Screening for cervical cancer: an exploratory study of urban women in Tamil Nadu, India

University of Iowa Iowa Research Online Theses and Dissertations Spring 2012 Screening for cervical cancer: an exploratory study of urban women in Tamil Nadu, India Robin Marie Beining University of Iowa Copyright 2012 Robin Marie Beining This dissertation is available at Iowa Research Online: http://ir.uiowa.edu/etd/2820 Recommended Citation Beining, Robin Marie. "Screening for cervical cancer: an exploratory study of urban women in Tamil Nadu, India." PhD (Doctor of Philosophy) thesis, University of Iowa, 2012. http://ir.uiowa.edu/etd/2820. Follow this and additional works at: http://ir.uiowa.edu/etd Part of the Community Health Commons

SCREENING FOR CERVICAL CANCER AN EXPLORATORY STUDY OF URBAN WOMEN IN TAMIL NADU, INDIA by Robin Marie Beining An Abstract Of a thesis submitted in partial fulfillment of the requirements for the Doctor of Philosophy degree in Interdisciplinary Studies - Ph.D. degree in Social Medicine in the Graduate College of The University of Iowa May 2012 Thesis Supervisor: Professor R. Rajagopal

1 ABSTRACT Cervical cancer is the single most common cancer in India, affecting an estimated 134,420 women in 2008. With access to early detection and basic treatments, most cases of cervical cancer are preventable. Moreover, if treatment is administered during the earliest stages of cervical cancer, 5-year survival rates can be increased to higher than 90 percent. Unfortunately, despite the availability of methods for prevention, more than 95 percent of women in India have never been screened for cervical cancer. Consequently, women in India are most often diagnosed during later stages of cervical cancer, significantly reducing survival prognosis. The objective of this study was to explore the role of awareness and knowledge of cervical cancer as a barrier to screening participation among urban women in Tamil Nadu; and further to identify the potential impact of increased cervical cancer awareness and knowledge on screening attitude. Quantitative and qualitative methods were used to characterize existing levels of awareness and knowledge of cervical cancer and screening among 207 women from the metropolitan area of Chennai. The results suggest that the majority of women (69.6%) were not aware of cervical cancer and very few (16.4%) were aware of screening. Demographically, women with secondary levels of education or higher were significantly more likely to have heard of cervical cancer and screening. Of the women that were aware of cervical cancer screening, most reported receiving information through television (33%) or a healthcare provider (28.6%). To describe the potential benefit of providing women with basic information about the secondary prevention of cervical cancer, levels of knowledge, measured before and after an educational session, were compared. This study further explored changes in associations between awareness, knowledge, perceived susceptibility, and screening attitude. It was observed that an overwhelming majority of women were receptive to participating in free cervical cancer screening, independent of previous knowledge of

2 cervical cancer. Results also suggest that although lack of awareness appears to be a major barrier to participation in cervical cancer screening, providing women with information about cervical cancer has the potential to change the attitude of a significant proportion (58.3%) of women who were previously unreceptive to screening. Further, perceived susceptibility to cervical cancer appeared to be strongly associated with a positive screening attitude before and after receiving information. Finally, we examined and compared the socio-demographic characteristics of three subgroups of women: those who were receptive to screening without information, those who were receptive to screening after receiving information, and those who were not receptive to screening at either point. We found that younger, more educated women were receptive to screening without information. In addition, previously unscreened women who were less educated and illiterate in Tamil were most likely to acquire a positive attitude toward screening after receiving information. It also appeared that women who were most likely to be unreceptive to cost-free cervical cancer screening were more likely to be older and previously screened. These findings from our exploratory research with insights from additional comments made by several participants who were unreceptive to cost-free screening suggest that perceptions of free versus private healthcare may have influenced responses in this study. Abstract Approved: Thesis Supervisor Title and Department Date

SCREENING FOR CERVICAL CANCER AN EXPLORATORY STUDY OF URBAN WOMEN IN TAMIL NADU, INDIA by Robin Marie Beining A thesis submitted in partial fulfillment of the requirements for the Doctor of Philosophy degree in Interdisciplinary Studies -- Ph.D. degree in Social Medicine in the Graduate College of The University of Iowa May 2012 Thesis Supervisor: Professor R. Rajagopal

Graduate College The University of Iowa Iowa City, Iowa CERTIFICATE OF APPROVAL PH.D. THESIS This is to certify that the Ph.D. thesis of Robin Marie Beining has been approved by the Examining Committee for the thesis requirement for the Doctor of Philosophy degree in Interdisciplinary Studies Ph.D. degree in Social Medicine at the May 2012 graduation. Thesis Committee: R. Rajagopal, Thesis Supervisor Sudershan K. Bhatia Amy C. Butler David Osterberg Erica Prussing

To James Lloyd Beining and Kaleb Taylor Beining ii

ACKNOWLEDGMENTS This research is truly the result of the collaborative efforts of so many individuals and organizations, each contributing in a significant way. I am immensely grateful to each and every individual who believed in and supported this research endeavor. First, I would like to thank each of my committee members for their unique guidance, support, and unwavering encouragement. Specifically, I would like to thank my thesis advisor, Professor R. Rajagopal, for his steadfast commitment to and encouragement in my personal and professional development; without his dedication, enthusiasm, and support this research project would never have been possible. It was Professor R. Rajagopal who never let me lose sight of the eye of the bird and who taught me to always approach research objectives with an open mind. I would also like to thank my exceptionally supportive and encouraging interdisciplinary committee members, Dr. Sudershan K. Bhatia, Professor Amy C. Butler, Professor David Osterberg, and Professor Erica Prussing. Their unique expertise was immeasurably helpful throughout this research process. In addition to my committee members, I would like to acknowledge the numerous collaborators in Tamil Nadu. First, I would like to extend my sincerest thanks to Dr. Venkatesan Perumal, Associate Director at the Indian Council of Medical Research (ICMR) Center in Chennai and Professor of Epidemiology (Sri Ramachandra Medical College and Research Institute, Chennai) for his continuous support and organization for the collaboration of this study. I would also like to express heartfelt thanks and gratitude to Professor P.V. Geetha and her colleagues and students at the Meenakshi College for Women in Chennai for their hard work in developing and implementing the Tamil Nadu Health Behavior Survey. Without their dedication to improving the lives of women in their community, none of this research would have been possible. Additionally, I would like to thank each and every participant in the Tamil Nadu Health Behavior Survey who iii

so graciously and openly discussed their personal views on reproductive health. Further, I would like to recognize and thank Dr. N. Sethuraman, Founder and Chairman of Meenakshi Mission Hospital and Research Centre (MMHRC) and his staff in Madurai for their collective support in the conceptualization of my research objectives. I also owe gratitude to Dr. Esmy and others at the Christian Fellowship Hospital in Ambilikkai for the opportunity to observe and be inspired by an outstanding field model for cervical cancer prevention. I am also forever indebted to Usha R. Balakrishnan and the nonprofit organization CARTHA for their consistent and generous financial and motivational support during the research project. It truly is an inspiration to be a part of so many collaborative doers. I would also like to acknowledge Joyce E. Moore and my fellow co-workers at Evaluation & Examination Service for their continuous encouragement during the writing of my dissertation. It was with their moral support that I persevered. Last, but not least, I would like to thank my family and friends who have supported me throughout my entire academic journey and made my trips to India possible. iv

ABSTRACT Cervical cancer is the single most common cancer in India, affecting an estimated 134,420 women in 2008. With access to early detection and basic treatments, most cases of cervical cancer are preventable. Moreover, if treatment is administered during the earliest stages of cervical cancer, 5-year survival rates can be increased to higher than 90 percent. Unfortunately, despite the availability of methods for prevention, more than 95 percent of women in India have never been screened for cervical cancer. Consequently, women in India are most often diagnosed during later stages of cervical cancer, significantly reducing survival prognosis. The objective of this study was to explore the role of awareness and knowledge of cervical cancer as a barrier to screening participation among urban women in Tamil Nadu; and further to identify the potential impact of increased cervical cancer awareness and knowledge on screening attitude. Quantitative and qualitative methods were used to characterize existing levels of awareness and knowledge of cervical cancer and screening among 207 women from the metropolitan area of Chennai. The results suggest that the majority of women (69.6%) were not aware of cervical cancer and very few (16.4%) were aware of screening. Demographically, women with secondary levels of education or higher were significantly more likely to have heard of cervical cancer and screening. Of the women that were aware of cervical cancer screening, most reported receiving information through television (33%) or a healthcare provider (28.6%). To describe the potential benefit of providing women with basic information about the secondary prevention of cervical cancer, levels of knowledge, measured before and after an educational session, were compared. This study further explored changes in associations between awareness, knowledge, perceived susceptibility, and screening attitude. It was observed that an overwhelming majority of women were receptive to participating in free cervical cancer screening, independent of previous knowledge of v

cervical cancer. Results also suggest that although lack of awareness appears to be a major barrier to participation in cervical cancer screening, providing women with information about cervical cancer has the potential to change the attitude of a significant proportion (58.3%) of women who were previously unreceptive to screening. Further, perceived susceptibility to cervical cancer appeared to be strongly associated with a positive screening attitude before and after receiving information. Finally, we examined and compared the socio-demographic characteristics of three subgroups of women: those who were receptive to screening without information, those who were receptive to screening after receiving information, and those who were not receptive to screening at either point. We found that younger, more educated women were receptive to screening without information. In addition, previously unscreened women who were less educated and illiterate in Tamil were most likely to acquire a positive attitude toward screening after receiving information. It also appeared that women who were most likely to be unreceptive to cost-free cervical cancer screening were more likely to be older and previously screened. These findings from our exploratory research with insights from additional comments made by several participants who were unreceptive to cost-free screening suggest that perceptions of free versus private healthcare may have influenced responses in this study. vi

