, 80 per cent of head and neck cancers are found in the oral cavity and oropharynx (10;11). In 2002, two–thirds of the new cases and deaths occurring in the world due to oral cancer were observed in resource-poor countries (12). Annual incidence rates for oral and pharyngeal cancer are estimated at 25 cases per 100,000 in resource-poor countries and 10 cases per 100,000 in the United States (13;14). The World Health Organization reported 2,481 oral cancer cases in 2004 in Vietnam (15). More recent information is not available in Vietnam. In Canada, oral cancer represents approximately 2.3 per cent of all cancers (2.6% in males and 1.4% in females) (16). In 2008, these rates are expected as approximately 3,400 new cases, and 1,150 deaths (16). Approximately 60 per cent of people diagnosed with oral cancer will survive only up to five years (13). Oral cancer is one of the few cancers whose survival rate has not improved over 30 years (17). Moreover, in the  2  past three decades there has been a 60 per cent increase in oral cancer in adults under the age of 40 (11). The diagnosis of oral cancer may be delayed because a clinician did not suspect the malignant nature of the lesion due in part to the limitations of visual and manual examination of the oral cavity, head and neck and/or due to lack of experience (17-19).  Pathogenesis of Oral Cancer Development The National Institute of Dental and Craniofacial Research has provided a biological model of oral cancer. All neoplastic transformations or cancers result from mutations in genes that control cell growth and behaviour. These genes normally restrict cell proliferation and direct the cell to repair DNA damage or to self-destruct, a process called apoptosis. The mutated genes free the cancerous cell from these controls, allowing it to divide continuously and to pass on the mutation(s). Cancer cells multiply uncontrollably and can metastasize from the site of origin to other parts of the body where they continue to multiply (20). Research has revealed the pathogenesis of cancer at the genetic level. Multiple mutations in specific classes of genes contribute to head and neck cancer. The two classes of genes mostly characterized are proto-oncogenes and tumour suppressor genes. Protooncogenes code for proteins that stimulate cell division; altered forms, called oncogenes, can cause stimulatory proteins to be overactive, with the result that the cell divides more rapidly than usual. The following oncogenes (EGFR)/c-erb 1, ras family, c-myc, int-2, hst1, PRAD-1 (CCND1 or cyclin D1), and bcl-1 have been identified as possible participants in head and neck cancers (21).  3  Tumour suppressor genes code for proteins that inhibit cell division. When these genes mutate, the corresponding protein may no longer be produced correctly and cell division may occur when it should not. Inactivated tumour suppressor genes that are suspected in head and neck cancer include Rb, p16 (MTS1 or CDKN2), and p53, whose failure is already implicated in approximately 60 percent of all human cancers. The gene p53 has been of great interest to cancer researchers since it was discovered that the molecule could stop tumours from forming when it is functioning properly. Located on the short arm of chromosome 17, p53 works by recognizing damage to a cell's DNA and stopping the process of cell growth and division until the damage is repaired. If that fails, p53 can cause the cell to undergo apoptosis (21). Based on recent genetic studies and clinical implications, a genetic progression model of oral cancer has been described by a team from The Netherlands. In the initial phase, a stem cell acquires a genetic alteration; subsequently a patch is formed, a clonal unit consisting of the stem cell with its daughter cells that all share the DNA alteration. The next critical step is the conversion of a patch into an expanding field as a result of additional genetic alterations. This mucosal field replaces the normal epithelium and in the oral cavity such fields have been detected with dimensions of over 7 centimetres in diameter. Sometimes these fields are visible as leukoplakia (21).Ultimately, clonal selection leads to the development of carcinoma within this neighbouring field of pre-neoplastic cells. An important clinical implication of this model is that fields of the primary tumour often remain after surgery and may consequently lead to new cancers, designated by clinicians as second primary tumours or local recurrences (22).  4  The aetiology of cancer is multifactorial. Genetic mistakes may be inherited or acquired as a result of exposure to chemicals, radiation, or viruses. Random mistakes also occur each day in the course of duplicating the three billion units in the DNA during cell division. No one mutation is enough to make a cell cancerous. Multiple genetic changes, in specific classes of genes, are needed to transform a normal cell into a neoplastic cell that grows out of control. Some people inherit susceptibility for certain types of cancer (20). Scientists now understand that oral cancers (the category of head and neck cancers) result from a multistep process of accumulated genetic mutations caused by many risk factors. Tobacco, alcohol and betel quid use, diet, viruses, and a possible genetic susceptibility may all work synergistically to cause these cancers (20). Virtually all oral cancers are squamous cell carcinomas or cancers of the epithelial cells that line the mouth. These cancers can develop in any part of the oral cavity or oropharynx. The most common sites are the tongue, the lips, and the floor of the mouth (21). Research has shown that changes in oral epithelial cells often are manifested as lesions called leukoplakia (a white patch) or erythroplakia (a red patch) which can be early indications of oral cancer (21).  Risk Factors of Oral Cancer The recognized aetiological agents and risk factors (behaviour, environmental exposure, or inherent human characteristic that is associated with an increased probability of a particular health-related outcome) (23) for oral cancer include tobacco use, alcohol misuse, the use of areca nut, a compromised immune system, a past history of cancer, inadequate diet and less well-established factors such as infection with certain types of human papilloma viruses (9;24-  5  27). Alarmingly, 25 per cent of newly diagnosed cases of oral cancer do not fit the identified high-risk profile (28;29). It has been reported that rapid urbanization leading to an unhealthy lifestyle, such as increased access to and the utilization of tobacco in its various forms as well as abuse of alcohol, possibly leads to an increased incidence of oral pre-cancerous and cancerous lesions (14). Tobacco use is one of the main risk factors of oral cancer with at least 75 per cent of those diagnosed with oral cancer being tobacco users (8). When tobacco use is combined with frequent alcohol consumption, the risk increases significantly as these risk factors act synergistically i.e. they exacerbate each other’s harmful effects (8;30). Furthermore, oral cancers are more common in parts of the world where areca nut in betel quid is chewed. The International Agency for Research on Cancer has classified betel quid with or without tobacco as a human carcinogen (1). Consequently, the use of areca nut in any form is not safe. Commercially manufactured forms of areca nut with additives such as sugar are available to all ages of the public worldwide thereby increasing the risk of cancerous lesions and dental health risks such as caries. As oral cancer rates increase throughout the world, the once uniquely Southeast Asian traditional cultural habit of betel quid chewing is now a worldwide phenomenon that is increasing at an alarming rate (1;5;31). Public awareness of such cultural risk habits and the resulting negative oral health effects are necessary to assist in curbing the increasing incidence of oral cancer.  Oral Cancer in Asia Oral cancer accounts for approximately 40 per cent of all malignancies in parts of South East Asia and India (32). Age standardized incidence of oral cancer per 100,000 range  6  from 13.2 in men and 10.2 in women (Chennai, India) to 1.9 in men and 2.1 in women (Hanoi, Vietnam) (33). The age standardized incidence rate is calculated first by estimating the agespecific rates and then applying these rates to the reference population (34). In India, the incidence of oral cancer in women is three to seven times higher than in resource-rich countries possibly due to tobacco smoking and chewing of betel quid with tobacco (35). In most regions of India, oral cancer is the most common cancer in men and the third most common cancer in women (36). A review of the approximately 1.5 million cancer deaths in England and Wales from the years 1973-1985 has shown that Indian-born men had greater than two times and Indian-born women had five times higher risk of oral cancer mortality than native English and Welsh individuals (37). Information emerging from Taiwan and China indicates that the incidence of oral cancer in men has tripled since the 1980’s due to the chewing of betel quid (1). Truck-drivers are reported to chew betel quid for its stimulant effect to keep them awake for longer periods of driving time. Tobacco generally is not added to the betel quid in those regions (1).  Burden of Oral Cancer in Vietnam Vietnam is a resource-poor country with numerous challenges. Oral health care in Vietnam is aggravated by poverty, inadequate living conditions, lack of health education, and lack of government funding and policies to employ a sufficient number of oral health care workers (38). Cancer of the mouth and pharynx ranks third in resource-poor countries with 0.06 per cent of the total (19.80%) oral mucosal lesions diagnosed in Vietnam as oral cancerous lesions. In Dr. Khanh’s report, the percentage of males and females diagnosed with oral cancerous lesions were 0.03 per cent and 0.03 per cent respectively (9). In 2003, Vietnam’s population reached 80.3 million of which 65 per cent  7  were less than 30 years and approximately 10 per cent were over 55 years. Census estimates for the population in 2007 were 87.375 million. New cancer cases are estimated at 80,000 per year (34). There are two main government supported oncology hospitals. One is located in the capital city of Hanoi in the northern part of the country and the other in Ho Chi Minh City (HCMC), in the south. Approximately 40 million people are served by the HCMC hospital. The Oncology Hospital is the largest cancer treatment facility for the south of Vietnam with almost 150,000 admissions per year. However, the number of patients with cancer is more than the hospital can serve as the burden of cancer is great in such a large population. The burden of cancer affects all countries throughout the world and even more in a resource-poor country such as Vietnam. The life expectancy in Vietnam is 70 years (34). As the lifespan of Vietnamese people is short, the amount of years spent in the working force is relatively small and even more if burdened by disease. The skilled working force is few, thereby negatively impacting the development of the country and increasing the burden to populate. As people in Vietnam are acquiring advanced oral cancer at a young age, the consequential and detrimental implication is decreased productivity and increased healthcare costs affecting the country’s economy. Few people are productive as the country’s morbidity rates increase. Furthermore, the burden of oral cancer on the healthcare of the country is complex and costly often due to ineffective therapeutic procedures using radiotherapy, chemotherapy and advanced reconstructive surgery (39).  8  1.3 Behavioural and Cultural Habits Related to the Risk of Oral Cancer 1.3.1 Tobacco Use Worldwide, 4 million people die each year from tobacco use and that number is expected to rise to 8.5 million a year by 2020 (1). Approximately 80 per cent of the world’s smokers live in resource-poor countries such as Vietnam where smoking rates have been reported to have increased dramatically in the past few decades (12). The association between smoking and oral carcinoma has been firmly established from epidemiological studies, revealing more than twice as many smokers among oral cancer patients as among control populations (19). Smokers are six times more likely to develop oral cancer than those who do not smoke (13). Tobacco smoking has been demonstrated to increase the risk of squamous cell carcinoma of the head and neck in a dose-response fashion (40). Worldwide, Vietnam has the highest rate of smoking among males (9). During the 1990s, smoking rates for Vietnamese males was 72.8 per cent while the rate for females was only 4.3 per cent (41). A higher prevalence of smokers was found among those with a low education (less than six years) than among more educated people (41). The prevalence of smoking in 2000 has been reported among women at 20% (9). Smoking rates in Vietnamese women may be underestimated because it is not culturally acceptable for women to smoke. An increasing uptake of smoking by youth and women is being reported (42). Vietnamese who both smoke and abuse alcohol, or who smoke and chew betel quid, have two to three times higher risk for oral precancerous and cancerous lesions compared with those who only smoke (9).  9  1.3.2 Alcohol Abuse Alcohol abuse, defined as more than twenty-one standard drinks in one week, is also a well-known risk factor for oral cancer (8;43;44). Canadian recommendations are not to exceed more than two standard drinks per day, one standard drink being 13.6 grams of alcohol (43). Further recommendations for alcohol use are not to exceed more than nine drinks per week for women and not to exceed more than fourteen drinks for men (8;43;44). Excessive alcohol consumption related to oral cancer in southern Indian males was six times more common in alcohol users than in non-users (45). Alcohol's effect on the mouth may be the key to understanding how it works with tobacco to increase the risk of developing cancer. The dehydrating effect of alcohol on cell walls enhances the ability of tobacco carcinogens to permeate mouth tissues (8;46). Furthermore, nutritional deficiencies associated with heavy drinking can lower the body's natural ability to use antioxidants to prevent the formation of cancers (8;47). Tobacco use has been proven to increase the risk of oral cancer, consequently people who use both alcohol and tobacco are at an especially high risk of developing the disease (48). The combined effects of tobacco and alcohol were reported in a study of over 350 individuals who had oral cancer and a mortality rate of 31 per cent in 5 years (48). In December 2006, The Vietnamese Deputy Minister of Health, Le Ngoc Trong, emphasized that excessive alcohol consumption had reached alarming proportions with serious consequences for the health and safety of the public (49). Many Vietnamese males consume from 0.5 to 1.5 litres of alcohol daily although the concentration in terms of absolute alcohol consumed was not determined. Apart from individual suffering, alcohol abuse hampers national development and economic growth. According to the Vietnamese Health Strategy and Policy Institute, the cost of dealing with the consequences of excessive  10  consumption of alcohol typically accounts for 2%-8% of the national gross domestic product (49). Research suggests that Vietnamese youth (15-20 year olds) are consuming more alcohol. Of 480 surveyed youth, 30 per cent had consumed alcohol and approximately 20 per cent of young men, and to a lesser extent young women, reported intoxication in a six-month period (50). As oral cancer is increasingly seen in younger populations in both resource-rich and resource-poor countries, it is necessary to increase awareness about the detrimental effects of alcohol abuse and the associated health risks (8). 