TABLE OF CONTENTS LIST OF TABLES...x LIST OF FIGURES... xii LIST OF ABBREVIATIONS... xiii CHAPTER 1 PERSPECTIVES ON GLOBAL HEALTH DISPARITIES, NON- COMMUNICABLE DISEASE, AND CANCER...1 Global Health Disparities...1 Public Health Significance of Inequalities and Inequities...1 10 Facts at a Glance Health Inequities...2 An Introduction to Health Inequities in India, the Case of Cervical Cancer...3 Non-communicable Diseases...4 Incidence and Prevalence of Non-communicable Diseases...4 Global Trends...4 10 Facts at a Glance Non-communicable Diseases...7 Trends in India...7 Cancer...9 Public Health Significance of Cancer...9 10 Facts at a Glance Cancer...9 Incidence and Prevalence of Cancer...10 Global Trends...10 Trends in India...13 Trends in Chennai Population-Based Cancer Registry...13 CHAPTER 2 PERSPECTIVES ON CERVICAL CANCER FROM THE GLOBAL TO THE LOCAL (CHENNAI)...16 10 Facts at a Glance Cervical Cancer...16 Incidence, Mortality, and Etiology of Cervical Cancer...17 Global Trends...17 Trends in India...21 Trends in Tamil Nadu...25 Etiology and Pathogenesis of Cervical Cancer...28 Associated HPV Cancers...32 Prevention of Cervical Cancer...32 Primary Prevention...32 Secondary Prevention...33 Considerations for Screening in Low Resource Settings...35 Barriers to Cervical Cancer Control Programs...35 Limited Awareness and Knowledge as a Barrier...36 Rationale for An Exploratory Study of Cervical Cancer in Tamil Nadu...39 Social Medicine, Interdisciplinarity, and Exploratory Research...39 Social Medicine...40 vii

Interdisciplinary Studies...40 Exploratory Research...40 CHAPTER 3 METHODOLOGY AND STUDY DESIGN...42 Study Setting...42 Qualitative Methods...46 Quantitative Methods...48 Study Design...48 Participants...49 Survey Design and Procedures...57 Statistical Analyses and Variable Definitions...59 Definitions of Selected Study Variables...59 Statistical Methods and Criteria...60 Stepwise Logistic Regression (Backward Elimination)...61 Quantification of Overall Cervical Cancer Knowledge Level...63 Study Strengths and Limitations...64 CHAPTER 4 DISCUSSION OF FINDINGS...69 Variables under Investigation in this Study...69 Aim I: Baseline Cervical Cancer Awareness and Knowledge...70 Objectives...70 Findings...70 Awareness of Cancer...71 Awareness of Cervical Cancer and Screening...72 Level of Knowledge about Cervical Cancer and Screening...77 Tests of Association of Cervical Cancer and Screening Awareness within Sociodemographic Classifications...78 Sources of Cervical Cancer Awareness and Knowledge...84 Participant Questions about Cervical Cancer and Screening...86 Aim II: Associations between Cervical Cancer Knowledge, Perceived Susceptibility, and Screening Attitude...88 Objectives...88 Findings...88 Changes in Perceived Susceptibility...91 Changes in Perceived Benefits of Screening among Healthy Women...94 Changes in Screening Attitude...94 Factors Associated with Screening Attitude...94 Factors Associated with Perceived Susceptibility...95 Aim III: Associations between Sociodemographic Characteristics and Stage at Change in Attitude Toward Cervical Cancer Screening...109 Objectives...109 Findings...109 viii

Sociodemographic Characteristics of Women Willing to Screen Prior to Receiving Health Information...110 Sociodemographic Characteristics of Women Willing to Screen after Receiving Health Information...111 Sociodemographic Characteristics of Women Not Receptive to Free Screening...111 CHAPTER 5 CONCLUSIONS AND RECOMMENDATIONS...117 Conclusions...117 Summary of Study Approach and Objectives...117 Summary of Study Findings...118 Established Guidelines for Comprehensive Cervical Cancer Control...124 Future Research...126 REFERENCES...130 APPENDIX A TAMIL NADU HEALTH BEHAVIOR SURVEY CERVICAL CANCER ENGLISH VERSION...140 APPENDIX B TAMIL NADU HEALTH BEHAVIOR SURVEY CERVICAL CANCER TAMIL VERSION...157 ix

LIST OF TABLES Table 1. Table 2. Incidence of Cervical Cancer by Regions and Sub-regions of the World, 2008...20 Mortality of Cervical Cancer by Regions and Sub-regions of the World, 2008...21 Table 3. Predicted Cervical Cancer Incidence by Year for India...22 Table 4. Predicted Cervical Cancer Mortality by Year for India...23 Table 5. Incidence of Cervical Cancer in India by Population-Based Cancer Registry...26 Table 6. HPV Prevalence among Women with Normal Cytology, 2008...30 Table 7. Provisional Population Statistics of Tamil Nadu, 2010 Census...43 Table 8. Provisional Population Statistics of the District of Madurai, 2010 Census...44 Table 9. Provisional Population Statistics of District of Chennai, 2010 Census...44 Table 10. Provisional Population Statistics of the District of Dindigul, 2010 Census...45 Table 11. Distribution of Study Participants by Districts of Tamil Nadu...50 Table 12. Distribution of Study Population by Sociodemographic Factors...52 Table 13. Definitions of Dependent Variables...69 Table 14. Cancer Awareness among Respondents...72 Table 15. Frequency of Cancer Types Identified by Participants Compared to Estimated Incidence Rates in India...73 Table 16. Awareness and Knowledge of Cervical Cancer Among Respondents...74 Table 17. Awareness and Knowledge of Cervical Cancer Screening among Respondents...76 Table 18. Cervical Cancer Awareness by Sociodemographic Characteristics...80 Table 19. Logistic Regression Analyses of Cervical Cancer Awareness as a Function of Age Group and Educational Attainment...81 Table 20. Odds Ratio Estimates for Cervical Cancer Awareness as a Function of Age Group and Educational Attainment...81 Table 21. Screening Awareness by Sociodemographic Characteristics...82 x

Table 22. Logistic Regression Analyses of Awareness of Cervical Cancer Screening as a Function of Educational Attainment...83 Table 23. Odds Ratio Estimates for Cervical Cancer Screening Awareness as a Function of Educational Attainment...83 Table 24. Cervical Cancer Knowledge by Sociodemographic Characteristics...85 Table 25. Primary Source of Information about Cervical Cancer or Screening...86 Table 26. Frequency of Respondent Generated Questions about Cervical Cancer...87 Table 27. Change in Cervical Cancer and Screening Awareness, Knowledge, and Attitude after the Intervention...90 Table 28. Pre-intervention Screening Attitude by Cancer Awareness...97 Table 29. Logistic Regression Analyses of Pre-intervention Screening Attitude as a Function of Awareness of another Person Diagnosed with Cancer...98 Table 30. Odds Ratio Estimates for Pre-intervention Screening Attitude as a Function of Awareness of another Person Diagnosed with Cancer...98 Table 31. Pre-intervention Screening Attitude by Cervical Cancer Awareness and Knowledge...100 Table 32. Pre-intervention Screening Attitude by Cervical Cancer Screening Awareness and Knowledge...102 Table 33. Pre-intervention Screening Attitude by Perceived Susceptibility...103 Table 34. Post-intervention Screening Attitude by Perceived Susceptibility...104 Table 35. Pre-intervention Perceived Susceptibility by Cancer Awareness...105 Table 36. Pre-intervention Perceived Susceptibility by Cervical Cancer Awareness and Knowledge...107 Table 37. Pre-intervention Perceived Susceptibility by Cervical Cancer Screening Awareness and Knowledge...108 Table 38. Pre-intervention Screening Attitudes by Sociodemographic Characteristics...113 Table 39. Relationships between Stage at Receptiveness toward Cervical Cancer Screening by Sociodemographic Characteristics...115 xi

LIST OF FIGURES Figure 1. Distribution of Age-standardized Non-communicable Disease Mortality Rates among Males, 2008...5 Figure 2. Distribution of Age-standardized Non-communicable Disease Mortality Rates among Females, 2008...6 Figure 3. Percent of Moralities in India by Cause, 2008...8 Figure 4. Distribution of Age-standardized Cancer Mortality Rates among Males, 2008...11 Figure 5. Distribution of Age-standardized Cancer Mortality Rates among Females, 2008...12 Figure 6. Top 10 Sites of Cancer among Females in Chennai, 2001-2002...14 Figure 7. Top 10 Sites of Cancer among Males in Chennai, 2001-2002...15 Figure 8. Distribution of Global Burden of Cervical Cancer: Age-standardized incidence rates per 100,000 women...18 Figure 9. Estimated Cervical Cancer Incidence by Global Economic Development Region...19 Figure 10. Estimated Cervical Cancer Mortality by Global Economic Development Region...19 Figure 11. Age-specific Curve for Cervical Cancer Incidence Comparing India, The World, and The United States, 2008...24 Figure 12. Age-specific Curve for Cervical Cancer Mortality Comparing India, The World, and The United States, 2008....25 Figure 13. Distribution of Age-standardized Incidence Rates of Cervical Cancer in India, 2002...27 Figure 14. District Map of Tamil Nadu...43 Figure 15. Age Distribution of Study Population...54 Figure 16. Family Income Distribution of Study Population...55 Figure 17. Individual Income Distribution of Study Population...56 Figure 18. Pre-intervention Cervical Cancer Knowledge Scores...92 Figure 19. Post-intervention Cervical Cancer Knowledge Scores...93 Figure 20. India s National Cervical Cancer Screening and Follow-up Protocol...127 xii

LIST OF ABBREVIATIONS ACCP ASR DACR DNA HPV ICMR IQR IARC IRB NCD NCRP OR PAP PBCR INR SES TNHBS VIA VILI WHO Alliance for Cervical Cancer Prevention Age-Standardized Rate Dindigual Ambilikkai Cancer Registry Deoxyribonucleic Acid Human Papillomavirus Indian Council of Medical Research Inter Quartile Range International Agency for Research on Cancer Institutional Review Board Non-Communicable Disease National Cancer Registry Program Odds Ratio Babes-Papanicolaou Test Population Based Cancer Registry Indian Rupees Socioeconomic Status Tamil Nadu Health Behavior Survey Visual Inspection with Acetic Acid Visual Inspection with Lugol s Iodine World Health Organization xiii

1 CHAPTER 1 PERSPECTIVES ON GLOBAL HEALTH DISPARITIES, NON-COMMUNICABLE DISEASE, AND CANCER The background information presented in this chapter will provide a contextual framework for realizing the importance of cervical cancer among Tamil women, which is at the heart of this research. The discussion will begin with a brief introduction to global health disparities, highlighting the unequal distribution of disease burden observed among global populations. The focus will then turn to pointing out the role of noncommunicable diseases and cancer in contributing to overall disparities in health. Finally, the chapter will conclude with an overview of health disparities in Tamil Nadu, focusing on the undue burden of cervical cancer among Tamil women. Global Health Disparities Public Health Significance of Inequalities and Inequities Over ninety years ago, in a science magazine article, Winslow 1 lamented about the untilled fields of public health, stating that,.public health is the science and art of preventing disease, prolonging life and promoting physical health and efficacy through organized community efforts for the sanitation of the environment, the control of communicable infections, the education of the individual in personal hygiene, the organization of medical and nursing services for the early diagnosis and preventive treatment of disease, and the development of social machinery which will ensure every individual in the community a standard of living adequate for the maintenance of health; so organizing these benefits in such a fashion as to enable every citizen to realize his birthright and longevity. In a recent compilation of world facts and figures, ironically reminding us of Winslow s lament of 90 years past, the World Health Organization (WHO) has highlighted the top ten present day global health inequities and their causes,

2 10 Facts at a Glance Health Inequities 2 1. Disparities in social conditions often lead to unjust inequities in health status. 2. Impoverished children are most likely to die of preventable diseases. 3. 99 of 100 women who die from childbirth live in developing countries. 4. Poverty increases risk of tuberculosis and tuberculosis increases risk of poverty. 5. 8 out of 10 cases of non-communicable disease occur in developing countries. 6. On average, people in developing countries die 36 years younger. 7. Health inequities occur within and between countries. 8. Both rural and urban populations are at risk for health inequities. 9. Health inequities are a financial burden to societies. 10. Poverty leads to inequities in health and inequities in health lead to poverty. The WHO has defined health as a holistic state of physical, mental, and social-being well-being, beyond the absence of disease or infirmity. 3 Disparities in health have been contextualized with two terms, inequality and inequity. Inequality describes an observed difference in rates of disease morbidity or mortality between populations; while equitability refers to an ethical judgment of the fairness of observed differences. 4 Whitehead et al. further described inequities in health as differences which are unnecessary and avoidable, but also may be considered as unfair and unjust 4 Further to this construct, what is equal is not necessarily equitable and what is equitable need not be equal. Public Health is based on a fundamental doctrine of promoting equitable health outcomes, across populations, through the use of preventive health approaches. 1 In order to achieve this goal it is necessary to not only consider etiologic causes of disease inequalities, but also to address underlying social determinants of inequities. 5-11 Worldwide, poverty has been suggested as the single greatest threat to health. 5-8,10,12 The WHO estimates that nearly 45 percent of the total disease burden in economically developing countries is directly related to risks resulting from poverty, including poor

3 sanitation, lack of access to safe water, exposure to indoor smoke from solid fuels, and malnutrition. 13 Further, the majority of these deaths resulting from social and economic disparities can be avoided with access to existing, low-cost treatments and preventive measures. 12 An Introduction to Health Inequities in India, the Case of Cervical Cancer Cervical cancer is a significant public health concern in India, with an estimated 134,420 incident cases and 72,825 associated mortalities in 2008. 14 However, in reality, this may be a low estimate of the true burden of cervical cancer among women in India. Although India has an excellent private healthcare system, many government-sponsored hospitals and clinics, intended to provide equal access to healthcare for the poor, are severely underfunded and overwhelmed. Health policy analysts have cited India as having one of the lowest per capita rates of government healthcare expenditure in the world, amounting to approximately USD 2.20 per capita, per year. 15 Furthermore, 80 percent of this healthcare allotment is budgeted for salaries. 15 Perhaps even more disconcerting is the disparity in the allocation of the already scare health care resources. It is estimated that approximately 30 percent of the healthcare funds provided by the government of India are consumed by the wealthiest 20 percent of the population. 15 Meanwhile, a stark 10 percent of the government s contribution to healthcare is spent on the poorest 20 percent of the population. 15 Additionally, approximately 80 percent of total expenditure on healthcare is paid directly by consumers to private, for-profit, healthcare facilities. 16 These figures not only suggest a significantly lower level of access to healthcare among the poor in India, but also highlight how health easily becomes a commodity. As is the case for many diseases, in India, a woman s risk of cervical cancer is largely mediated by socioeconomic factors. Compared to women in the United States, women in India are five times more likely to develop and seven times more likely to die

4 from cervical cancer 14 simply because they face multiple barriers, many of which are socially determined, in accessing basic screening and treatment services. 17-20 Based on this, the observed differences in cervical cancer morbidity and mortality, between women in the United States and India can be considered as a health inequity. Non-communicable Diseases Incidence and Prevalence of Non-communicable Diseases Global Trends Contrary to popular thought, compared to infectious diseases, non-communicable diseases represent a larger proportion of disease burden in economically developing regions of the world. In 2008, 63 percent of the 57 million deaths occurring worldwide were attributed to non-communicable diseases, including cardiovascular and cerebrovascular disease, cancer, respiratory illness, and diabetes. 21 Four out of every five deaths related to non-communicable diseases occur among populations living in low- or middle-income regions of the world. 21 As shown in Figures 1 and 2, after adjusting for age, both males and females living in economically developing regions of the world are significantly more likely to die from a non-communicable disease compared to their counterparts in developed regions of the world. For example, males in the former Soviet bloc, China, Afghanistan, and parts of Africa experience significantly higher rates of death from non-communicable diseases, including cardiovascular disease and cancer, largely attributable to tobacco, alcohol, and poor access to healthcare (Figure 1). Likewise, as shown in Figure 2, women living in central African countries, the former Soviet bloc, China, Afghanistan, and India also experience significantly higher mortality from non-communicable diseases, also linked to limited access to healthcare. Based on current estimates, it is predicted that by

5 the year 2030, non-communicable diseases will be the most common cause of death, worldwide. 21 Figure 1 Distribution of Age-standardized Non-communicable Disease Mortality Rates among Males, 2008. Source: World Health Organization Map Production: Public Health Information and Geographic Information Systems (GIS) World Health Organization. Available from: http://gamapserver.who.int/maplibrary/, accessed on: 03/15/12.