1.3.3 Areca Nut and Betel Quid Use Areca nut (usually incorporated in betel quid) is the fourth most common psychoactive substance in the world (after caffeine, alcohol and nicotine) (5).The areca nut is used as a chewing substance by approximately 600 million people worldwide (51). Betel quid chewing worldwide is a known risk factor for oral leukoplakia, oral submucosal fibrosis, and oral squamous cell carcinoma (1;6;52-54). The World Health Organization has reported the use of betel quid as a widespread global risk habit that has spread due to increased migration of Southeast Asian communities to all continents resulting in an increase in oral cancers around the globe (1). Betel quid is a mixture of areca nut and other substances (in manufactured or processed form) that is placed in the mouth where it is chewed slowly or ‘rubbed’ along the buccal mucosa (6). The major constituents of betel quid are areca nut (from the areca tree) and slaked lime (calcium hydroxide) wrapped within a betel leaf (from the Piper betel vine) although this varies between individuals and communities and may include tobacco, various spices, sugar  11  and chemicals. Approximately 10%-20% of the world’s population chew areca nut in some form, often mixed in betel quid with or without tobacco (55). Betel quid chewing is a social and cultural practice known for its stimulant effects, and it is thought to strengthen the teeth, diminish hunger, sweeten the breath and keep the gums healthy. The usage of areca nut is indigenous to India, Sri Lanka, Maldives, Bangladesh, Myanmar, Taiwan and numerous islands in the South Pacific (55). This risk habit is popular in parts of Thailand, Indonesia, Malaysia, Cambodia, Vietnam, Philippines, Laos, China and in migrant communities from these countries. The chewing practice of betel quid dates back thousands of years and is deeply entrenched in the culture of the population in several parts of south-east Asia (55). The teeth become heavily dark brown stained from the areca nut as well as through the use of ‘tobacco rubbing’ and ‘tobacco sticking’. This is accomplished by rubbing a small ball of raw dried tobacco over the front of the teeth and buccal mucosa and then sticking the tobacco ball in the buccal mucosa or cheek vestibule with the betel quid or on the other side. When chewed, the betel nut creates a red juice dyeing the lips red that traditionally was considered to be attractive to men. In Vietnam, only women are known to chew betel quid, although in a recent study one man was identified as chewing betel quid for 35 years (56). Areca nut is chewed dry or fresh and may be red or white. In spring, the areca nut is chewed in dry form as it is dried from the previous fall or harvest. As areca nut is harvested in the fall, at this time it is then chewed fresh. The red or white betel quid refers to the slaked lime used with red dye or naturally according to one’s preference. Today in Vietnam, there is an increasing social stigma associated with this habit among younger women who refer to this habit as being for old women only.  12  Public health concern of a worldwide epidemic of oral cancer relates to the use of betel quid and its substitutes by an increasing number of young adolescents (53). Studies have revealed cases of oral mucosal lesions in children due to chewing betel quid in manufactured forms. A 2002 case report study in England revealed a 12-year-old Bangladeshi boy presenting with submucosal oral fibrosis related to the chewing risk habit of betel quid (57). Oral submucosal fibrosis is a chronic progressive disease of the buccal mucosa associated with an inflammatory reaction to the irritant of the betel quid. The epithelial tissue of the buccal mucosa becomes stiff which causes trismus (the inability to open the mouth) and the inability to eat.  1.4 Rationale for the Study of Oral Squamous Cell Carcinoma and its Risk Factors in a Resource-Poor Country A partnership between the University of British Columbia (UBC), the University of Medicine and Pharmacy in HCMC, and the Oncology Hospital in HCMC has established the basis for both research and education. Recognizing the need for increased oral health care, oral health prevention and rehabilitative treatment, the UBC Faculty of Dentistry General Practice Residency program initiated a collaborative international rotation in Vietnam. This international experience has been designed to broaden the scope of learning for dental graduate and postgraduate students aiming to increase an understanding of cultural characteristics, regional diseases and treatment modalities. Tobacco use, alcohol abuse and traditional betel quid use are prevalent habits in communities throughout Vietnam. An important consideration is that social and cultural contexts of betel quid use may lead to retaining these habits among its users following migration from these countries to North America (5). Consequently, as these populations with  13  their unique cultural habits move to Canada, the incidence of oral lesions related to betel quid use may rise as it has in other countries of migration (5;6). Oral health professionals in North America should be aware of the manifestations of precancerous and cancerous lesions related to betel quid use with or without tobacco in Southeast Asian migrant populations as these lesions may be seen more frequently in the future (6). The role of the clinician is to recognize oral health disease and oral conditions related to unique cultural habits. The association between betel quid use and increase of precancerous conditions and oral cancerous lesions highlights the importance of education not only on tobacco cessation and moderate alcohol use, but also betel quid cessation. An active preventive approach is required to limit the imminent increase in oral cancer due to these habits (6).  1.5 Aims of the Study 1. To explore oral health care in Vietnam, oral health awareness, patient referral and follow up pathways, 2. To examine the patterns of oral squamous cell carcinoma and its cultural risk indicators in southern Vietnamese patients at the Benh Vien Buou Oncology Hospital in Ho Chi Minh City and 3) To estimate time trends in prevalence of risk habits in Vietnamese oral squamous cell carcinoma patients.  14  CHAPTER 2 MATERIAL AND METHODS 2.1 Study Design The present retrospective clinical study was approved by the University of British Columbia’s Clinical Ethics Board (Appendix B. #C05-0148), by the directors of the Oncology and National Hospitals and the dean of the Faculty of Odonto-Stomatology, University of Medicine and Pharmacy in HCMC, Vietnam. The data was collected from July 1, 2005 to April 1, 2006 and included information about newly admitted and confirmed clinical cases of oral squamous cell carcinoma (OSCC) at Benh Vien Buou, Oncology hospital in HCMC, Vietnam. The study was supervised by Dr. Nguyen Thi Hong and Dr. Tran Kin Cuc, oral pathologists at the Faculty of Odonto-Stomatology at the University of Medicine and Pharmacy in HCMC, Vietnam. The two clinicians, Dr. Nguyen Thi Hong and Dr. Nguyen Thi Phuong Thao, performed all clinical examinations and recorded verbatim transcription of information during the interview. Subjects for the present study were pre-selected at admission to the ward of the head and neck department at the Oncology hospital. The chosen subjects were requested to provide written consent for the collection of personal data and hospital record information which was collected in the dental clinic as well as in the surgery department in the Oncology hospital. All patients received dental treatment and care in the clinic regardless if they consented to participate in the study or not. The self reported data was acquired by means of a structured interview and questionnaire presented in the subject’s native Vietnamese language. (For English version, 15  please refer to Appendix A). Subsequently, the Vietnamese verbatim transcription was translated into English. The structured interview inquired about the patient’s medical history and the history of the lesion. The questionnaire included demographic data such as age, gender, occupation and place of residence. Cultural risk habits such as tobacco, alcohol and betel quid use and their amount, type and frequency, tooth brushing frequency and reason for the last dental visit were also recorded. Oral hygiene status was measured using the ‘Simplified Oral Hygiene Index’ (OHI-S) by examining six index teeth (Table 1) (58). The OHI-S has two components: the Debris Index and the Calculus Index. Each of these indices, in turn, is based on numerical determinations representing the amount of debris or calculus found on the selected tooth surfaces. The individual or group debris and calculus scores are combined to obtain the Simplified Oral Hygiene Index (58). Table 1. Simplified Oral Hygiene Index (OHI-S) Simplified Oral Hygiene Index (OHI-S) * Examination of 6 specific teeth: 16, 11, 26, 31 (buccal), 36, 46 (lingual). OHI-S Evaluation 0: no plaque, calculus 1: plaque, calculus covering up to 1/3 tooth face 2: plaque, calculus covering < 2/3 tooth face 3: plaque, calculus covering ≥ 2/3 tooth face OHI-S: Oral Hygiene Classification 0.0 - 1.2:  good oral hygiene  1.3 - 3.0:  moderate oral hygiene  3.1 – 6.0:  poor oral hygiene  * Introduced by Green và Vermillion in 1964 (58)  The structure of oral health care and referral pathways in Vietnam was explored through personal communication with the following key persons: Dr. Andrew Tsang and Dr.  16  Zed, University of British Columbia, Vancouver, Canada; Dr. Dang Huy Quoc Thinh, Nguyen Chan Hung and Dr. Tzan Thi Anh Tuong, Oncology Hospital; Nguyen Thi Hong, Tran Thi Kim Cuc and Dr. Huynh Anh Lan, Faculty of Odonto-Stomatology at the University of Medicine and Pharmacy in HCMC; and Dr. Ngo Dong Khanh at the Institute of OdontoStomatology (National Hospital). The inquiry included the following topics: patient oral health awareness as well as referral pathways and follow-up of patients in southern Vietnam. In order to estimate the time trends in prevalence of risk habits in Vietnamese OSCC patients, the prevalence of the behavioural and cultural risk habits was compared among patients of the present study, to patients from past studies and to the general population. The information about OSCC patients from previous years was acquired from available archives. The following information was assessed by Dr. Tran Dang Ngoc Linh regarding the epidemiological, pathological and clinical features and treatment of oral cancer patients at the Oncology hospital from the years 1993 to 1996; a study by Dr. Vi and Dr. Huynh Anh Lan in 1998-1999 of oral cancer patients at the Oncology hospital; a study from 2000-2002 by Dr. Nguyen Thi Hong of OSCC patients at the Oncology hospital; and a doctoral thesis of oral precancer and cancerous lesions in the general population in 1996-1997 by Dr. Ngo Dong Khanh. A deeper insight into Vietnamese cultural betel quid habits was acquired during visits to local markets in HCMC and Hoc Mon, a suburb of HCMC where areca nut and betel leaves are grown. Interviews were conducted with betel quid vendors and the betel quid chewing people.  2.2 Subjects The present study examined patients assessed at the Oncology hospital. They were from 24 to 85 year olds among which there were 106 males and 55 females. Thirty seven of 17  these were from central Vietnam, 32 from HCMC, 35 from southeast Vietnam, and 57 from southwest Vietnam. Fifty subjects were urban and 111 were rural dwellers. Of the 161 cases, 147 subjects were diagnosed with OSCC, 7 subjects were diagnosed with adenoid cyst carcinoma, 4 with mucoepidermoid carcinoma, 2 with histocytoma of soft tissue and 1 with submandibular gland carcinoma. Due to a small number, 14 subjects not diagnosed with OSCC were excluded from further analysis. The total number of 147 OSCC subjects comprised of 100 males and 47 females.  2.3 Clinical Assessments The clinical assessments included: clinical examination, imaging including computerized tomography (CT) scan and/or panoramic x-ray, pathology reports, biopsy and surgical reports. The clinicopathological assessment of the oral cancerous lesion evaluated the type, size, location and severity of the lesion. A drawing of the clinical description of the lesion was recorded using the diagram as presented in Figure 1.  Figure 1. Diagram for the drawing of the clinical description of the lesion The staging of cancer (severity of cancer) was assessed by describing the tumour size and its spread throughout the body. Other observed oral mucosal abnormalities were also  18  described and recorded. Oral mucosal lesions associated with betel quid chewing included lichen planus-like lesions, leukoplakia, oral submucosal fibrosis (OSF), betel chewers’ mucosa (BCM) and pre-cancerous lesions. The grade of the lesion was recorded to assess how closely the lesion resembles normal cells and how aggressive it is. Oral squamous cell carcinoma commonly presents itself as three tumour types: exophytic, ulcer and infiltration (59). The exophytic lesion is generally most common with an appearance being enlarged often with a tumour nodule and a verrucous (wart) mass surface found on the lip, gingiva or buccal mucosa. The size of the lesion was measured with a disposable probe called Vivacare TPS Probe (Vivadent Ets., Bendererstrasse 2 FL-9494, Schaan/Liechtenstein). The information about cancer staging was taken from hospital pathology reports. In Vietnam, one of the most commonly used staging systems is the ‘Tumour, Lymph Nodal Involvement, Metastasis (TNM) system (Table 2) (60). Table 2. International Cancer Classification (TNM)  International Cancer Classification - Tumour, Lymph Nodal Involvement, Metastasis (TNM) * Tumour Involvement Stage I= T1 N0 M0 Stage II = T2 N0 M0 Stage III = T1 N1 M0, T2 N1 M0, T3 N0, N1 M0 Stage IV = T4 N0, N1 M0, any T N2, N3 M0, any T any N M1 Lymph Nodal Involvement  19  International Cancer Classification - Tumour, Lymph Nodal Involvement, Metastasis (TNM) * N - 1= 1 node <3cm 2= A: 1 node 3-6cm B: many nodes <6cm / same site C: many nodes <6cm/ different sites 3= >6cm Metastasis Involvement M – 0 = no metastases 1 = distant metastases *International Union Against Cancer (UICC) Classification – 1997 The TNM system has been accepted by the International Union Against Cancer (UICC) (60) and the American Joint Committee on Cancer (AJCC) therefore, most medical facilities use this system as their main method for reporting cancer staging (61). This system identifies three important characteristics of cancer and assigns a level of severity to each of them. The TNM staging system is based on the extent of the tumour (T), spread to lymph nodes (N), and metastasis spread to other parts of the body (M) (60). In this system, the ‘T’ component and the scores 1-4 define the size of the tumour and whether or not it has spread or extends to surrounding tissues. A higher score indicates either a larger tumour or one that has a more detrimental effect on the tissues (61). The ‘N’ component and number 0-2 describes whether or not the tumour has spread into the surrounding lymph nodes, the number of nodes involved, their size and indication of a more severe condition (61). The ‘M’ component of the system indicates if any distant metastases were found. A metastatic growth is one that is in a location distinct from the original site of tumour formation (61). For 20  example, a 0 paired with M indicates that there are no distant metastases, while M1 indicates that there are distant metastases. Each tumour is assigned a series of identifiers including a T, N, and an M to establish an overall stage for the cancer, described as stage 0, I, II, III, or IV. A lower number in the TNM grading corresponds to a lower stage and less severe cancer (61). For example, stage 0 represents early cancer that is present only in the layer of cells in which it began. Stages I, II, and III indicate a more extensive disease, greater tumour size, and/or spread of cancer to nearby lymph nodes and/or organs close to the primary tumour. Similarly, the Stage IV indicates the cancer has spread to another organ (61). A physical functional status scale, most often used in hospital research in Vietnam in patients with a terminal disease is the Karnofsky Performance Scale (KPS) (Table 3). This scale measures the decline in functional status in the context of physical performance. Concomitantly it is used as an important indicator of survival. Each subject is given a percentage value ranging from 100% for normal to 0% for deceased. Table 3. The Karnofsky Performance Scale The Karnofsky Performance Scale  %  Normal; no complaints; no evidence of disease  100%  Able to carry on normal activity; minor signs and symptoms of disease  90%  Normal activity with effort; some signs and symptoms of disease  80%  Cares for self; unable to carry on normal activity or do work  70%  Requires occasional assistance, but is able to care for most personal needs  60%  Requires considerable assistance and frequent medical care  50%  Disabled; requires special care and assistance  40%  21  The Karnofsky Performance Scale  %  Severely disabled; hospitalization indicated although death not imminent  30%  Very sick; hospitalization necessary; requires active support treatment  20%  Moribund; fatal processes progressing rapidly  10%  Deceased  0%  2.4 Data Analyses The SPSS version 16 (2008) statistical program was used for data analyses and included univariate and bivariate analyses. The univariate analyses were used to describe frequency distributions of patient demographics and habits. The bivariate analyses included: the independent sample t test, Chi Square Test or Fisher’s Exact Test and Spearman’s Correlation. The mean age difference between two genders was compared by independent sample t test. The Chi Square test was used to compare prevalence of different risk habits and patterns of OSCC between two genders. Spearman’s correlation was used to correlate the stage of cancer with the histologically assessed severity of oral cancer. Similarly, the node size was correlated with the stage of cancer and with the quantity of alcohol consumed. The quantity of cigarettes smoked per day was correlated with the quantity of alcohol consumed. By convention, associations are considered statistically significant when the corresponding p-value is equal to or less than 0.05 and not significant when the p-value is greater than 0.05.  22  CHAPTER 3 RESULTS 3.1 Oral health awareness, structure of oral health care and referral pathways in Vietnam. Vietnamese individuals with an oral health problem usually go to the drugstore without having a doctor’s prescription and explain to the pharmacy assistant about their oral lesion or symptoms. Generally antibiotics are given (amoxicillin or ampicillin) and pain medication such as ‘Efferalgan’ without the individual knowing the drug name. Furthermore, individuals in Vietnam do not usually go to the dentist unless they experience pain or have an oral problem (67.0%). Some patients in the present study indicated that they had gone to see the dentist. On arrival to the Oncology hospital, 50 per cent of the head and neck patients were diagnosed with gingival cancer and 20 per cent of the subjects were diagnosed with cancer on the tongue prior to pathology testing. Vietnam has a population of 86 million of which 65 per cent are less than 30 years old (34). The health care system in Vietnam was restructured in 2004 consisting of: 10,886 health centers in villages at the Commune level; 667 district health hospitals and 677 district preventive centres at the district level; 350 hospitals, 64 provincial prevention centers, 28 malaria centers, 22 infection disease controls and 53 secondary medical schools at the provincial level; and 30 hospitals, 15 institutions and 14 medical colleges at the central level with 16 departments of the Ministry of Health reporting to the government (62). The information about the structure of oral health care and referral pathways in Vietnam was collected from online sources and from discussions with various authorities, directors and surgeons in hospitals in HCMC. Dr. Ngo Dong Khanh described the referral pathway of patients with precancerous and cancerous lesions to the Oncology hospital or National  23  hospital in HCMC. The actual percentage of referred patients to cancer hospitals is not known. Dr. Khanh states that when individuals with precancerous and cancerous lesions are diagnosed at the general admissions of the provincial hospital, they will be referred to the Oncology Hospital; while those that are seen at the Department of Odonto-Stomatology at the provincial hospital will be referred to the National hospital in HCMC. The National hospital has a database where information is recorded regarding the number of patients treated and the type of cancer observed. Since January 2006, the southern regional hospital in Can Tho has been treating patients with cancerous lesions with cobalt radiation; however, no information is available as to the number of individuals being referred or receiving this type of treatment as there is no system in place for data record keeping. Provincial hospital referrals are not registered in an official database. Past treatment is recorded at the HCMC Oncology Hospital based upon the patient’s memory. Patient medical records are kept at the Oncology Hospital, however; a formal database is not established due to the lack of human resources and an absence of a computerized charting system. As there is no electronic patient recording system in the Oncology Hospital, patient data has to be retrieved manually from archives of medical records by doctors dedicated to attain more comprehensive information. The Oncology hospital of HCMC has 12 departments with a government allowance of 1000 beds. However, there are approximately 600 patients at night with only space for 300 beds, resulting in half of the patients sleeping on the floor. Of the 500 patients that are seen everyday, only 50 are admitted in one day. There are 40 beds in the oral surgery department with 20 new patients admitted per day, often resulting in more than three persons per bed. Of  24  all, 80 per cent of the individuals that come to the hospital for diagnosis and treatment are seen as outpatients. Individuals are initially seen at the hospital admissions. The local oncologist Dr. Tzan Thi Anh Tuong noted that more than 50 per cent of the individuals come to the hospital in the late stages of oral cancer. The treatment of patients is determined at the admissions department and either surgery, chemotherapy or radiation treatment will be prescribed. The patients that are admitted to the head and neck department for radiation are examined at the hospital dental clinic (assisted by UBC and University of Medicine and Pharmacy in HCMC) for dental treatment. In the Oral Surgery department, 30 surgeries are performed weekly with an average waiting period of 6 weeks. If there is a nodal involvement, patients are referred to the Head & Neck and Radiation departments and radiation therapy is recommended. Dr. Tuong states that only 20 per cent of patients are prescribed radiation after surgery. A follow-up of patients is recommended after one and three months. More than 70 per cent of patients return to the hospital for the one month recall especially if complications occur. Fewer patients return for the three month recall as they think they are cured and their cancer cannot reoccur. According to Dr. Linh’s study of oral cancer patients, only 56.9 per cent returned for a follow up appointment. In the Head & Neck Cancer department, there are six ward rooms consisting of three for men, two for women and one for severe cases. There are 14 to 16 beds in each room with three persons having to share one bed. The cost for one night in the cancer hospital is  25  $0.70US. Meals are provided at $0.70US for lunch and dinner or discounted if the patient cannot afford it. Breakfast is provided by charity organizations. Most cases of oral cancer and squamous cell carcinoma are presented to the Oncology hospital in HCM City. According to Dr. Nguyen Thi Hong (Oral pathologist at the University of Medicine and Pharmacy in Ho Chi Minh City), the hospital reported approximately 67.7 per cent of the cases diagnosed at stage III or IV; therefore, often only palliative radiation was recommended. Cobalt radiation is the treatment most used for external radiation. At the Oncology hospital, a patient may refuse treatment due to the cost of cobalt radiation (approximately $200 US), fear, or there may be other complicating diseases such as AIDS and the patient will be referred for further care to the National hospital. Although patients have been referred to the National hospital, the Oncology hospital is not aware if the actual referral occurred or follow-up has been performed. Furthermore, the Oncology hospital is not large enough for the high demand of prescribed radiation treatment. Even the new building with three linear accelerator units is not sufficient to take care of all patients. Until 2003 radium was used for internal radiation and since 2004 iridium is used. New linear accelerator radiation units have opened in March 2006 at the Linac Radiation Therapy Center across the street from the Oncology Hospital. During the first few weeks of the testing period, patients were not charged for the treatments. Later the patient cost was from $1500 to $2000US for the new radiation treatment; however, the majority of people in Vietnam could not afford this cost. Moreover, the majority of patients do not have enough money to go to hospitals or to pay for the diagnosis and cancer treatment. The Vietnamese doctors explained that patients (especially the rural farmers) often have to sell their house, motorbike (only means of transportation) and even their land to cover the costs related to cancer treatment.  26  Therefore, the new linear accelerator radiation therapy is available only for the wealthy at the Oncology Center, the National hospital or at the private Chinese or French hospitals. An unpublished study at the Oncology hospital by Dr. Tuong discusses the complications of radiation therapy and specifically focuses on osteoradionecrosis (ORN). Dr. Tuong’s study had a total of 51 cases of ORN from 2001-2004 (63). ORN is an acute form of osteomyelitis with sequestra formation due to severe radiation that destroys tumour cells as well as normal cells and blood vessels (64). Such radiation damage to the small arteries reduces circulation to the area, depriving it of oxygen and other necessary nutrients. Consequently, because bone normally has minimal vascularity, particularly the bones in the mandible, bone is subject to severe infections that are slow to resolve (64). The reported percentage of ORN in Vietnam is high i.e. 15 per cent of all recalled patients from the Oncology hospital having received head and neck radiation (63). In comparison, a study at the Vancouver Cancer Centre from 1975-1993 identified that 6 patients (3.37%) resulted in ORN OSCC patients who received ipsilateral radiation (65). A study in England from 1970 and 1981 found only 7.8 per cent ORN reported in 2,853 cases of head and neck tumours receiving radiation (66). In contrast, a US 1983 study of 26 patients with tonsil cancer from 1964-1975, resulted in 42 per cent of patients with ORN (67). The management of ORN is difficult and often unsuccessful and certainly disfigurement and possible morbidity is imminent. Curettage of the necrotic tissues (64) as well as oxygen delivered at hyperbaric pressures have been shown to produce new blood vessels in the irradiated area and stimulate wound healing (68). Unfortunately, no such therapeutic modalities are available at the Oncology hospital. As well there is not sufficient hospital space in the plastic surgery department for orofacial reconstruction and oral prosthesis facility. To address this need, the oral surgeons have requested more plastic  27  surgeons and personnel training. Dr. Tuong’s study concluded that osteoradionecrosis is detected too late due to a lack of knowledge by both oncologists and patients, lack of economical and human resources and a preventive protocol for oral cancer patients (63). In Vietnam, there is a trend of an increasing flow of rural to urban migration. This trend compounds the oral health problems of the urban poor population including increased oral treatment needs (69). For example, high rental costs for housing in the city demand more than one job to sustain a family. As parents and workers are often not at home being at various part time jobs, fast food and high sugar snacks for families and themselves are a replacement for well-balanced meals. Consequently, this often leads to oral health problems such as caries, periodontal problems that may lead to pain, bleeding or the impediment of oral function. As procrastination of oral care increases, the cost of oral health care increases. In Vietnam, neglect of oral professional care is prolonged due to a multitude of behavioural reasons such as the lack of time due to work schedules, fear of pain, fear of being told they did something wrong or a low designation of oral health priority. At the same time as the socio-economic status of a resource-poor country increases without subsequent health awareness, the increased incidence of oral cancer relates to the rising affluence and its consequences in increased exposure to tobacco and alcohol (70). Medical surgeons, oncologists and general doctors at the HCMC Oncology hospital in Vietnam are concerned about the oral health awareness of patients. For example, people are frightened and confused about their disease often perceiving oral cancer as contagious. The low level of oral health literacy of oral cancer patients has been related to the hospital’s extreme patient load, lack of time of health care professionals for education and lack of human resources. In the Oncology hospital, the doctors recommend that patients quit their cultural  28  risk habits which possibly caused their cancer; however, there are no available programs for risk habit cessation in the hospital. Some patient education was made available in the Head and Neck cancer wards, including a flip chart of basic questions and answers regarding oral health and oral cancer management during and after radiation. Furthermore, dental hygiene students, as part of their curriculum guidelines, presented weekly oral health education using educational tools in the oral cancer patient wards.  