6 Figure 2 Distribution of Age-standardized Non-communicable Disease Mortality Rates among Females, 2008. Source: World Health Organization Map Production: Public Health Information and Geographic Information Systems (GIS) World Health Organization. Available from: http://gamapserver.who.int/maplibrary/, accessed on: 03/15/12.

7 The significance of non-communicable diseases in the overall global burden of disease, the disparities in the distribution, and the causes contributing to inequities in this group of diseases, are highlighted by the WHO in the following facts, 10 Facts at a Glance Non-communicable Diseases 21 1. 63% of all deaths, worldwide, are attributable to non-communicable diseases. 2. 80% of deaths from non-communicable diseases occur in developing countries. 3. 1 in 4 people who die from non-communicable diseases are less than age 60. 4. The number of women affected by non-communicable diseases is equal to men. 5. Many non-communicable diseases can be prevented with behavior modifications. 6. Poverty and many non-communicable diseases are intrinsically linked. 7. Overweight and obesity are major public health problems among adults. 8. Childhood overweight and obesity is another major public health challenge. 9. 1 in every 10 deaths is attributable to tobacco use. 10. Incidence of the top four non-communicable diseases, cardiovascular, stroke, diabetes, and cancer, can be reduced by 40 to 75% through risk factor reduction. Trends in India In India, which is classified as a lower-middle income country, 53 percent of all deaths in 2008 were attributed to non-communicable diseases, compared to 37 percent for infectious diseases. 22 In 2008 alone, there were more than 5.2 million people in India who died from a non-communicable disease. 22 Approximately three million of these deaths occurred among men. 22 Of the 2.3 million non-communicable disease deaths among women, 32.1 percent occurred among women younger than 60 years. 22 As shown in Figure 3, cardiovascular disease was the leading cause of mortality, contributing to nearly one in every four deaths in India during 2008. Also shown in Figure 3, respiratory diseases, cancer, and diabetes were other leading causes of mortality reported among the Indian population in 2008.

8 Figure 3 Percent of Moralities in India by Cause, 2008. NCDs = Non-communicable diseases. CVD = Cardiovascular disease. Source:World Health Organization NCD Country Profiles, 2011. [Internet]. Available at: http://www.who.int/nmh/countries, accessed on 03/15/12.

9 Cancer The WHO defines cancer as a collective term used to classify a set of diseases, affecting any area of the body, which is characterized by the rapid proliferation of abnormal cells that have the potential to metastasize to other areas of the body. The International Agency for Research on Cancer currently recognizes more than 100 different types of cancer. Public Health Significance of Cancer Cancer is the seventh leading cause of mortality in the world, accounting for 21 percent of all non-communicable disease deaths in 2008. 23 In 2008, there were an estimated 12.7 million incident cases of cancer and 7.6 million associated mortalities worldwide. 14 Globally, the most frequently diagnosed types of cancer are lung, breast, colorectum, stomach, and prostate. 14 Assuming risk is shared equally across all populations, every person has a 19 percent cumulative risk of being diagnosed with any type of cancer and an 11 percent cumulative risk of dying from any type of cancer before age 75 years. 14 The probability of cancer diagnosis and mortality is slightly higher among males as compared to females. If current cancer rates persist, the WHO estimates that in the year 2030 there will be 21.4 million incident cases of cancer, of which 67 percent will occur in low- or middle-income countries. 14,24 In a recent compilation of ten facts about cancer, it is evident that the burden of cancer is not distributed equally across all populations of the world. Rather, those living in economically developing regions experience a disproportionate burden of cancer, 10 Facts at a Glance Cancer 23 1. More than 100 different types of cancer have been identified. 2. Worldwide, 13 out of every 100 people who died in 2008 died because of cancer. 3. 7 out of 10 people who die from cancer live in developing countries. 4. Top 5 fatal cancers in men are lung, stomach, liver, colorectal, and oesophagus.

10 5. Top 5 fatal cancers in women are breast, lung, stomach, colorectal, and cervical. 6. For every 100 people who die of cancer, 22 deaths could be avoided by not smoking. 7. Worldwide, 1 in 5 cases of cancer is the result of a chronic viral infection. 8. Breast, colorectal, and cervical are treatable with early detection. 9. Many cancer victims die in pain because they lack access to palliative care. 10. 5 out of 10 cancer deaths in developing countries can be prevented through behavior modification and vaccination. Incidence and Prevalence of Cancer Global Trends As highlighted by the compilation of facts from the WHO, significant differences in the incidence and mortality rates of cancer are observed between countries (Figures 4 and 5). Often, these differences in cancer trends echo global indicators of regional economic development. In 2008, approximately 44 percent of all cancer cases in the world were diagnosed amid populations living in economically developed regions of the world. 14 However, during that same time period, 64 percent of all cancer-related deaths were reported among individuals living in economically developing regions of the world. 14 The low incidence to mortality ratio reported for economically developing regions of the world suggest under-registration of cancer data. 25 The registered frequency and fatality of specific cancer types also varies significantly by global region. In economically developed regions of the world, the top five cancers are colorectal, lung, breast, prostate, and stomach. 14 These types of cancers are largely attributable to lifestyle factors, including obesity, lack of physical activity, tobacco use, and poor dietary habits. In comparison, among populations in economically developing regions of the world, cancers of infectious etiology, such as liver and cervical cancer, are frequently observed. 14

11 Figure 4 Distribution of Age-standardized Cancer Mortality Rates among Males, 2008. Source: World Health Organization Map Production: Public Health Information and Geographic Information Systems (GIS) World Health Organization. Available from: http://gamapserver.who.int/maplibrary/, accessed on: 03/15/12.

12 Figure 5 Distribution of Age-standardized Cancer Mortality Rates among Females, 2008. Source: World Health Organization Map Production: Public Health Information and Geographic Information Systems (GIS) World Health Organization. Available from: http://gamapserver.who.int/maplibrary/, accessed on: 03/15/12.

13 Trends in India As of 2011, the population of India was the second largest in the world, with an estimated 1.2 billion people. In 2008 there were approximately 950,000 incident cases of cancer and 634,000 associated mortalities reported in India. 14 Overall, the most commonly reported types of cancer in India were cervical, breast, lip/oral cavity, lung, and oesophagus. 14 The highest age-standardized mortality rates, across both sexes, were reported for cervical and breast cancer 14, both preventable and treatable with early detection. In India, the lifetime risk of being diagnosed with cancer or dying from cancer before age 75 years was similar for males and females, with males experiencing a slightly lower lifetime risk of developing cancer (10%) before age 75 years as compared to females (11%). 14 However, in India, males have a marginally greater risk of dying from cancer (7% vs. 8%) during the same time period. 14 According to India s most recent population census, if India s population continues to grow at an annual rate of 1.4 percent (The World Bank, 2011), sometime after the year 2030 the population of India will likely outnumber that of China. If this projection holds true, nearly one-fifth of the global population will live in India, potentially making cervical cancer the single most common cancer in the world. Trends in Chennai Population-Based Cancer Registry As reported by the Cancer Institute in Chennai (WIA), the leading cancers among women in 2001/02 in the Chennai district are cervical, breast, oral, and ovarian (Figure 6, Cancer Institute (WIA), Chennai). Among men, the most common sites of cancer are mouth, stomach, tongue, and lung (Figure 7, Cancer Institute (WIA), Chennai). As shown in Figure 6, during registry years 2001 and 2002, cervical cancer accounted for 32.2 percent of all cases diagnosed in Chennai. Cervical cancer is one of only several cancers that can be effectively prevented through early detection. Therefore, the

14 disproportionately high burden of cervical cancer in Chennai suggested an important inequity in health, deserving of further study. The remaining chapters in this dissertation focus specifically on cervical cancer. Chapter two provides background information on the epidemiology, etiology, and prevention of cervical cancer. Additionally, the next chapter discusses several issues important to cervical cancer prevention in Tamil Nadu, including alternative approaches for screening in low resource settings, common barriers to cervical cancer control, and the role of awareness and knowledge in screening participation. Chapters three, four, and five provide information about study methodology, findings, and conclusions, respectively. Figure 6 Top 10 Sites of Cancer among Females in Chennai, 2001-2002. Number shown is the relative proportion (%). Source: Cancer Institute (WIA), Chennai, Annual Report 2001-2002 [Internet]. Available at http://www.ncrpindia.org.

15 Figure 7 Top 10 Sites of Cancer among Males in Chennai, 2001-2002. Number shown is the relative proportion (%). Source: Cancer Institute (WIA), Chennai, Annual Report 2001-2002 [Internet]. Available at http://www.ncrpindia.org.