3.2 Clinical study of the patterns of Oral Squamous Cell Carcinoma and its Risk Habits in Patients in the Oncology Hospital in Ho Chi Minh City The highest percentage of OSCC in males was found in the youngest group and in females in the oldest group (Table 4). The highest frequency of oral cancer was observed in two age groups: 50-59 years (32.8%), and 65-74 years (27.8%) The provincial hospitals referred approximately half of the admitted patients. The highest frequency and advanced stages of oral cancer was observed in farmers (59.5%). Most patients had no previous history of cancer. Of all examined, 90 per cent of the subjects had a value on the KPS scale between 80 per cent and 90 per cent regarding their general status. This finding indicates that most patients were able to carry out normal activities despite their disease. Table 4. Background and baseline clinical data of patients diagnosed with OSCC in the Oncology Hospital HCMC, Vietnam in 2005-2006 Background characteristics  Frequencies (%) (Number)  Gender Males Females  68.0 (100) 32.0 (47)  Patient age groups 29  Background characteristics Youngest group: 24-51 years Middle group: 52-66 years Oldest group: 67-85 years Referred from other hospitals Province hospital Cancer hospital Can Tho hospital National hospital  Frequencies (%) (Number) 34.8 (39 M, 9 F) 34.8 (38 M, 14 F) 30.4 (23 M, 24 F)  26.9 4.8 2.8 1.4  (31M, (6 M, (1 M, (1 M,  8 F) 1 F) 3 F) 1 F)  Most common occupation Farmer  59.5 (48 M, 17F)  Personal Medical History No previous cancer Hypertension Heart disease History of cancer Tuberculosis  78.4 (77 M, 8.2 ( 7 M, 6.0 ( 4 M, 4.1 ( 3 M, 3.0 ( 2 M,  KPS Scale (%) 0 70 80 90 100  0.7 1.5 50.0 39.6 8.2  27 F) 4 F) 4 F) 3 F) 2 F)  ( 1 M, 0 F) ( 0 M, 2 F) (47 M, 20 F) (34 M, 19 F) ( 9 M, 2F)  In the present study, sixteen individuals (10.9%) went to the doctor at the provincial hospital where antibiotics were prescribed for stomatitis. Often Vitamins A, D, E and pain medication were also recommended. As these individuals did not notice any decrease in their lesions, they returned to the doctor and subsequently were referred to the Oncology hospital in HCMC. Provincial hospitals referred 26.9 per cent of these patients to the oncology hospital. Six individuals reported using Asian traditional herbal medicine (4.1%) to treat their oral lesions(s). A comparison of the present study with past studies enabled the study of the patterns of OSCC and its related risk habits and oral lesions (Table 5). The prevalence of smoking among  30  male patients was high (91%) and was comparable to Linh’s study (89.4%). The Khanh study reports smoking in the general population of males to be substantially lower (32.9%) than in OSCC patients (66.4%) (41;71). The prevalence of smoking in the present study among females (2.1%) was only marginally different from Linh’s study (0.0%) (41;71). However, in 2000, Khanh reported that 10.0 per cent of females from the general Vietnamese population smoked compared to a higher percentage in OSCC patients (19.9%). A study by Hoang et al. concluded that rural Vietnam is experiencing an increase in smoking, alcohol abuse and betel quid chewing and that there is urgent need of interventions to reduce the prevalence of these risk factors (72).  31  Table 5. Time Trends- A comparison of risk behaviours Studies Sample Sample size  Lesion location Tongue Floor of the mouth Gingiva Lip Hard palate Buccal mucosa Retromolar mucosa  Present study (20052006) Oral Squamous Cell Carcinoma patients  Linh study (1993-1996) Oral cancer patients  Vi/Lan study (19981999) Oral cancer patients  Hong study (20002002) Oral Squamous Cell Carcinoma patients  Khanh study (19961997) Oral precancerous & cancer/ General populations  147 cases Males (M) Females (F) (%) (%)  1084 cases Males (M) (%)  304 cases Males (M) (%)  Females (F) (%)  110 cases Males (M) (%)  9000 subjects  Females (F) (%)  43.0 25.0 12.0 3.0 7.0 2.0 8.0  38.3 4.3 17.0 21.3 4.3 10.6 4.3  41.9 17.4 12.1 2.9 17.1 8.6 Included with palate  22.3 4.2 18.4 21.2 6.8 27.1 Included with palate  43.9 16.6 12.7 4.5 15.3 7.0 unknown  23.1 4.8 15.0 22.4 6.8 27.9 unknown  47.3 M&F 10.0 M&F 9.1 M&F 12.7 M&F 7.3 M&F 12.7 M&F 0.0 M&F  18.6 M&F unknown 8.53 M&F 13.3 M&F unknown 30.7 M&F 29.0 M&F  55.8  63.6  64.0 M&F  61.0 M&F  15.0-75.0 M&F  91.0 79.0 00.0 85.0  4.3 2.1 43.5 unknown  89.4 59.4 00.0 59.4  unknown unknown 76.1 unknown  92.4 76.4 00.0 73.2  9.5 unknown 64.6 unknown  87.5 63.3 00.0 63.3  unknown unknown 64.8 unknown  66.4 19.9 54.1 6.3 00.0 4.2 18.2 M&F  00.0  00.0  00.0  00.0  00.0  00.0  00.0  00.0  Females (F) (%)  Males (M) (%)  Females (F) (%)  Average age (years) Risk habit Smoking Alcohol Betel Quid Smoking and Alcohol Smoking & betel quid chewing  32  32  63.0 M&F  1.0 M&F  Studies Sample Sample size  Present study (20052006) Oral Squamous Cell Carcinoma patients  Linh study (1993-1996) Oral cancer patients  Vi/Lan study (19981999) Oral cancer patients  Hong study (20002002) Oral Squamous Cell Carcinoma patients  Khanh study (19961997) Oral precancerous & cancer/ General populations  147 cases Males (M) Females (F) (%) (%)  1084 cases Males (M) (%)  304 cases Males (M) (%)  110 cases Males (M) (%)  9000 subjects  Females (F) (%)  Females (F) (%)  Females (F) (%)  Males (M) (%)  Females (F) (%)  Smoking patterns Number of years of smoking No smoking 9.0 95.7 < 5 years 4.2 2.1 5-9 years 5.9 0.0 10-20 years 26.5 0.0 >20 years 54.4 2.1 Number of cigarettes smoked per day 1-2 per day 9.4 95.7 3-5 per day 10.4 2.1 6-9 per day 12.5 0.0 10 - >20 per day 67.7 2.1 Alcohol patterns Years of alcohol use No drinking 11.8 <5 years 1.5 5-9 years 5.9 10-20 years 26.5 >20 years 54.4 Betel quid chewing patterns No betel 100.0 chewing 0.0 0.0 < 5 years 5-9 years 0.0 10-20 years 0.0 >20years  33  33  7.6 3.1 3.7 15.9 69.5  12.5  33.6 24.7 22.2 12.2 7.3  67.8  4.8 17.3 18.6 59.3  18.3 19.4 21.4 40.9  97.9 0.0 0.0 0.0 2.1  23.6 7.6 10.8 15.3 42.8  100.0 0.0 0.0 0.0 0.0  56.5 2.2 0.0 2.2 39.1  100.0 0.0 0.0 0.0 0.0  36.7 4.8 2.1 11.5 44.9  35.4  60.9  95.8 1.0 2.0 1.2 (> 10 years)  Studies Sample Sample size  Present study (20052006) Oral Squamous Cell Carcinoma patients  Linh study (1993-1996)  147 cases Males (M) Females (F) (%) (%)  Hong study (20002002) Oral Squamous Cell Carcinoma patients  Khanh study (19961997) Oral precancerous & cancer/ General populations  1084 cases Males (M) (%)  304 cases Males (M) (%)  110 cases Males (M) (%)  9000 subjects  Females (F) (%)  Females (F) (%)  Oral hygiene status (OHI-S) Greene -Vermillion Index Good 3.0 8.5 Medium 18.0 14.9 Poor 24.0 17.0  29.6 M&F 33.6 M&F 36.8 M&F  Clinical characteristics of lesions Exophytic 49.0 44.7 Ulcer 24.0 21.3 Infiltration 8.0 6.4 Combined 12.0 17.0 Others 7.0 10.6  52.9 M&F 17.8 M&F 8.5 M&F 19.4 M&F 1.4 M&F  51.9 M&F 18.7 M&F 9.5 M&F 18.0 M&F 1.9 M&F  Size of lesion 0-2 cm > 2 cm–4 cm > 4 cm  14.0 61.3 24.7  2.2 66.7 31.1  14.9 M&F 40.3 M&F 44.7 M&F  T1: 14,5 M&F T2: 30.9 M&F T3: 33.5 M&F T4: 21.1 M&F  T1: 19.2% T2: 36.4% T3: 30.0% T4: 15.4%  Stage of Cancer Stage I Stage II Stage III Stage IV  9.0 30.0 33.0 28.0  12.8 40.4 27.7 19.1  11.8 M&F 20.6 M&F 26.8 M&F 40.9 M&F  12.5 M&F 17.7 M&F 32.3 M&F 37.5 M&F  10.9 M&F 23.6 M&F 36.4 M&F 29.1 M&F  60.5 M&F 27.7 M&F 4.8 M&F 3.5 M&F  57.6 M&F 28.9 M&F 4.3 M&F 4.3 M&F  50.0 M&F 40.0 M&F 7.3 M&F 2.7 M&F  Oral Squamous Cell Carcinoma grade Grade I 55.6 60.9 Grade II 38.4 32.6 Grade III 6.1 6.5 Verrucous carc. 0.0 0.0  34  33  Oral cancer patients  Vi/Lan study (19981999) Oral cancer patients  Females (F) (%)  Males (M) (%)  Females (F) (%)  Dr. Khanh’s study reported alcohol abuse among males from the general population (54.1%) being highest in the age group of 25-29 years (9). He also notes that alcohol abuse is almost twice as high in rural areas (60.6%) as in urban areas (39.4%). Dr. Khanh reported precancerous and cancerous lesions to be associated with betel quid chewing in females in South Vietnam as 3.73 per cent of the total oral mucosal lesions (11.49%) (9). A study (56) performed in the Hoc Mon suburb of HCMC, was presented at the 2006 ‘Oral Cancer of Asia Pacific’ conference proceedings in Malaysia, reporting the habit of betel quid chewing much higher in women with cancer (45.6%) than in women from the general population of Vietnam (6.7%) (73). The report explained that 81.7 per cent of betel quid chewers in south Vietnam add tobacco by ‘rubbing and sticking’ it between the lips and cheeks (56). Dr. Lan reported betel quid with tobacco use in females at approximately the same percentage (76.2%) as the Hoc Mon study with the average starting age of chewing betel quid at 33 years and increasing in amount with increased age (74). In the present study, approximately half of the females that chewed betel nut also practiced tobacco rubbing and sticking. In the present study most women chewed from 10-20 pieces of betel nut daily (35.0%) and were 67-85 years of age. Fewer amounts were reported in Nguyen’s study in the community of Ba Diem of the district of Hoc Mon, HCMC where betel quid users chewed 3-9 quid daily (48.1%) with the majority being over 70 years of age (75). A few studies reported that a high percentage of female oral cancer patients chewed betel quid for over 20 years (Nguyen’s study 84.2%) (75), (Tran T.K. Cuc et. al. 84.3%) (56), ( present study 90.0%). In the reviewed Vietnamese studies, the most frequently reported age group of betel quid chewers was between 55 and 77 years with the majority of them being over 70 years (9).  35  In the present study, the most common type of areca nut used in the quid was dry or fresh areca with white slaked lime (50%) compared to Nguyen’s study where 18.4 per cent preferred white over red or pink slaked lime (75). 3.2.1 Self Reported Data of Risk Indicators and Univariate and Bivariate Statistics The gender differences regarding self reported risk habits in OSCC Vietnamese patients are presented in Table 6. Table 6. Gender differences in risk habit distribution in OSCC Vietnamese patients * Risk determinant  Males %  Females %  Total %  Most common risk habits Smoking 91.0 4.3 62.6 Alcohol 79.0 2.1 58.5 Betel Quid Chewing 0.0 43.5 13.7 All differences statistically significant (Chi Square Test, P=.000)  Smoking Years of smoking No smoking 9.4 97.9 38.9 5-9 years 5.2 0.0 3.5 10-20 years 20.8 0.0 14.6 >20years 64.6 2.1 43.1 All differences statistically significant (Chi Square Test, P=.000) Number of cigarettes smoked per day None 9.4 95.7 38.2 3-5 cigarettes per day 10.4 2.1 8.3 6-9 cigarettes per day 12.5 0.0 7.6 10-20 cigarettes per day 67.7 2.1 45.8 All differences statistically significant (Chi Square Test, P=.000)  Alcohol use Years of alcohol use No drinking <5 years  11.8 1.5  97.9 0.0  45.6 1.8  36  Risk determinant Males % Females % Total % 5-9 years 5.9 0.0 3.5 10-20 years 26.5 0.0 15.8 >20 years 54.4 2.1 33.3 All differences statistically significant (Chi Square Test, P=.000) Quantity of alcohol used per day No drinking 11.8 97.9 45.6 < .25 litre per day 14.7 quantity 8.8 .25 to .50 litre per day 48.5 unknown 29.8 .50 to 1 litre per day 20.6 13.2 >1 litre per day 4.4 2.6 All differences statistically significant (Chi Square Test, P=.000)  Betel Quid use Years of betel quid use No betel quid use 100 56.5 86.3 <5 years 0.0 2.2 0.7 10-20 years 0.0 2.2 0.7 >20 years 0.0 39.1 12.3 All differences statistically significant (Chi Square Test, P=.000) Number of pieces of betel quid per day No history 100 57.8 86.9 <3 pieces 0.0 8.9 2.8 3-5 pieces 0.0 8.9 2.8 6-9 pieces 0.0 8.9 2.8 10-20 pieces 0.0 15.6 4.8 All differences statistically significant (Chi Square Test, P=.000) Type of areca nut Dry areca White lime 0.0 24.4 7.1 Fresh areca White lime 0.0 24.4 7.1 Dry areca Red lime 0.0 14.6 4.3 Fresh areca Red lime 0.0 17.1 5.0 All differences statistically significant (Chi Square Test, P=.000) Additives to Betel Quid Tobacco pieces 0.0 4.8 1.4 Bark of tree, pomello peel 0.0 12.2 3.5 Tobacco sticking 0.0 25.6 7.2 Tobacco rubbing 0.0 28.2 7.9 All differences statistically significant (Chi Square Test, P=.000) *Chi Square Test or Fisher’s Exact Test  37  The most prevalent self reported risk habit for males was smoking (91.0%), revealing males in the 41-71 year old age group smoking most (84.0%) and for an average for over 20 years. Two females (4.3%) reported smoking for over 20 years. Daily alcohol use was reported by 84.0 per cent of males and by 2.1 per cent of females. Approximately half of the males reported drinking for over 20 years and in the amount of 0.25 to 0.50 litres per day. Betel quid chewing has cultural and traditional social significance particularly among elderly Vietnamese women. There is a common saying in Vietnamese social circles "the betel begins the conversation"(76) . The traditional wedding gift from a groom to the bride’s mother is an assortment of areca nut, piper betel leaf, slaked lime, tobacco and additives such as the bark of the areca nut tree, peel of the areca nut and the pomello fruit peel even if betel quid chewing is not practised (76). Based on a folk tale, the betel leaf and areca nut are important symbols of love and marriage and the phrase "matters of betel and areca" (chuyện trầu cau) is synonymous with marriage (76). The self reported data revealed that over 40% of the women with OSCC chewed betel quid (43.5%), two women reported using betel quid as well as smoking (4.3%) and one (2.1%) practiced all three risk habits i.e. betel quid chewing, smoking and alcohol abuse. Most of the women using betel quid were aged 67-85 years and in average chewed 10-20 pieces of betel quid daily. The most common type of areca nut used in the quid was dry or fresh areca with white lime. One quarter of the females used additives in their quid such as the bark of the areca tree, pomello peel or areca nut peel. Only two women used tobacco in the betel pieces yet 11 patients practiced tobacco rubbing and sticking. None of the male patients reported to chew betel quid. During the field trip to Hoc Mon for research study (56), some of the  38  betel quid users provided a demonstration of this practice. The majority of the female subjects chewed betel quid on both sides of the buccal mucosa. Oral hygiene status (Table 7) as evaluated by the OHI-S index (Table 1) was mostly ‘poor’ (50.8%) and ‘moderate’ (36.9%) status although the majority of patients brushed two times per day. Table 7. Oral Hygiene Status of OSCC patients  Oral Hygiene Status  Males (%)  Females (%)  Total (%)  Brushing amount per day No brushing 10.1 17.1 12.0 One time 37.1 37.1 36.8 Two times 41.6 28.6 39.2 Three times 11.2 17.1 12.0 Gender differences not statistically significant (Chi Square Test, P.=.565) Oral hygiene Status-‘Simple Oral Hygiene Index’ (OHI-S) Good (0.0 - 1.2) 3.0 8.5 12.3 Moderate (1.3 - 3.0) 18.0 14.9 36.9 Poor (3.1 - 6.0) 24.0 17.0 50.8 Gender differences not statistically significant (Chi Square Test, P=.235) Dental visit frequencies Never 25.8 36.0 28.6 Emergency: dental problem 68.2 64.0 67.0 Regular ( annual) 6.1 0.0 4.4 Gender differences not statistically significant (Chi Square Test, P=.328)  The most reported reasons for seeking professional help at the Oncology Hospital (Figure 2) were ‘noticing an ulcer’ (69.4%), ‘pain’ (27.2%) and ‘tumour’ (27.2%). Previous history of cancer was reported by 7.4 per cent. The reported site of the lesion was as follows:  39  the right side of the tongue (21.1%), the floor of the mouth (18.6%), the left side of the tongue (12.4%), the lower gingiva (8.7%) and the lip (7.5%).  Cancer  3, 2% 1, 1% 4, 3% 7, 4% 6, 4% 16, 10% 27, 17%  Hospital referrals Tumour Ulcer Pain  27, 17%  Lesion Difficulty to swallow 69, 42%  Bleeding Quick increase in size  Figure 2. Self reported reasons for seeking professional help at the Oncology hospital  Gender differences regarding clinical characteristics of cancerous lesions are presented in Table 8. The most common locations of the lesion (Figure 3) in males were: tongue, floor of the mouth, and the gingiva and for females were: tongue, lip, and the gingiva. More than 85 per cent of the lesions were two centimetres in size or larger. The exophytic, ulcer and infiltration type of lesion were reported. The most common type of lesion was the exophytic lesion which grows outward and proliferates on the exterior (47.6%). Of all, 22.4 per cent of patients had an ulcerous lesion which is invasive in the tissue and an open sore most often found on the tongue and floor of the mouth. The infiltration type of lesion is the most invasive and most often found in late diagnosis of OSCC, realized by touch. The infiltration  40  type is a less common combined tumour and was most frequently located on the tongue and floor of the mouth (14.3%).  