16 CHAPTER 2 PERSPECTIVES ON CERVICAL CANCER FROM THE GLOBAL TO THE LOCAL (CHENNAI) Over the past 70 years, deaths from cervical cancer have markedly declined in many Western populations. This decline in observed cases of cervical cancer directly corresponds to the adoption of routine cervical cancer screening practices. Given the effectiveness and direct public health impact, the cytology-based Babes-Papanicolaou (Pap) test has been cited as one of the top ten public health achievements of the 20th century. 26 However, despite the documented benefits of screening, significant disparities in cervical cancer morbidity and mortality exist between economically-defined regions of the world. 14,24,27 The observed inequities in cervical cancer are attributable to differences in population-level screening coverage. Cervical cancer is preventable and treatable. Global inequities in cervical cancer deaths are preventable and therefore may be viewed as unjust. The significance of cervical cancer among cancers affecting women, the disparity of its prevalence, the role of sexually-transmitted Human Papillomavirus (HPV) it its etiology, and the effectiveness of screening strategies in its prevention, are highlighted by the following facts at a glance, 10 Facts at a Glance Cervical Cancer 1. Worldwide, cervical cancer is the third most common cancer among women. 14 2. Worldwide, every two minutes a woman dies from cervical cancer. 14 3. 86% of cervical cancer cases and 88% of deaths occur in developing regions. 14 4. In India, cervical cancer is the single most common cancer. 14 5. For every 35 women in India, one will be diagnosed with cervical cancer. 27 6. In the United States, one in every 192 women will develop cervical cancer. 27

17 7. Sexually transmitted HPV is a necessary factor in cervical cancer. 27 8. Worldwide, 70% of cervical cancer is caused by HPV types 16 and 18. 27 9. More than 80% of women will be infected with HPV at some time. 27 10. Cervical cancer is one of three cancers effectively prevented with screening. Incidence, Mortality, and Etiology of Cervical Cancer Global Trends Despite the availability of effective methods for prevention, cervical cancer is the third most common cancer among women worldwide and the seventh most common cancer overall. 14 As shown in Figure 8, in many economically developing regions of the world, including Africa, Asia, South and Central America, and parts of the Pacific region, cervical cancer is the single most common cancer among women with an agestandardized rate (ASR) ranging from 30 per 100,000 women in parts of Eastern and Western Africa to 24.6 per 100,000 women in South-Central Asia. 14,27,28 In 2008 there were an estimated 530,000 incident cases and 275,000 associated mortalities. 14 Current data suggest that of the total global burden, 86 percent of all cervical cancer diagnoses (Figure 9) and 88 percent of associated mortalities (Figure 10) occur among women living in economically developing regions of the world. 14,27 In addition to significant disparities in the actual incidence of cervical cancer between countries, substantial differences in the overall contribution of cervical cancer to total cancer burden also exist. In many economically developing countries, cervical cancer represents 13 percent of all females cancers compared to less than six percent in other regions of the world. 14 Observed disparities in cervical cancer incidence and mortality are largely accounted for by inequities in cervical cancer screening. 27,28 In countries with wellorganized screening programs, rates of cervical cancer morbidity and mortality have declined significantly over the past several decades. 29-32 However, in many economically

18 developing countries where cervical cancer is not recognized as a public health priority and screening programs are mostly opportunistic, the incidence of cervical cancer remains unchanged, and in several cases continues to increase. 24,33-39 Figure 8 Distribution of Global Burden of Cervical Cancer: Age-standardized incidence rates per 100,000 women. Source: Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM. GLOBOCAN 2008 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer, 2010. Available from: http://globocan.iarc.fr, accessed on 03/15/12.

19 Figure 9 Estimated Cervical Cancer Incidence by Global Economic Development Region. Source: Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM. GLOBOCAN 2008 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer, 2010. Available from: http://globocan.iarc.fr, accessed on 03/15/12. Figure 10 Estimated Cervical Cancer Mortality by Global Economic Development Region. Source: Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM. GLOBOCAN 2008 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer, 2010. Available from: http://globocan.iarc.fr, accessed on 03/15/12.

20 As shown in Tables 1 and 2, a significant proportion of the incidence and mortality related to cervical cancer in developing regions of the world occurs in Asia, especially in the region of South Central Asia, comprising the countries of Afghanistan, Bangladesh, Bhutan, India, Iran, Kazakhstan, Kyrgyzstan, Nepal, Pakistan, Sri Lanka, Tajikistan, Turkmenistan & Uzbekistan. Again, within this region, 77 percent of the incidence (134,420 of 173,917 cases) and 76 percent (72,825 of 95,871 deaths) of mortality from cervical cancer occur in India (Tables 1 and 2). Table 1 Incidence of Cervical Cancer by Regions and Sub-regions of the World, 2008. Population N Age-specific-rate Crude rate 15-44 45-54 55-64 65+ ASR World 530,232 11.4 39.1 43.8 35.5 15.8 15.2 1.6 Developed 76,701 9.7 21.0 18.3 16.1 12.1 9.1 0.9 Regions Developing 453,531 11.8 45.1 54.7 47.2 16.6 17.7 1.9 regions Asia 312,990 11.3 39.7 44.6 35.4 15.6 15.3 1.6 South-Central. 173,917 14.1 65.9 81.7 68.1 20.7 24.6 2.6 Asia India 134,420 16.1 70.4 89.7 72.9 23.5 27.0 2.8 ASR = Age-standardized rate. Cum risk = Cumulative risk [0-74 yrs], percent. Crude and age-standardized rates per 100,000 women per year. Cum risk Source: Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM. GLOBOCAN 2008 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer, 2010. Available from: http://globocan.iarc.fr, accessed on 03/15/12.

21 Table 2 Mortality of Cervical Cancer by Regions and Sub-regions of the World, 2008. Population N Age-specific-rate Crude rate 15-44 45-54 55-64 65+ ASR World 275,008 3.5 18.6 26.0 30.6 8.2 7.8 0.9 Developed 32,931 1.9 7.6 8.8 11.5 5.2 3.1 0.3 regions Developing 242,077 3.8 22.2 33.3 42.5 8.9 9.7 1.1 regions Asia 159,894 3.4 18.5 26.5 32.8 8.0 7.9 0.9 South-Central. 95,871 5.7 33.3 49.3 57.5 11.4 14.1 1.6 Asia India 72,825 6.2 34.4 53.7 63.0 12.8 15.2 1.7 ASR = Age-standardized rate. Cum risk = Cumulative risk [0-74 yrs], percent. Crude and age-standardized rates per 100,000 women per year. Cum risk Source: Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM. GLOBOCAN 2008 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer, 2010. Available from: http://globocan.iarc.fr, accessed on 03/15/12. Trends in India Cervical cancer is the single most common cancer among women in India. In 2008, an estimated 134,420 women in India were diagnosed with cervical cancer (Table 1), while 72,825 (Table 2) died as a result. 14,27 The peak age for diagnosis was in the range of 55-64 years, while the highest mortality rates occurred among women approximately one decade later in life. 14 Women in India have a significantly increased risk of cervical cancer compared to women living in other parts of the world. During their lifetime, 1 in 35 (Table 1, last line, Cumulative Risk of 2.8) women in India will develop cervical cancer as compared to 1 in 192 (Cumulative Risk of about 0.52) women in the United States. 14,24,27,28 Presently, there are approximately 367 million women in India,

22 age 15 years and older, at risk for cervical cancer. 28 In light of India s rapidly growing and aging population, the overall burden of incidence and mortality of cervical cancer in India is projected to increase by 68 and 78 percent, respectively, by the year 2030, 14 signifying the overall importance in addressing this avoidable health disparity (Tables 3 and 4). Furthermore, the burden of cervical cancer incidence and mortality will be significantly higher in the elderly population (age 65 years and older) and is projected to increase by 120 percent by 2030 (Tables 3 and 4). Table 3 Predicted Cervical Cancer Incidence by Year for India. Year N Age-category < 65 years > 65 years 2008 134,420 112,814 21,606 2010 141,768 118,917 22,851 2015 161,147 134,402 26,745 2020 182,027 148,655 33,372 2025 203,757 163,508 40,249 2030 226,370 178,864 47,506 N = Estimated number of new cases. Population forecasts were extracted from the United Nations, World Population Prospects, the 2008 Revision. Numbers are computed using age-specific rates and corresponding populations for 10 age-groups. Source: Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM. GLOBOCAN 2008 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer, 2010. Available from: http://globocan.iarc.fr, accessed on 03/15/12.