Lip: 38.3% females Gingiva: 12.0 % males 17.0 % females Tongue: 43.0 % males 38.3% females Floor of mouth: 25.0% males  Figure 3. Locations of OSCC lesions in males and females  Table 8. Gender patterns in clinical characteristics of lesions in OSCC patients *  Males (%)  Females (%)  Total (%)  History of Lesion < 6 months 79.6 6 months 8.2 7 months-1 year 10.2 >1 year 2.0 Gender differences not statistically significant  66.7 76.2 8.9 9.1 15.6 11.9 8.9 2.8 (Chi Square Test, P=.193)  Clinical characteristics of lesions Exophytic 49.0 Ulcer 24.0 Infiltration 8.0 Combined 12.0 Others 7.0  44.7 21.3 6.4 17.0 10.6  47.6 22.4 7.5 14.3 8.2  41  Males (%) Females (%) Total (%) Gender differences not statistically significant (Chi Square Test, P =.709) Size of lesion 0-1cm 5.4 >1cm-2cm 8.6 >2-3cm 32.3 >3-4cm 29.0 >4cm 24.7 Gender differences not statistically significant  2.2 4.3 0.0 5.8 40.0 33.8 26.7 28.8 31.1 27.3 (Chi Square Test, P =.215)  Stage of Cancer Stage I 9.0 Stage II 30.0 Stage III 33.0 Stage IV 28.0 Gender differences not statistically significant  12.8 11.0 40.4 32.9 27.7 31.5 19.1 24.7 (Chi Square Test, P =.428)  Oral Squamous Cell Carcinoma Grade Grade I 55.6 Grade II 38.4 Grade III 6.1 Gender differences not statistically significant  60.9 56.5 32.6 36.7 6.5 6.8 (Chi Square Test, P =.653)  Nodal Involvement None 46.0 1 node 36.0 2 nodes 14.0 >2 nodes 4.0 Gender differences not statistically significant  63.8 52.4 23.4 31.3 12.8 16.3 0.0 0.0 (Chi Square Test, P =.162)  Type of leukoplakia Homogeneous 2.1 4.7 2.9 Non-homogeneous 0.0 2.3 0.7 Gender differences not statistically significant (Chi Square Test, P =.220) Location Tongue 43.0 38.3 41.5 Floor of the mouth 25.0 4.3 17.7 Lip 3.0 21.3 8.8 Gingiva 12.0 17.0 13.7 Retromolar Mucosa 8.0 4.3 6.1 Buccal Mucosa 2.0 10.6 5.4 Palate 7.0 4.3 6.8 Gender differences statistically significant (Chi Square Test, P =.000)  42  Males (%)  Females (%)  Total (%)  Treatment Radiation (external) 89.6 66.7 (P=.002) 81.7 Radiation (internal) 11.6 9.1 (P=.776) 10.7 Chemotherapy 2.1 2.4 (P= 1.00) 2.2 Surgery 35.4 56.5 (P= .010) 43.4 No treatment 3.0 4.3 (P= .655) 3.4 Some gender differences statistically significant (for (Chi Square Test, P values refer above) *Chi Square Test or Fisher’s Exact Test In the present study, two thirds of the cases of OSCC were diagnosed at the 2nd and 3rd stage of cancer (48 and 46 out of 147 respectively). The most common reported stage of cancer for males was Stage III and for females Stage II. The more advanced stages of cancer were observed in males than in females. Approximately one third of the patients had at least one nodal involvement. The histology of OSCC (males and females combined) was most frequently reported as OSCC Grade 1. In most cases, radiation therapy was prescribed for the majority of the patients. Although the mean age of female OSCC patients (63.6 years) was higher than the mean age of males (55.8 years), this difference was not statistically significant. The stage of cancer correlated (Pearson correlation) significantly with the histologically assessed severity of oral cancer (coeff. =0.255, p=.011). The increase of node size correlated weakly with the late stage of cancer (coeff. =0.260, p=.007) and with the quantity of alcohol use (coeff. =0.262, p=.023). The number of cigarettes per day correlated with the quantity of alcohol use (coeff. =0.252, p=.030). Upon noticing their lesion, men tended to seek professional help relatively soon although the oral cancerous lesion was in an advanced stage. A higher percentage of males (71.6%) than of females (28.4%) sought professional help early i.e. within 6 months of  43  discovery of their lesion. No statistically significant gender differences in regards to delayed diagnosis were observed.  44  CHAPTER 4 DISCUSSION 4.1 Oral health awareness, structure of oral health care and patient referral pathways in Vietnam Oral health awareness is virtually non-existent in resource-poor countries such as Vietnam. People are not aware about the use of cultural risk factors such as tobacco, alcohol abuse and betel quid chewing and the association with compromised or deteriorated health. People go to the dentist only if they notice a problem or have pain rather than seek preventive oral health care i.e. regular dental appointments. Public oral health education is scarce as skilled public health personnel are few and financial resources are minimal.  Oral cancer is often not being detected and diagnosed in Vietnam until a very late stage. In Vietnam, people only go to the doctor if they are sick. Some Vietnamese people believe that if someone has cancer, it is the fault of the person, and he or she did not take good care of themselves. As a result, treatment at such an advanced stage is often only palliative. Oral cancer is therefore considered among the most debilitating to normal oral function and disfiguring of all cancers (77). In the Oncology hospital in HCMC, the head and neck cancer patients are immuno-compromised with considerably increased secondary risk of oral diseases and oral infections. The hospital protocol is that Computerised (Axial) Tomography (CT) scans are performed on patients only when there are brain or bone symptoms. The imminent oral health problems and risk factors have been acknowledged by the dentists of the General Practice Residency program, Faculty of Dentistry, University of British Columbia, Vancouver, Canada while in HCMC, Vietnam. As many as 26 cases in 1000 patients, admitted daily at the HCMC Oncology Hospital, are diagnosed with advanced oral  45  cancer possibly due to tobacco use and inadequate diet. These observations of such an advanced oral disease may be the result of cultural, socio-economic and behavioural challenges such as limited access to oral health care, inadequate oral health and nutritional information, lack of funds and cultural risk factors such as the use of tobacco, frequent alcohol use, and the use of betel quid. Notable differences are reported in oral cancer mortality and incidence between population groups according to ethnicity and socio-economic status. Evidence suggests that the socio-cultural lifestyles of a population play an important role in the aetiology and pathogenesis of oral cancers (78). The natural course and history of oral cancer is a two-step development from normal to hyperplasia to dysplasia to neoplasia. Histologically, this is explained without evidence and with evidence of invasion of cancer cells. The course of oral cancer development is represented by initial lesions such as precancerous, precursor  and pre- and potentially  malignant lesions such as leukoplakia and oral conditions such as oral submucous fibrosis and lichen planus (79). Leukoplakia is a known precursor lesion with global estimates of 2.6 per cent; however, it is generally regarded as underreported (80). Furthermore, not all dysplasia will develop into oral cancer and further research is aimed at relating biological characteristics to the malignant potential of leukoplakias. As oral cancer rates are causing increasing concern worldwide, the World Health Organization is urging the implementation of evidence-based strategies for prevention, early detection, diagnosis, treatment, rehabilitation and palliative care and the evaluation of the strategies of oral cancer control (81). The 2005 World Health Assembly Resolution encouraged the scientific research necessary to increase knowledge about the burden and cause of oral cancer that has high incidence rate in low-resource countries (81). Further  46  comprehensive approaches are required to combat oral cancer uniquely tailored to the cultural and socioeconomic context of resource-poor countries and the neighbouring related communities worldwide. The present study in Vietnam reveals the necessity of increasing the general awareness and prevention strategies for oral cancer. One recommendation from this study is for clinical intra- and extra-oral examinations by health professionals to be performed. Another recommendation is to strengthen general health by recommending not indulging in common cultural risk habits such as tobacco use, alcohol abuse and betel quid chewing. These recommendations could be incorporated when individuals go to the primary health care provider for vaccinations or general health concerns. However, for these strategies to occur the primary health care providers must be educated in the awareness of oral cancer and what constitutes healthy and non-healthy mucosal tissues. The structure of oral health care in Vietnam is organized by the Ministry of Health. The health system in Vietnam is a mixed public-private provider system. The majority of people in Vietnam live in poverty and the rural areas with limited funds for healthcare. A large disparity in access to health care facilities exists across regions and population groups, particularly in the mountainous rural areas, among minority ethnic groups and the poor. There are no hospitals in the rural areas of Vietnam although a few community health centers with limited human resources service these regions. Health care expenses for Vietnamese are very high i.e. many individuals can not afford to travel to the city for diagnosis and subsequently pay for a costly treatment. Such an economical problem contributes to a delayed diagnosis as observed in the present study. Fear is another factor which may further explain a delayed visit to a health professional.  47  Patient follow-up and referral pathways in Vietnam are not well established. Patient education informing the importance of and the recommendation of follow-up after treatment appears to not be effective. Patient reports in the present study reveal that Vietnamese seem to have misconceptions about oral cancer in that they perceive cancer as a contagious disease or believe that cancer once treated will not re-occur. These misconceptions may give the explanation as to why almost 50 per cent of treated Vietnamese cancer patients do not return to the hospital for their follow-up examinations. To solve this problem, recommendations have been presented to the Ministry of Health by oral pathologists and oncologists of the need to provide access of information about oral cancer and the associated risk factors to both health care professionals and their patients. In Vietnam, there are no federal guidelines for drug administration such as prescriptions of drugs and medications, therefore patients acquire their medications recommended by pharmacists or pharmacist assistants prior to coming to the Oncology hospital. Frequently health advice is given by health care workers and herbalists who do not possess adequate medical expertise i.e. they are incompetent to diagnose the individual’s problem. Consequently, this self-administration of drugs has possibly resulted not only in misdiagnosis but also a subsequent delay of professional help leading to diagnosis at the late stages of cancer, as well as a possible overuse and misuse of antibiotics. In the present study, there were an increased number of people seeking medical attention from the central areas of Vietnam that travelled for healthcare south to HCMC rather than north to Hanoi. This notable preference is due to patients’ belief that Hanoi and northern Vietnam is politically closed to the world and therefore may be lacking in modern healthcare and equipment.  48  In earlier studies, more cases of oral cancer were seen from rural areas while recently more patients with cancer were from urban areas (9). People from rural areas tend to increase their smoking and alcohol abuse when relocating to urban areas. This phenomenon occurs due to the increased affluence of people and the ability to financially support risk habits. As expected, the prevalence of risk habits such as smoking and alcohol abuse was higher among OSCC male patients than among the general Vietnamese male population. The trend of these risk habits was reverse for females, i.e. female cancer patients had a lower prevalence of smoking and alcohol abuse than females from the general Vietnamese population. These differences were only marginal and as previously commented could possibly be attributed to the underreporting of culturally unaccepted behaviour among females. Worldwide, today’s women’s rates of oral cancer are reported to be lower than men’s. However, the age-standardized rates (ASR) per 100,000 inhabitants for oral cancer in the Hanoi (North) Registry (1993-1997) were 0.8 in males and 1.1 in females. In the HCMC (South) Registry (1995-1998) the ASR for oral cancer was 1.9 for males and 1.3 for females (11). During the past 10 years, the male/female ratio of prevalence of oral cancer gradually changed from a female to male predominance: 1.0 males/1.5 females in 1993 to 1.1 males/1.0 females in 2000 and 1.3 males/1.0 females in 2001 (11). These numbers show a possible trend of decreasing oral cancer in females. Possibly this improvement might be related to the decrease in betel quid chewing among women.  4.2 Patterns of Oral Squamous Cell Carcinoma and its Risk Factors in Patients in the Oncology Hospital in Ho Chi Minh City A comparison between past studies and the present study showed similar patterns of location of OSCC lesions. In all the studies, as shown in Table 5, the location of the majority 49  of male OSCC lesions were found on the tongue, floor of the mouth, hard palate and gingiva. As revealed in the same table, the location of the majority of female OSCC lesions were found on the tongue, lip, gingiva and buccal mucosa. The present study observed more lesions to be on the gingiva than the buccal mucosa. Possibly this finding relates to a higher number of males than females in the present study. Cancer of the gingiva was associated with tobacco use and alcohol abuse in males and cancer of the lip was associated with betel quid chewing. The most commonly found type of lesions in Vietnamese OSCC patients were the exophytic and ulcerous type of lesions. The present as well as previous studies in Vietnam reported similar findings. Further research may explore as to which type of lesion may be due to the type of cultural risk habits used or to the uniqueness of the Southeast Asian population (78). The size of lesions in the present study was smaller than previous studies. Possibly patients became aware of the necessity of seeking medical or dental attention earlier than in previous years. The oral cancer lesions in the present study were diagnosed histologically at an earlier stage than in earlier studies possibly due to increased education regarding awareness of the signs of cancer. The OSCC grade of cancer was similarly reported in the reviewed studies. Smoking rates in Vietnam appear to be decreasing (66.4% to 53%) (82;83). This could be due to the adoption of the Vietnam National Tobacco Control program launched in 2002 and measures to restrict tobacco i.e. banning of tobacco advertisements, smoking restrictions, taxation and labelling (71). Public health education may have increased the public’s awareness of smoking as a risk factor for cancer. A possible further explanation for the reduction in smoking is that in the past Government employees had been given a monthly ration of cigarettes by the government. However due to the economics change to marketing, they have been ‘deprived’ of this ration since 1986 (84).  50  In the present study, daily alcohol use in men was highly prevalent (79.0%) while low in women (2.1%). This substantial difference between genders in regards to smoking and alcohol use can be explained by cultural norms. Concomitantly, as it is culturally not acceptable for women to smoke or drink alcohol in Vietnam, one can expect the possible underestimation of these two risk habits in female Vietnamese patients. The comparison of findings in the present study as compared to Linh’s study seven to ten years earlier revealed that there may be an increase (20%) in alcohol abuse among male OSCC patients. None of the females reported alcohol use in Linh’s study, and a few (2.1%) reported this habit in the present study. In Khanh’s study of the general population five years earlier than the present study, alcohol use among males was similar in Hong’s and Linh’s study of OSCC patients. The present study revealed that the majority of men who drank alcohol also smoked cigarettes. Seemingly, alcohol abuse appears to be rising among males. Betel quid chewing among Vietnamese women is still prevalent and needs to be addressed in health promotion campaigns as little information about its association with oral cancer and pre-cancerous lesions is available to the public (73). In the present study, over 40 per cent of the female patients with OSCC reported having lesions associated with betel nut chewing including leukoplakia (10.6%), oral submucosal fibrosis (6.4%), erythroplakia (2.1%), lichen planus like lesions (2.1%), and other lesions (12.8%). Moreover, previous studies in Vietnam reported pre-cancerous lesions to be associated with betel quid chewing (9). Dr. Khanh’s study concluded that betel quid chewing is a substantial risk to develop precancerous lesions and showed oral lichen planus to be 15 times higher in female betel quid chewers as compared to females not reporting this habit. Similarly, the presence of submucosal fibrosis was 124 times higher in betel quid chewers as compared to non-betel quid chewers.  