23 Table 4 Predicted Cervical Cancer Mortality by Year for India. Year N Age-category < 65 years > 65 years 2008 72,825 53,962 18,863 2010 77,096 57,090 20,006 2015 88,578 65,155 23,423 2020 101,362 72,365 28,997 2025 115,171 79,976 35,195 2030 129,792 88,008 41,784 N = Estimated number of deaths. Population forecasts were extracted from the United Nations, World population prospects, the 2008 revision. Numbers are computed using age-specific rates and corresponding populations for 10 age groups. Source: Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM. GLOBOCAN 2008 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer, 2010. Available from: http://globocan.iarc.fr, accessed on 03/15/12.

24 As shown in Figures 11 and 12 (note the log scale on the y-axis), at every age bracket, women in India have the highest age-specific cumulative rate (stochastic dominance) for both incidence and mortality related to cervical cancer. In contrast, economically developed nations, such as the United States, have the lowest age-specific rates of cervical cancer, while the world averages lie in the middle of the spectrum. The above discussions clearly indicate that Indian women face a disproportionately high burden from cervical cancer. Also, as shown earlier in Tables 3 and 4, incidence of cervical cancer is expected to witness a 68 percent increase from 134,420 in 2008 to 226,370 by 2030, and mortality is expected to witness a 78 percent increase from 72,825 in 2008 to 129,792 by 2030. Figure 11 Age-specific Curve for Cervical Cancer Incidence Comparing India, The World, and The United States, 2008. Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM. GLOBOCAN 2008 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer, 2010. Available from: http://globocan.iarc.fr, accessed on 03/15/12.

25 Figure 12 Age-specific Curve for Cervical Cancer Mortality Comparing India, The World, and The United States, 2008. Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM. GLOBOCAN 2008 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer, 2010. Available from: http://globocan.iarc.fr, accessed on 03/15/12. Trends in Tamil Nadu Across India rates of cervical cancer vary vastly by population, including those defined by geographic and demographic characteristics. Within India the highest ASR of cervical cancer was reported among women in the south Indian state of Tamil Nadu. 40 There is a high incidence belt in the northeastern districts of Tamil Nadu, as well as in two districts in the northeastern region of the country (Figure 13, National Cancer Registry Programme and World Health Organization). As shown in Figure 13, the rates in the south are the highest around the districts surrounding and including Chennai (Table 5), a metropolitan city in Tamil Nadu, and lowest in Thiruvanathapuram, the capital of

26 Kerala, the southwestern state in the southern tip of India (National Cancer Registry Programme and World Health Organization). However, estimates for the ASR of cervical cancer vary vastly within Tamil Nadu, ranging from 30.6 per 100,000 women reported by the Chennai Population Based Cancer Registry (PBCR) 41,42 to 65.4 per 100,000 women reported for the Dindigul Ambilikkai Cancer Registry (DACR). 43 As reported, the ASR for cervical cancer among women in Dindigul District (one of the south central districts of Tamil Nadu) is the second highest in the world. 43 Further, cervical cancer accounted for more than half of the total reported cases of cancer in this population, 43 suggesting the vast importance of cervical cancer prevention in improving the overall health of women in this population. Table 5 Incidence of Cervical Cancer in India by Population-Based Cancer Registry. Cancer registry Crude rate ASR Chennai 24.2 28.0 Karunagappally 8.9 10.6 Mumbai 11.8 14.5 Nagpur 15.2 18.4 New Delhi 12.9 19.5 Poona 13.5 17.3 Trivandrum 9.6 9.4 ASR = Age-standardized rate, per 100,000 women per year. Standardized rates have been estimated using the direct method and the world population as the reference. Source: Adapted from WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Human Papillomavirus and Related Cancers in India. Summary Report 2010. Available from: www.who.int/hpvcentre, accessed on 03/15/12.

27 Figure 13 Distribution of Age-standardized Incidence Rates of Cervical Cancer in India, 2002. Source: National Cancer Registry Program, Bangalore [Internet]. Bangalore, India, 2002. Available from: http://www.ncrpindia.org/cancer_atlas_india.

28 Etiology and Pathogenesis of Cervical Cancer Clinically, cervical cancer is defined as abnormal cellular changes that originated from the surface of the cervix. 44 The cervix is the anatomical junction between the lower part of the uterus and the upper part of the vaginal canal. Cellular level changes in the cervix are often referred to as dysplastic or carcinoma-in-situ. In both stages, cells have changed in appearance, shape, size, or rate of proliferation. However, the primary distinguishing pathological characteristic between dysplasia and carcinoma-in-situ is that dysplastic cells may revert to normal cells or progress to cancer. In carcinoma-in-situ, the biologic and genetic characteristics of the cells have been changed irreversibly and the abnormal cells have the potential to metastasize to other anatomical regions. 44 Cervical cancer can be classified based on where it originates in the cervix. The most common type of cervical cancer is defined as squamous cell carcinoma, having originated in the ectocervix or side facing the vaginal canal. Adenocarcinomas are cervical cancers that develop in the endocervix or portion of the cervix facing the uterus. Cervical cancer that originally involves both the ectocervix and endocervix are usually classified as adenosquamous carcinomas or mixed carcinomas. 44 Persistent infection with one or more oncogenic subtypes of Human Papillomavirus (HPV) is well-established as a necessary, but insufficient cause of cervical cancer. 31,32,45-47 Currently, there are more than 100 identified subtypes of HPV, of which at least 15 are considered to have oncogenic potential. 45 Globally, oncogenic HPV subtypes 16 and 18 are the most prevalent subtypes of HPV, 48 and are implicated in at least 71 percent of all invasive cervical cancer cases. 49,50 Further, invasive cases of cervical cancer associated with HPV subtypes 16 and 18 are reported to present at a younger mean age compared to cases associated with other high risk types of HPV. 49 Pooled results from eleven case control studies, spanning nine countries, suggest that in addition to HPV subtypes 16 and 18, HPV subtypes 31, 33, 35, 39, 45, 51, 52, 56, 58, 59,

29 66, 68, 73, and 82 also pose a high risk for the development of a HPV-related cancer. 51 The same study suggest that HPV subtypes 26, 53, and 66 are also likely carcinogenic. 51 In many populations, HPV is considered to be the most common sexually transmitted infection. 45 Worldwide, it is estimated that at any given time more than ten percent of women with normal cytology are harboring a HPV infection (Table 6). 45 Although women in India who are younger than 25 years are less likely to be infected with HPV compared to this age group of women in the United States, the opposite is true for older age brackets (Table 6). In a recent study of 27,192 middle-aged, ever married women living in Maharashtra state in India, 10.3 percent were found to be infected with at least one type of high risk HPV. 52 Though infection with one or more oncogenic types of HPV has been established as a necessary factor in the development of cervical dysplasia, 32,46,47 HPV may not always be sufficient to incite the development of dysplasia or subsequent progression to cervical cancer. In laboratory studies, it has been noted that progression of HPV to cancer requires additional factors, which remain poorly defined. 51 In Epidemiology, risk factors for diseases are typically defined as modifiable and non-modifiable. Modifiable risk factors, such as tobacco use, sexual behaviors, and unhealthy diets, are often related to individual behaviors. On the other hand, nonmodifiable risk factors typically refer to physical characteristics, such as increasing age or genetic predisposition. With exception to age and sex, most risk factors for developing cervical cancer can be considered as modifiable. Modifiable behaviors that increase a woman s possibility of being infected with HPV include: multiple sexual partners 53 and earlier age of onset of sexual activity. 54 Biological risk factors that may or may not be modifiable include a compromised immune system 55 and a current or previous vaginal or sexually-transmitted infection. 56 In general, younger women are more likely to be infected with HPV. Some have postulated that the increased risk is due to increased levels of sexual activity among younger

30 women, while others have proposed an increase in susceptibility to HPV because of physical immaturity. 57 Table 6 HPV Prevalence among Women with Normal Cytology, 2008. Country/region Age group (yrs) HPV prevalence World All ages 11.4 < 25 20.8 25-34 13.5 35-44 7.9 45-54 6.2 55+ 6.8 India All ages 7.9 < 25 15.7 25-34 13.1 35-44 12.8 45-54 12.9 United States All ages 13.3 < 25 26.5 25-34 12.0 35-44 5.5 45-54 4.1 55+ 3.0 Source: Adapted from WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Human Papillomavirus and Related Cancers inworld. Summary Report 2010. Available from: www.who.int/hpvcentre, accessed on 03/15/12.

31 Modifiable behaviors that increase risk for the development of dysplasia and/or progression to cervical cancer among women with HPV infection include smoking, 58 increasing parity, 51 and having ever used hormonal contraceptives for five years or longer. 59 Increasing age 58 has been cited as a non-modifiable risk factor in the development of cervical cancer as well as many other types of cancer. Psychological stress 60 and a current or previous vaginal or sexually-transmitted infection 56 are also risk factors for cervical cancer. Certain socioeconomic (SES) and sociodemographic factors have been associated with an increased risk of delayed screening and therefore an increased risk of progression to cervical cancer across many global populations. Most of these risk factors for delayed screening are considered to be individually non-modifiable, but socially constructed determinants leading to inequities in morbidity and mortality. It is likely that these socially constructed risk factors are the most salient risk factors for the development of cervical cancer among women in India. 17,19,20,52,61 Social determinants which may mediate access to cervical cancer screening include lower levels of educational attainment, occupation, income, and wealth. 5,6,9-12 Overall, cervical cancer screening is uncommon across all sociodemographic populations of women in India. However, studies of cervical cancer screening participation in India have suggested that women living in rural areas 17,19,52,61 who are older, unmarried, and of lower educational attainment are less likely to have participated in cervical cancer screening 19,62 as compared to women living in urban settings who are younger and/or more educated. 17 In addition to age, education, and geographical location, individual income has also been associated with cervical cancer screening behavior among women in India. However, in contrast to what might be expected, women in India who have higher levels of income have been reported to be less likely to participate in cervical cancer screening compared to women with lower levels of income. 17

32 Associated HPV Cancers Although cervical cancer is the most common type of cancer associated with HPV, there is increasing evidence that HPV is an important etiologic agent in several less prevalent, but equally important types of cancer. Specifically, studies suggest that 90 percent of anal, 63 65 percent of vaginal, 63 50 percent of vulvar, 64 and 35 percent of penile 64,65 cancer cases are associated with oncogenic-type HPV infections. Additionally, data suggest that approximately 60 percent of people who develop oropharyngeal cancer are infected with at least one oncogenic subtype of HPV. 65,66 Interestingly, a geographical correlation between incidence of anal, vulvar, vaginal, penile, and head and neck cancers has been observed. Similar to the distribution in the burden of cervical cancer, the majority of cases of vulvar, vaginal, penile, and head and neck cancers occur among populations in developing regions of the world. 14 The global distribution of HPV-related cancers is of particular importance because primary and secondary methods for the prevention of cervical cancer in women may also be relevant in reducing the overall burden of other cancers linked to HPV, including those that affect men. 27 Prevention of Cervical Cancer secondary. In preventing disease there are two categories of approaches: primary and Primary Prevention Primary disease prevention involves eliminating the risk or causative agent before it has been established. In the case of cervical cancer, vaccination to prevent high risk HPV infections or male circumcision to reduce the likelihood of chronic HPV infection and transmission are both examples of primary prevention approaches. Unlike primary prevention, secondary prevention methods do not seek to entirely prevent disease risk, but to detect early pathological changes through screening, before clinical symptoms

33 have appeared. This thesis will focus on issues of secondary prevention of cervical cancer through screening. Secondary Prevention Secondary prevention of cervical cancer focuses on early detection through screening and treatment of precancerous lesions. Screening is viewed by many to be the most feasible and sustainable approach to preventing cervical cancer. Furthermore, primary approaches to prevention of cervical cancer do not benefit women who are already infected with HPV and at risk for developing cervical cancer. There are currently four established methods for cervical cancer screening. Traditionally, cytology-based Babes-Papanicolaou (Pap) tests or liquid-based cytology have been used in economically developed regions of the world. A cytology-based test involves sampling of cells of the cervix, slide preparation, and pathological interpretation of the results. Unfortunately, in low resource settings economic, social, and technical barriers have limited the success of cytology-based screening programs. 67-69 Specifically, Pap tests require trained healthcare professionals, laboratories, and sufficient medical supplies. Further, a meta-analysis reported that only 53 percent of precancerous lesions were detected through cytologybased screening among North American and European populations, 70 suggesting the effectiveness of cytology-based screening programs relied on routine, repeat screening. Similarly poor levels of sensitivity for cytology-based cervical cancer screening were reported for studies in Latin America (53%) 71 and Peru (26%) 72. The second and third methods for cervical cancer screening are based in direct visual inspection. It is thought that these methods are most feasible in low resource settings, given the low level of required technology, immediate results, and basic testing supplies. 61,71,73-80 Visual Inspection with Acetic Acid (VIA) is a relatively simple procedure where the cervix is swabbed with 3 to 5 percent acetic acid (vinegar) and then directly visualized with a bright light. Vinegar causes the precancerous lesions on the

34 cervix to temporarily appear white. Visual Inspection with Lugol s Iodine (VILI), also known as Schiller s Test widely advocated in the 1930s, 81 employs a similar approach as VIA. During a VILI test, iodine is applied to the cervix and the cervix is then visually inspected with a bright light. After applying iodine, precancerous lesions on the cervix will appear as a mustard color, while the unaffected part of the cervix will be stained brown. Both VIA and VILI are reported to correctly identify a greater number of precancerous cervical lesions in low resource settings compared to cytology-based screening. 73,74,77,79,82-84 However, VILI has been found to be more specific in identifying precancerous cervical lesions compared to VIA. 85 Therefore, a combination of VIA and VILI testing is frequently used. In a VIA-VILI approach, the cervix is first screened with vinegar and then with iodine. Initial studies of the sensitivity (68.1%) and specificity (90.8%) of this combined approach suggest that it may be superior to VIA and VILI, individually. 80 The most recent approach to screening for cervical cancer involves testing for the presence of HPV DNA. In this approach, cervical cells are sampled and stored in a preservative solution until a laboratory DNA assay (genetic analysis) can be performed. HPV DNA testing is considered to be superior to other methods of testing because it offers the ability to identify women who are infected with oncogenic subtypes of HPV before they develop precancerous cervical lesions. 71,72,75 Further, HPV DNA testing offers the possibility of self-sampling among populations of women who are reluctant to undergo a pelvic examination because of embarrassment. 72,75,86 However, HPV DNA testing involves relatively new technology, which requires well-equipped laboratories. Therefore, until lower cost HPV DNA tests are developed, HPV DNA testing is not a sustainable screening option for most low resource settings. 75 And perhaps most importantly, HPV DNA testing does not eliminate loss to follow-up, a significant barrier to effective cervical cancer control in low resource settings. 75

35 Considerations for Screening in Low Resource Settings In many countries where a large percentage of the population has never been screened for cervical cancer, resources are often limited. Therefore, it is critical that when establishing guidelines for screening to incorporate practices that are not only effective, but also efficient. With this in mind, data suggest that in low-resource areas, such as India, screening a woman just once in her lifetime, optimally between the ages of 30 and 39 years, has the potential to significantly reduce overall lifetime risk of cervical cancer. 87 Data collected on a cohort of women in India suggest once in a lifetime screening during a woman s third decade of life, using VIA, can reduce a woman s lifetime risk of cervical cancer by 38 percent and her risk of death from cervical cancer by 66 percent. 77 Furthermore, it is estimated that with the implementation of an effective screening program, an estimated 60,000 cases of cervical cancer among women in India could be prevented annually. 28 Further, to overcome technological and organization barriers several studies have demonstrated the cost-effectiveness, feasibility, and reliability of using a screen and treat approach. 75,77,88 This approach allows women to be screened through use of VIA and treated, if necessary, by cryotherapy, during a single visit. A major advantage of using this approach in a system with mostly opportunistic screening is that it significantly reduces loss to follow-up. Furthermore, this very effective screening and treatment approach can be performed in low-resource settings by local community health workers, nurses, and midwives, 77 Barriers to Cervical Cancer Control Programs Although the importance and effectiveness of cervical cancer prevention through screening has been demonstrated, and the sociodemographic populations of women least likely to participate in screening have been enumerated, the underlying reasons to explain why the majority of women are not utilizing available screening services have not been

36 well described. Several proposed barriers to cervical cancer screening uptake for women in low-resource settings include: low levels of awareness and knowledge about the disease and preventive services, 89-95 stigma and misconceptions of female gynecological diseases and cancer, socioeconomic limitations, technical and organizational insufficiencies in screening delivery, and an overall lack of nationalized cervical cancer screening priorities, guidelines, and policies. 43 Specific to women in India, several studies have demonstrated the relationship between low levels of awareness and knowledge about cervical cancer and delayed screening. Further, at least one study has demonstrated the potential impact of increased awareness on cervical cancer screening participation in India. 95 In Barshi India, following a cervical cancer awareness campaign, researchers noticed that among the population receiving the intervention, 76 percent of all women were aware of cervical cancer compared to 25 percent among women living in areas not included in the intervention. 95 Jayant et al., also noted a significant improvement in stage of diagnosis among the more aware population. 95 Limited Awareness and Knowledge as a Barrier In a variety of cultures with low resource settings, lack of awareness and knowledge has been cited as a significant barrier in the uptake of cervical cancer screening among women. 96-101 The Health Belief Model (HBM) is one theoretical framework that has been widely used to understand why an individual chooses to participate in a health-promoting behavior, such as cervical cancer screening. 91,94 The HBM postulates that cues to participation in preventive health behaviors, such as screening, can be explained by psychosocial factors, including perceived susceptibility to and severity of the target disease, and perceived benefits and costs of participating in the preventive health behavior. 102-104 Multiple studies have explored the relationship between psychosocial barriers to cervical cancer screening behaviors. 62,89-95,105 Through these