51  Khanh reported in his general population study that less than five percent of females chew betel quid. The majority of the OSCC female patients in Khanh’s and Hong’s study chewed betel quid, while the present study reported that less than half of the OSCC female patients chewed betel quid. This difference might be related a possible positive trend towards the reduction of betel quid chewing among females. Further positive change is that less females in the present study than in the past chewed betel quid with tobacco added. Possibly this decrease in female betel nut use may be related to increased oral health awareness. Khanh’s study reported that the risk of betel quid chewers using tobacco and developing oral precancerous and cancerous lesions is three times higher than of those betel quid chewers without the use of tobacco (9). Tobacco chewing among Southeast Asians reveals a higher risk than smoking, possibly due to the enhanced topical effect of nitrosamines which are resent in higher concentrations in exudations from betel quid than in tobacco smoke (85) . In order to reduce health risks and consequently prevent occurrence of oral cancer, it is important to launch population-based health education campaigns for increasing knowledge about cancer and its related risks. As expected, different oral cancer related cultural risk habits such as tobacco, alcohol and betel quid use was lower in the general Vietnamese population than in cancer patients. Due to increased public health awareness of the detrimental effects of these risk habits and the advertising of negativity towards people smoking, social norms are changing in Vietnam. With such well-known risk factors as tobacco and alcohol, theoretically it is possible to prevent oral cancers. A large intervention trial and ten year follow-up study in India provides evidence that even if individuals had precancerous lesions, the chance of the lesion becoming cancerous is reduced if patients stop their dependence on tobacco (86). A study in Sri Lanka in  52  1984 suggested that using primary health care workers to educate adults to stop or not to be involved in the habit of betel-quid chewing might be five times more cost effective in reducing mortality than providing the very costly treatments necessary for those with the disease (87). Implications of educating children as to not taking up the betel quid habit may be considerably greater. General health promotion strategies such as discouraging the common risk habits of smoking, alcohol abuse and betel quid use may be directed to the public to lower oral cancer incidence; however, evidence of cost effective methods for reliably promoting such behaviour has not yet been established. (88). Prevention of oral cancer through education is one approach. A further approach of prevention strategy is the possibility of population screening. Oral cancer screening is based on the idea that early detection will increase survival and quality of life. Screening programs can be based on three types called invitational (89), opportunistic (90), or case finding (91). Invitational screening programs for oral cancer and precancerous lesions have been found to have poor volunteer attendance being approximately 15 per cent with 5 per cent of attendees being identified for further testing (92). One opportunistic program revealed a prevalence of disease at approximately 3 per cent (90). Evidence to support the use of screening tests must be identified as to its validity in its ability to distinguish between who has the disease and who does not. The test parameters of the validity of screening tests is based on sensitivity in identifying correctly those who have the disease and specificity in identifying correctly those who do not have the disease (23;93). Often the tests results are compared to another definitive test (usually histology) that has been in use as the ‘gold standard’ identifying who has the disease and who does not (23). Relevant to the benefit of screening are the positive and negative predictive value both dependent on the  53  prevalence of a particular disease (23;93). In all screening programs, people identified as positive to having the disease include those who really have the disease (true positives) and those who do not have the disease (false positives) (23;93). The issue of false positives has considerable individual as well as cost related implications i.e. those who are brought back for further testing experience considerable anxiety and distress and unnecessary tests are an economical burden on the health care system (93). Similarly, the issue of false negatives has a serious health consequence as those who do have the disease continue to be undiagnosed. In the case of oral cancer as a disease that is curable in its early stages, being a false-negative could be fatal (93). Therefore, the importance of sensitivity and specificity of screening tests as well as their positive and negative predictive values have both individual as well as population related implications. Curing the disease depends on the nature and severity of the disease being screened for, the effectiveness of available treatments, and whether the effectiveness of reducing disease rates is considerably related to diagnosis at an early stage of the natural history of the disease (93). The value of a screening program is complicated by the possibility of different sources of bias which may give misleading indication of success such as self-selection (volunteer) bias (individuals from higher socio-economic groups might be more concerned about health and unlikely to have the disease), lead time bias (diagnosis of oral cancer is determined yet without altering the time of mortality), and length bias sampling (fast growing tumours may not be diagnosed early enough in screenings of extended intervals) (93;94). These biases may cause false optimism to the benefits of an oral cancer screening program (94). Opportunistic screening for oral cancer is often suggested in the context of a clinical assessment linked to routine oral health care and the provision of information to patients who may be at high risk. The recommended age for screening is the age of forty years and the  54  screening to be employed in a general dental or medical practice (95). A large randomized clinical trial of oral visual screening for oral cancer has been performed in Kerala, India since 1995 (96). An outcome was a 34 percent reduction in the tobacco and alcohol use, a reduction in the mortality of high risk individuals and an example of how to prevent morbidity from oral cancer worldwide (96). Population based screening for oral cancer in the world and particularly in Vietnam regardless of risk factors might not be feasible. A review of studies on oral cancer screening recommends early diagnosis of oral cancer detected by clinical examination as the best method of prevention (94;97). This approach might be supported by the fact that the present study showed that individuals self-reported that they do not go to the dentist or primary health care professional regularly due to cost and being unaware of oral cancer and its consequences. It is essential to know whether a screening program is cost-effective and who has to cover the related costs of it. For example, clinical screening with toluidine blue staining, direct fluorescence visualization or other procedures add to the possible cost to the individual (17). Furthermore, the risk factors of OSCC researched being tobacco use, alcohol abuse and betel quid chewing or a combination of these habits may require screening at different rates and intervals to determine the success of prevention or early diagnosis of oral cancer. Cultural risk habits unique to South-east Asians such as betel quid chewing may necessitate screening as early as at adolescent age that adds to the total cost of screening. A more cost effective approach might be to reduce the prevalence of cancer related factors. This approach might also be prioritised as reducing the prevalence of risk factors aiming at reducing the causes of disease instead of treating its symptoms. Given screening is chosen as an option to reduce the burden of oral cancers, one may consider a high-risk approach in screening.  55  Global variations in ethnicity and socio-economic status indicate specific populations to be more at risk than others; however, further research is necessary to identify which oral cancer screening programs are most effective and efficient for utilization (78).  4.3 Time trends in prevalence of risk habits in Vietnamese OSCC patients The present study expected to observe a decrease in the prevalence of risk habits when compared to previous studies due to population based oral health education. However, the time trend comparison in the prevalence of some risk habits showed an overall increased trend of more men and women using tobacco and abusing alcohol at present than in earlier years. Moreover, the prevalence of smoking among male OSCC patients has remained either at the same level over the years or even slightly increased. Similarly, the prevalence of alcohol abuse in male OSCC patients seems to be increasing. A further negative trend was observed as the age of male smokers is decreasing i.e. males start to use tobacco earlier in age. A positive time trend could be observed for females as chewing betel quid seems to be decreasing compared to previous years. In order to confirm this trend, cohort studies are needed where standardized measurements are taken which will allow comparisons among studies. The present study found a consistent pattern of a delayed diagnosis in the majority of OSCC males with stage III cancer as compared to the majority of females who were diagnosed at stage II cancer. Concomitantly, males sought medical care earlier than females. However, these differences should be interpreted with caution. A gender difference might primarily relate to a difference in risk habits between two genders, i.e. men smoke cigarettes and drink alcohol while women chew betel nut. These different risk habits might have varying effects or  56  at least of varying magnitude in regards to oral cancer development. Possibly, smoking particularly combined with alcohol facilitates the disease development more rapidly than betel nut chewing particularly without tobacco. The premise is that observed gender differences may not be attributable to the attitude of seeking professional help earlier, but that these differences may be associated with the difference in risk factor distribution i.e. males are more likely predisposed to develop more aggressive forms of cancer which are also more function impeding (by affecting speech and swallowing with pain) than cancers which females develop. This explanation might indirectly support a finding that pain appeared to be one of the major factors for seeking medical help. The findings of the present study at least partly support this hypothesis, as there were twice as many males than females who reported pain as their reason for seeking professional help. In two Vietnam studies, namely the Linh study (1993-1996) and Vi study (1998-1999), the most frequently reported oral cancer among males and females was diagnosed cancer at the most advanced stage IV(98). However more recently in Hong’s study (2001-2002), the advanced stage III was the diagnosis of the majority of cases (9;74). According to Lan’s conference report of a study from 2005, the diagnosis of oral cancer was most frequently observed at stages III and IV (9). All these studies clearly reveal the trend of late cancer diagnosis. Although the present study showed a possible slight decrease of later staging of oral cancer diagnosis in comparison with earlier studies, late staging diagnosis was still prevalent as almost half of the females and more than half of the males were diagnosed at late stages (III or IV) of OSCC. The grade distribution (histological diagnosis of aggressiveness) of oral cancer seems to be reported similarly among studies. Late cancer diagnosis considerably increases morbidity rates, therefore attempats should be made to detect cancer at earlier stages of disease  57  development. In order to facilitate earlier cancer diagnosis, an awareness of early signs and symptoms of common cancers needs to be achieved by both professionals and the population. Other difficulties relate to Vietnam’s limited health infrastructure of access to health care, shortage of economical resources and possibly fear to seek health care as people are unaware when they should seek professional help. Although the infrastructure of health care has changed with a reformed healthcare system, seemingly no change in people’s awareness or attitudes about this disease has occurred. All this might lead to the late diagnosis of cancerous lesions which may also be due to the lack of training of health care professionals and the lack of awareness of oral cancer, as well as its related risk habits among both patients and their health care providers. Diagnosis at a late stage of oral cancer has possible subsequent dramatic implications of imminent morbidity. The national register of mortality was introduced in Vietnam only in 1992 with a very limited database of cancer morbidity data available to date (99). Expectations are that oral cancer mortality rates in the country would lower due to an increased awareness and education about the known detrimental effects of smoking. Despite the limited register data, some comparisons in mortality rates are possible, e.g. in 2006 there were 30 per cent more males than females who died from oral cancer compared to 2005 (99). One can raise a question whether the incidence of oral cancer has actually increased from 2005 to 2006 or whether observed increased mortality can be explained by improved cancer register data. Therefore, future research is needed to estimate the actual time trend in oral cancer development in Vietnam.  