37 studies it has been demonstrated that the HBM can be useful for describing utilization of cervical cancer screening in a variety of populations. A key assumption of the HBM is that the target population is aware of a disease and the associated health-promoting behavior. Specifically, for a woman to be able to perceive susceptibility to cervical cancer she must first be aware of cervical cancer. Furthermore, in order for a woman who is aware of cervical cancer to decide whether or not to participate in screening, she must also be aware of the availability and preventive purpose of cervical cancer screening. It is obvious that without awareness of cervical cancer and/or screening it is unlikely that a woman would seek this health-promoting service. This hypothesis is supported by the findings of several studies, which have suggested that many unscreened women are unaware of cervical cancer. 62,90,92-95,106,107 Furthermore, multiple studies have reported that in populations observed to have low uptake of cervical cancer screening, many women who are aware of cervical cancer are either unaware of screening or misunderstand the purpose of screening. 62,89,90,93 For example, an exploratory study of women in Malaysia who had never been screened for cervical cancer found that in addition to overall low levels of awareness and knowledge of cervical cancer, many unscreened women who were, in fact aware of cervical cancer, were either unaware of screening or believed screening to be a method for diagnosing cervical cancer after the onset of symptoms, rather than a method for preventing the disease. 93 Misconceptions about the purpose for cervical cancer screening is not isolated to economically developing countries, it has also been suggested as a barrier to screening participation among populations in Canada, 89 the United Kingdom, 90 and the United States. Compounded by misconceptions about the purpose of screening, many women have limited or inaccurate knowledge regarding the etiology of, risk factors for, and symptoms associated with cervical cancer. An understanding of these factors, especially awareness of the facts that early stages of cervical cancer are often asymptomatic, and

38 screening is intended to detect cellular changes before there are symptoms, have been cited as important factors in determining when a women with seek screening. 93,105 Specifically among women in South India, it has been observed that among populations lacking knowledge of cervical cancer and/or screening, women were significantly more likely to screen only after the onset of symptoms of advanced stages of cervical cancer, such as excess vaginal bleeding. 62 Furthermore, the findings of this study suggest that women with lower levels of educational attainment are at even greater risk of delayed screening in the absence of symptoms compared to more education women. 62 In addition to awareness of a disease, based on the HBM, it is theorized that decisions to participate in health-promoting behaviors are dependent on individual perceptions of susceptibility, severity, cost, and benefit and therefore are at least in part, assumed to be reliant on disease knowledge. In the case of cervical cancer, in addition to being aware of the disease and screening, in order for a woman to reasonably perceive susceptibility to and severity of cervical cancer and weigh the costs and benefits of participating in screening, she must also possess at least a basic level of knowledge about risk factors for cervical cancer, the availability of treatment, consequences of delayed screening and benefits of early detection. and of Several studies have also suggested lack of perceived risk for cervical cancer or the belief that cervical cancer is fatal are also significantly less likely to participate in screening. 92,93,105 Therefore, it is important that women are not only aware of cervical cancer and screening, but also knowledgeable about the purpose for screening, potential symptoms, and the availability of treatment. Despite the recognition of lack of awareness and knowledge as a significant barrier to cervical cancer screening, 95 few studies have specifically addressed levels of awareness and knowledge of cervical cancer among women in India; though several studies of emigrated Indian women reported finding very low levels of awareness and knowledge of cervical cancer among women who had not previously screened. 108,109

39 Rationale for An Exploratory Study of Cervical Cancer in Tamil Nadu The following chapters in this dissertation discuss the methods and findings of an interdisciplinary, exploratory study of awareness, knowledge, and attitude toward cervical cancer and screening among women in urban Tamil Nadu. A review of the literature clearly supports the existence of inequities in cervical cancer morbidity and mortality experienced by women in Tamil Nadu. Furthermore, it is well established that existing cervical cancer screening programs in Tamil Nadu are largely underutilized by the majority of the population. Yet, beyond sociodemographic characterization of women at greatest risk for delayed screening, relatively little is known about why women in Tamil Nadu are not participating in screening. Although lack of awareness and knowledge have been suggested as significant barriers in establishing successful cervical cancer screening programs in Tamil Nadu, very little is known about existing populationlevels of awareness and knowledge related to cervical cancer or how awareness and knowledge influence attitude toward screening and whether or not this relationship differs by sociodemographic characteristics. To gain an understanding of the chosen study approach, and the rationale for this research, it is important to first define three concepts, including social medicine, interdisciplinarity, and exploratory research Social Medicine, Interdisciplinarity, and Exploratory Research My own research interests are in the field of social medicine, which in turn requires that I study, learn, and process information from a variety of related fields to gain insights on healthcare decision-making within a socioeconomic context. In this particular work, due to prevailing circumstances, I have opted to use and benefit from exploratory research based in both qualitative and quantitative framework.

40 Social Medicine According to Anderson et al., 110 the study of social medicine is guided by three underlying ideologies: 1. Social and economic conditions profoundly impact health, disease, and the practice of medicine, 2. The health of the population is a matter of social concern, and 3. Society should promote health through both individual and social means. Interdisciplinary Studies The National Institute of Health (http://nihroadmap.nih.gov/interdisciplinary/index.asp) has defined interdisciplinary studies as research which:..integrates the analytical strengths of two or more often disparate scientific disciplines to solve a given biological problem. For instance, behavioral scientists, molecular biologists, and mathematicians might combine their research tools, approaches, and technologies to more powerfully solve the puzzles of complex health problems such as pain and obesity. By engaging in seemingly unrelated disciplines, traditional gaps in terminology, approach, and methodology might be gradually eliminated. With roadblocks to potential collaboration removed, a true meeting of minds can take place: one that broadens the scope of investigation into biomedical problems, yields fresh and possibly unexpected insights, and may even give birth to new hybrid disciplines that are more analytically sophisticated. Exploratory Research John Tukey, 111 the founder and promoter of a set of principles called exploratory data analysis, made the following observations about analyzing a set of preliminary data:.a basic problem about any body of data is to make it more easily and effectively handleable by minds our minds, her mind, his mind. To this general end: 1. Anything that makes a simpler description possible makes the description more easily handleable.

41 2. Anything that looks below the previously described surface makes the description more effective. 3. So, we shall always be glad to simplify the description and to describe one layer deeper. Within social and behavioral sciences, exploratory research is one method frequently used to study a topic of which relatively little is known. Further, exploratory research is often useful in the generation of new hypothesis and the development, definition, and design of future health initiatives. Although exploratory research designs are generally not suitable for drawing conclusions or establishing causal associations, they are quite useful in identifying previously unidentified relationships, especially in the social and behavioral sciences. 112 With the principles of social medicine, interdisciplinary, and exploratory research in mind, the next chapter will describe the overall design of and methodology used in this study. The fourth chapter in this dissertation will present and discuss the quantitative findings of the research. Chapter five will conclude with recommendations for future experimental research on factors influencing cervical cancer screening participation among women in Tamil Nadu, as well as suggest population-based approaches to increase awareness of cervical cancer.

42 CHAPTER 3 METHODOLOGY AND STUDY DESIGN The overall objective of this study was to identify and describe factors that contribute to low cervical cancer screening participation rates among women in Tamil Nadu, using a mixed methodology approach. Specifically, the first part of the research involved a qualitative, observational study to identify barriers to screening as experienced by women in Tamil Nadu. The second half of the study involved further exploring hypotheses resulting from qualitative observations through descriptive quantitative methods. Study Setting For this study, both the quantitative data and qualitative observations were based on populations living in southeastern state of Tamil Nadu, India. The state of Tamil Nadu is comprised of 32 districts (Figure 14), with an estimated population of 72.1 million, based on the 2010 Census (Table 7). While the qualitative observations included in this research are based on field visits to two southern districts, Madurai and Dindigul, the quantitative findings are based on a subset of data from the Tamil Nadu Health Behavior Survey (TNHBS), drawn from populations in the northeastern district of Chennai (Figure 14). The district of Madurai is located within the southeastern region of Tamil Nadu (Figure 14). In 2010 the district of Madurai had an estimated population of approximately three million (http://www.census.tn.nic.in/). Further, according to the 2010 census, the district had a population density of 823 people per km 2, classifying it as a semi-rural area. In the district of Madurai, it is estimated that 82 percent of the population is literate, with literacy being slightly higher among males (87%) as compared to females (77%) (Table

43 8). Compared to other districts in Tamil Nadu, the estimated rate of literacy for Madurai district is slightly lower compared to the urban district of Chennai (90%) (Table 9). Figure 14 District Map of Tamil Nadu. Source: http://tnmaps.tn.nic.in/