58  As the lack of the awareness of the association of oral cancer and cultural risk habits such as smoking tobacco, alcohol abuse and betel quid chewing continues in Vietnam, no improvement in oral cancer incidence can be expected. This problem has a universal negative implication i.e. emigration from various resource-poor countries into resource-rich countries may lead to an increased incidence of severe oral diseases such as oral cancer with a subsequent increase in mortality. In a further comparison of resource–rich and resource-poor countries, Canada reports that over one-fifth (22%) of the population aged 12 or older and adults aged 20 to 44 (28%) smoked either daily or occasionally in 2005 and 2007 (100). One-third of Canadian men in the latter age group smoked, as did one-quarter of women (100). In Vietnam, smoking rates for males are higher (66%) but lower in females (20%) (11). According to the 2004 Canadian Addiction Survey, 44 per cent Canadians indicated drinking at least once a week and 9.9 per cent consumed alcohol four or more times a week in Canada (100). In comparison, daily alcohol use in Vietnam was reported at 54 per cent for males and 6 per cent for females (101). The noted substantial difference in the prevalence of risk habits such as smoking, and alcohol abuse between resource-poor and resource-rich countries is expected given insufficient education and low general awareness of health risks in resource-poor countries. Furthermore, betel quid is chewed by only 4 per cent of females in the general population in Vietnam, while the prevalence of this risk habit is considerably higher among OSCC patients (43.5%). This shows an association between betel quid use and oral cancer. The rates of betel quid use in Canada are unknown. The Health Protection Branch in Canada has banned the sale of areca nut products such as betel quid because of known  59  carcinogenic effects. However, it is anticipated that betel quid may be available in certain Southeast Asian communities residing in resource rich countries. The prevalence of oral cancer in Vietnam as reported by Linh (4.4%) is higher than in resource-rich countries such as Canada where these percentages are lower (2.6% for males and 2.0% for females) (16). In Canada, risk factors associated with oral cancer are less prevalent and the rates of oral cancer are lower. Affluence has negatively affected Vietnamese by increasing risk habits being a sign of more money and prestige. Consequently, without increasing the awareness of the detrimental effects of these habits, one can expect a further increase in both cancer rates and its associated risk habits in Vietnam if urbanization continues. In comparison, Canada shows an opposite trend, i.e. the more affluent and those with higher education are exposed to these risk factors to a lesser extent than their less affluent and less educated counterparts. This difference between countries might be attributed to a better awareness about health risks. One can hypothesize that this difference in risk factor prevalence also relates to a difference in caner rates between countries. Concomitantly, one has to consider the effects of more efficient patient referral pathways and follow-up of cancer patients in Canada than in Vietnam. A further challenge to the global oral health burden is the trend of the increasing flow of rural to urban migration leading to an increase in the prevalence of health risk behaviours, particularly in resource poor countries. Increased urbanization has evolved significantly over the past twenty years, and it is likely to become more the norm than the exception (69). Consequently, the increasing socio-economic status in the city as compared to rural living may negatively influence both oral health (70) as well as general health due to an increase in risk habits.. For example, a recent report in the Vietnamese Sunday Morning Post states “Cheap  60  food, cigarettes and city life are causing millions of early deaths in the developing world… as populations increase in cities. The tobacco scourge, now at epidemic levels in less-developed countries, exacts its tolls in many ways…”(102). Rising oral cancer statistics worldwide may  at least to some extent be a  reflection of the currently increasing urbanization and affluence in resource-poor countries (70;102). Focus only on increasing oral health awareness is insufficient for effective prevention of a disease or its re-occurrence (103). It is well known that knowledge alone does not necessarily change human behaviour. Firstly, human behaviour is extremely complex (103). Secondly, it is important to consider that lifestyles are formed in social environments i.e. they are not freely chosen and consequently, can not be easily changed by everyone without changing the cultural context in which these lifestyles primarily developed (103). A multi-factorial approach is necessary in order to effectively prevent chronic disease and cancer (104). It has been suggested that a comprehensive population-based health promotion is necessary to increase population awareness about health risks and subsequently facilitate the changes in lifestyle, cultural norms and attitudes (104). Improvements in oral health and a reduction in incidences of oral diseases are dependent upon the implementation of public health strategies focusing on the underlying behavioural determinants of oral diseases which developed within the contextual socioeconomic and cultural environments (103). A multidisciplinary promotion of health care for oral cancer patients is required (105;106). A wider access to public oral health care education is part of that approach. Although Vietnam has established a Cancer Prevention Program as well as an Oral Health Promotion National Program, presently the patients’ understanding about their oral disease is notably insufficient.  61  Moreover, the presence of other chronic diseases adds to major public health problems in Vietnam as well as in other resource-poor countries. Consequently, these problems are worth careful consideration in the context of global health programs. For example, dental caries affects nearly 100% of the populations in the resource-poor countries as well as the resource-rich countries. Periodontal diseases are prevalent in adult populations in resource-rich countries with the prevalence of severe periodontal disease being 10% to 15% (2;107). To seek efficient solutions, one has to consider the national context and what is feasible to implement given limited economical resources. The WHO Basic Package of Oral Care (BPOC) is an example of an acceptable, feasible and affordable strategy for most disadvantaged communities in order to better maintain oral health care for these populations (108). The three components of BPOC are oral urgent treatment, affordable fluoride toothpaste, and atraumatic restorative treatment (ART) (108). These services may be provided by dentally trained personnel such as dental therapists in Vietnam.  4.4 Limitations and Bias Bias is defined as “any systemic error in the design, conduct or analysis of a study that results in a mistaken estimate of an exposure’s effect on the risk of disease” (109). The World Health Organization describes bias as any trend in the collection, analysis, interpretation or errors occurring due to other reasons that can lead to conclusions or interpretation of findings that are systematically different from the truth (110). The present study comprises limitations, deficiencies and possible bias. Therefore, different aspects of possible bias will be identified and subsequently discussed. The main sources of possible bias in the present study relate to study design, measurements, comparisons made in the present study, sampling and examiners/interviewers. As being able  62  to make causal inferences is an ultimate aim of any clinical research and to understand the causality or risk of a disease in order to be able to control it; causality related issues will be discussed in a separate paragraph. Firstly, the appropriateness of the present study design for studying the link between cancer and its related risk factors should be considered. Although an experimental double blinded clinical randomized trial is considered to be the best study design for acquiring evidence, this experimental study design was completely unacceptable due to ethical reasons. Obviously, one should consider non-experimental designs as alternative options, among which the cohort study should be a first preference. In the cohort study the incidence of disease between subjects exposed to risk and the ones unexposed to risk is compared in a prospective follow-up design (93). However, the choice of the cohort design was not feasible due to a lack of both economical and human resources as well as due to the difficulties related to the organization and infrastructure inherent in a resource poor country. The next design choice would be a cross-sectional design where a random sampling is sought. The substantial limitation of this design is that the disease occurrence and risk factor exposures are studied at the same time (23;93). However, the implementation of a cross-sectional design in the present setting was also not feasible due to limited resources as well as limitations inherent in the infrastructure of Vietnam. The next consideration would be the case control study where the selection of both cases and controls should be sought carefully and adequately. This is the weakest study design in the hierarchy of evidence (111). However, the present study could not employ even this design due to the same reasons as noted earlier. The present design was a clinical retrospective study of cancer patients; this study design is the weakest design for acquiring evidence and does not allow generalizations as well as has  63  other limitations. Firstly, the disease in the present study was studied in a convenience sample i.e. cases (oral cancer patients) were identified at a hospital setting. Secondly, both disease outcome and risk factors were studied simultaneously (the same limitation as in cross-sectional studies); this excludes any possibility to make inferences of a causal nature as risk exposure and disease outcome were assessed at the same time (93). Thirdly, the present study did not comprise a control group (which is a requirement in both experimental and non-experimental studies such as cohort, cross-sectional and case control studies) (93). This means that although an association between disease and risk factors was observed in the present study, there is no certainty about its actual presence. Moreover, the inference of this association was made based on indirect comparisons of risk behaviours between oral cancer patients and general population in Vietnam, i.e. risk factors were more prevalent in cancer patients than in general Vietnam population; one still does not know how valid this finding is. Other limitations of the present study relate to measurements chosen as well as to how the comparisons with other studies were made. The survey design included open-ended questions which the patient answered in his/her own words and closed-ended questions where the patient answered by choosing from a number of semi-structured answers. The questions were clear and simple that the patient would be able to answer. However, the recording of the information was at times incomplete possibly due to work overload and lack of human resources i.e. the examiners may have asked the questions inconsistently. Such a deficiency was reported by one of the examiners and an explanation for this was that surgeons worked quickly and there was insufficient time for data recording. Moreover, recall bias might occur as patients may not have accurately recalled all the events related to the history of their lesion and/or frequency of their risk behaviours. Secondly, the validity of the questionnaire was  64  neither assessed nor secured at least to a certain extent which could have been possible given the forward and backward translation of the questionnaire was employed (112). Moreover, the interview surveys or questionnaires were translated verbatim from Vietnamese into English, therefore; the possibility of reporting bias cannot be excluded. Through this process of translation, some recordings may have been misinterpreted as the transfer of information from the questionnaire was tedious and open to human error. Clearly, limitations due to the way the interview questionnaire was administered might lead to interpretation bias. Through the comparison with other studies, certain bias might also be introduced. The comparisons of the available studies were limited due to the sample size; however, most of the OSCC patients were studied at the same Oncology hospital, used a similar interview questionnaire and also comprised a convenience sample of patients that were admitted to the same hospital but at earlier times. Another difficulty relates to findings of the Khanh study which was about risk factors in the general Vietnamese population. This was an important source of information to be translated from Vietnamese into English. Consequently, the impact of this translation is still unknown. Moreover, all compared studies were either clinical studies performed in patient samples or some of them were cross-sectional inquiries about cancer related risk factors in general populations. Consequently differences in study designs, sampling in these studies, measurements applied and different non-standardized examiners might be sources of bias. Moreover, cohort studies would have provided better comparisons but they were not available and at present are hardly feasible in Vietnam due to lack of human resources and due to the absence of a well-controlled referral and follow-up system in this resource poor country. Another deficiency is that information about risk habits in the general Vietnamese population was acquired not in the present study but from other studies where the  65  process of data acquisition might be different. Although assessments of risk factors were acquired from self reports in both studies, the wording in the questionnaires might be different; consequently this further might undermine both reliability and validity of comparisons among studies. However, in resource poor countries, one has to make the best use of information available despite all inherent limitations as otherwise none of the comparisons are possible. The third series of limitations relates to examiners. Examiners used in the present study were Vietnamese clinicians who although are familiar to examine oral cancer patients, still might introduce measurement bias due to the following reasons. Firstly, standardization of examiners was not performed. Secondly, the reliability of both intra-examiner and interexaminer agreement was not assessed. Thirdly, due to literacy problems of the Vietnamese patients, the self reports were acquired through face to face interviews. Examiner recording bias might have occurred due to interpretation problems. Fourthly, the influence of social stigma, i.e. cultural acceptance of certain risk behaviours but not others in different genders could introduce measurement bias. In Asian cultures it is important to be socially discreet or ‘save face’, therefore both questions and answers may have been adjusted particularly where data was acquired through interview. Given that it is culturally unacceptable for Vietnamese women to smoke cigarettes or drink alcohol, an inaccurate reporting by the female Vietnamese interviewer may have occurred. Consequently, it is possible that the female examiner did not ask all female patients if they smoked cigarettes or drank alcohol. Similarly, female patients might be negligent to report socially and culturally unacceptable behaviours. Thus, in culturally sensitive contexts, it is important to standardize and educate interviewers in order to acquire reliable answers to culturally sensitive questions. Furthermore, patients may have provided the  66  information but interviewers may have not recorded it or recorded it incorrectly. Another source of bias relates to the lack of human resources readily available in Vietnam. The insufficiency of human resources may provide errors in accurately reporting diagnosis as well as inconsistently recording lesion related clinical characteristics. Due to the lack of funds, trained people, equipment and facilities, the presence of metastasis was not assessed in this study at least for some participants. This might lead to a possible underestimation of frequency of metastasis. Moreover, examiners interviewed the patients using a semi - structured interview questionnaire comprising of direct ‘user-friendly’ questions. The questions were not pre-tested for both reliability and validity. A source for bias or error in the interview survey may be the way questions were asked by different examiners as questions phrased differently may have led to different interpretations by patients. The interviewers may not have asked the questions the way it was supposed to be asked or may have asked it incorrectly. Furthermore, the interviewers may have been biased by knowing the research hypothesis. Given that interviewees were oral cancer patients, interviewers may have probed more intensively seeking the information about the presence of risk factors. Interviewers may also possibly have been bolder in asking questions of the male patients than female patients regarding cultural risk habits. Another consideration of a possible source of bias is the sampling scheme and sample size. As discussed above, the present study comprised of a convenience sample which is a serious limitation at least for the generalization of study findings. Moreover, the data from the convenience sample will always be uncertain as to what extent these findings reflect the true values of Vietnamese cancer patients. The relatively small sample size in the present study is also a concern particularly given that sample size calculations were not employed prior to the  67  study. Consequently, the sample size of the present study might be insufficient to evaluate accurately the true prevalence of risk factors in cancer patients. To understand to what extent one can infer causally from study findings is one of the most important considerations in clinical research. In cancer research, this is even more important as compared to other medical inquiries as cancer has not only high morbidity rates but also very serious consequences to cancer survivors. Causality is defined as an association between two events (e.g. risk exposure and disease occurrence) in which a change in frequency or of one (e.g. risk) is observed to follow alteration in the other (disease outcome) (23). A cause may be defined as a factor that alters the probability of occurrence of a disease (113). The general guide of criteria for judging whether an association is causal or not is known as “Hill’s Postulates” and can be used to strengthen or weaken the case for causality (23). The following guide and additional criteria should be considered: temporal relationship clarifying the time order and the length of the interval between the exposure and disease; strength of the association identifying the stronger it is, the more likely the association is causal; dose-response relationship supports causality if there is a strong association between the amount, intensity or duration of risk exposure and subsequent amount and/or severity of the effect (disease outcome); findings consistently replicated in different studies and in different populations; biologic plausibility i.e. the association is in coherence with the current biologic knowledge; consideration of alternate explanations; cessation of exposure would expectantly decline or eliminate the risk of disease; and specificity of the association when certain exposure is associated with only one disease (93). Given all the limitations of the present study as discussed above, findings of the present study need to be validated in future studies where random samples of both cases and controls  68  are sought from the general population, examiners are standardized, both the interview and questionnaire questions are standardized and pretested, and the validity of the questionnaire is assessed prior to the study (114).  Implications of the Study Findings The present study showed a possible high prevalence of oral cancer cultural risk factors in both male and female cancer patients as well as a higher prevalence of risk factors when compared to the general Vietnamese population. An awareness of creating a healthy lifestyle and behaviour to prevent risk habits of oral cancer is dependent on changes of lifestyle, cultural norms as well as attitudes, all of which could be initiated through health education (103). Improvements in oral health are also dependent upon the implementation of public health strategies and policies focusing on the underlying broader determinants of oral diseases such as socioeconomic, cultural and environmental factors (103). Cancer control strategies in Vietnam are necessary to deal with challenges of a limited health infrastructure, late cancer diagnosis and high prevalence of risk factors. Such strategies should address how to reduce the prevalence of risk behaviours, increase awareness and early detection of oral lesions along with improved quality of treatment and increased knowledge of oral cancer by both medical professionals and the public. Tobacco use, alcohol abuse and traditional betel quid use are prevalent habits in communities throughout Vietnam and Southeast Asia. In Taiwan, betel nut is used primarily by men (1) as compared to Vietnam where only older women chew betel quid. Yet in India and Indian communities around the world, this cultural habit of chewing betel nut is common to men, women and most adolescents (1). The presence of behavioural cultural risk habits is  69  largely formed and sustained in socio-cultural contexts. Questions worth asking are “What influences culture? and ‘Who is the most influential body in a country to bring about change?.. Culture is based upon tradition, policies, economics and physical environment such as the media. The intrinsic motivation of society to change might be achieved through the influence of government policies. As the majority of the population in most resource-poor countries is below 35 years of age, culture is influenced greatly by values placed by the media and the appearances for social and peer acceptance in these societies. As cultural cancer related risk factors such as smoking, alcohol abuse and betel quid chewing are prevalent to different extents around the world; prevention of oral cancer by controlling these risk behaviours should be a global concern. Research is needed to understand why people do what they do and why they have certain beliefs detrimental to their health is a necessary step to identify the causes of culturally established behaviours.  4.5 Challenges, obstacles and adversities of a foreigner performing a study in a resource-poor country In support of UBC’s vision of global citizenship and promoting values of a civil and sustainable society, one of the interests of the present research was to learn about oral health in non-western cultures. While conducting research, it was considered helpful and informative to be inquisitive and receptive to learning, to see things differently through the eyes and experiences of others (115). The UBC Vietnam GPR program and assisted dental clinic in the HCMC Oncology hospital provided the opportunity to engage in dental research while respecting humanity’s inherent diversity and building a sustainable connection and global community.  70  The literature review referred to a reference from the WHO stating that oral cancer rates have tripled since the 1980’s in Taiwan and China (1). However, we do not know if this rate of oral cancer is a real increase in incidence of new cases. Possibly, the severe increase could be due to better diagnosis and recording systems. It is possible that fewer cancer lesions are being overlooked in some countries or better records are being registered in these than in earlier studies. Research of what and how evaluations are made by the WHO/IARC are based on the preamble to the International Agency for Research on Cancer Monographs. The preamble describes the objective and scope of the IARC programme, the scientific principles, procedures and evaluations used in developing a monograph, the types of evidence considered and the scientific criteria that guide the evaluations. Evaluations are identified when case reports, case series and correlation studies are taken together with case-control and cohort studies, which may add to the judgement that a causal relationship exists (1). One challenge with an English speaking Canadian doing a clinical study in Vietnam was in understanding the nuances of patients, health care providers and translators who speak in their native language and who probably share different perspectives and expectations from a western view on oral health. Furthermore, the study questionnaire that was recommended by the principal investigator was not the same that was used in the field study in Vietnam. Questionnaires and survey interviews were performed in past studies in Vietnam; therefore, examiners chose to follow their own familiar questionnaire. The only advantage of this approach was that it enabled direct comparisons with previous local studies. The difficulties in Vietnam were predominately related to acquiring meeting time with the authorities in order to obtain permission for the research. With much patience and  71  determination, letters of intent and approval were obtained from the Director of the Oncology hospital in Vietnam and the UBC Ethics Board in Canada.  Future Directions for Study The intentions for the present study were to analyze the information and share the results with those in Vietnam and in Canada who would benefit from the international collaborative research. Future directions for study of the prevalence of cultural risk factors in Vietnam such as tobacco use, alcohol abuse and betel nut chewing would be to use a longitudinal cohort prospective study design using random samples from two groups- those exposed to risk and those unexposed to risk. For a better overview of the prevalence of cultural risk factors, the same questionnaire should be used for both groups in the study and asked by the interviewers in the same way. A second choice is a cross-sectional design studying a random sample of oral cancer patients and a random sample of the general population are selected as representatives of the comparison groups. The sample size would be evaluated to be large enough for statistical significance. Such studies are challenging to accomplish at this time in Vietnam as it is a resource-poor country and no registration system of disease is in place. 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(114) Abramson J.H., Abramson Z.H. Survey Methods in Community Medicine Epidemiological Studies, Programme Evaluation, Clinical Trials. Fifth ed. Edinburgh: Churchill Livingstone; 1999. (115) Dickson M, Dickson GG. Volunteering: beyond an act of charity. J Can Dent Assoc 2005 Dec;71(11):865-9.  81  Appendix A. Interview Survey of Oral Squamous Cell Carcinoma Patients Research number:………………………………………… Cancer Hospital File number:………………………..……………..…  PATIENT QUESTIONNAIRE Name:………………………………………………………………………… Age:………………………… Sex: M / F Occupation:……………………………………………………………………………… …………………………………….……………………………….. Address:………………………………………………………………………..………… …………………………………………..Phone:………………….. Admission reason:…………………………………………………………….. Date of admission:…………………………. 1. Medical History Habit history Betel chewing: Yes …….. Time: < 5 years Pieces per day:  No 5-9 years  <3  Stopped……………. 10-20years  3-5  6-9  > 20years 10-20  Dry areca White lime Dry areca Red lime Fresh areca White lime Fresh areca Red lime Tobacco in betel pieces  Yes  Additives in betel pieces  (bark of tree, pomello peel, areca nut peel,……….….)  Grind before chewing Sites of betel chewing  Yes Left  No  No Right  Swallowing betel quid: Yes  No  Tobacco rubbing:  Yes  No  Tobacco sticking:  Yes  (Left  Both  Right  Both  )  No 82  Tobacco smoking: Time:  Yes  < 5 years  Cigarettes /day: <3 Kind of tobacco: cigarette  No  5-9 years  Stopped ………….. 10-20years  3-5  6-9  10-20  paper wrapped  Site where tobacco was put on: Left lip  pipe  Right lip  Betel chewing and tobacco smoking at the same time Alcohol drinking: Yes Time:  < 5 years  Quantity per day: <1/4litre  Sometimes 5-9 years  > 20years  Middle lip different time  Stopped………….. No 10-20years  1/4-1/2 litre  > 20years  1/2-1 litre  >1l  Medical history: Personal:………………………………………………………………………………… ……………………………………………. Family:…………………………………………………………………………………… …………………………………………….. History of lesion: When was lesion discovered by patient? How has it developed? What previous treatment before coming to hospital?...................................................................................................................................................... ...................................................................................................................................................................... ...................................................................................................................................................................... ...................................................................................................................................................................... 2. Clinical examination General status: Good  Average  Poor  KPS:…………….  Oral cavity and head examination: Primary tumour (T): location, appearance, size, texture, mobility, pain/no pain.  83  Oral mucosa : Leukoplakia:  Homogenous  Non hemogenous  Lichen planus Oral submucosal fibrosis (OSF) Betel chewer’s mucosa (BCM) Solar cheilosis Erythroleukoplakia Other lesions: …………………………………………………………………………………………… ………………………… Dental Hygiene: Good  Moderate  Poor  Tooth brush: ………….times /day Dental visit: Regular  When necessary  Prosthesis: Fixed  Never  Movable  Node (N): number, location, size, texture, mobility, pain/no pain……………………… ………………………………………………………………………………………. Distant Metastasis(M):………………………………………………………………… 3. Sub clinical examinations: Biopsy: ………………………………………………………………………... Histopathology…………………………………………………………………………… ……………………………………………………………………………………………. Radiographs: CT scan, Panorex……………………………………………. Other tests:…………………………………………………………………  84  4. Diagnosis………………………………………………………………. …………………………………………………………………T  N M  5. Treatment: Surgery ……………………………………………………………………………… Radiation ……………………………………………………………………………… Chemotherapy …………………………………………………………………………………………… ………… Day of Examination: ……../..…../………………  85  Appendix B. UBC Research Ethics Board Certificate of Expedited Approval The University of British Columbia Office of Research Services, Clinical Research Ethics Board – Room 210, 828 West 10th Avenue, Vancouver, BC V5Z 1L8  Certificate of Expedited Approval Clinical Research Ethics Board Official Notification PRINCIPAL INVESTIGATOR  Zed, C. DEPARTMENT  Oral Medicine NUMBER  C05-0286 INSTITUTION(S) WHERE RESEARCH WILL BE CARRIED OUT  Other CO-INVESTIGATORS:  Dharamsi, Shafik, Health Promotion Research; Mathias, Richard, Health Care/Epidemiology; Priebe, Sherry, ; Tsang, Andrew, ; Wyatt, Christopher, Oral Health Sciences; Zhang, Lewei, Oral Biological & Medical Sci SPONSORING AGENCIES  Unfunded Research TITLE :  Descriptive Epidemiology of Oral Squamous Cell Carcinoma in a Prospective Six Month Period in 2005 in Southern Vietnam APPROVAL DATE  28 June 2005 TERM (YEARS)  1 DOCUMENTS INCLUDED IN THIS APPROVAL:  Protocol; Subject Consent Form; Survey Tool CERTIFICATION:  In respect of clinical trials:  1. The membership of this Research Ethics Board complies with the membership requirements for Research Ethics Boards defined in Division 5 of the Food and Drug Regulations. 2. The Research Ethics Board carries out its functions in a manner consistent with Good Clinical Practices. 3. This Research Ethics Board has reviewed and approved the clinical trial protocol and informed consent form for the trial which is to be conducted by the qualified investigator named above at the specified clinical trial site. This approval and the views of this Research Ethics Board have been documented in writing.  The documentation included for the above-named project has been reviewed by the Chair of the UBC CREB, and the research study, as presented in the documentation, was found to be acceptable on ethical grounds for research involving human subjects and was approved by the UBC CREB. The CREB approval for this study expires one year from the approval date.  Approval of the Clinical Research Ethics Board by one of: Dr. Gail Bellward, Chair, Dr. James McCormack, Associate Chair, Dr. Alain Gagnon, Associate Cha  86  

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